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    Summary
    EudraCT Number:2011-000831-10
    Sponsor's Protocol Code Number:E5501-G000-305
    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:2012-05-29
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2011-000831-10
    A.3Full title of the trial
    A Phase 3, Multicenter, Randomized, Double-blind, Active-controlled,
    Parallel-group Trial with an Open-label Extension Phase to Evaluate the Efficacy and Safety of Oral E5501 versus Eltrombopag, in Adults with Chronic ImmuneThrombocytopenia (Idiopathic Thrombocytopenic Purpura)
    Estudio de fase 3, multicéntrico, aleatorizado, con doble enmascaramiento y control activo, de grupos paralelos, con fase abierta de ampliación, destinado a evaluar la
    eficacia y la seguridad de E5501 administrado por vía oral en comparación con eltrombopag en adultos aquejados de trombocitopenia inmunitaria crónica (púrpura trombocitopénica idiopática)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study on the Effect of E5501 (study drug) in Adults with Chronic Immune Thrombocytopenia
    Estudio en el efecto de E5501 (medicación de estudio) en adultos con
    Trombocitopenia inmunitaria crónica
    A.3.2Name or abbreviated title of the trial where available
    Not applicable
    A.4.1Sponsor's protocol code numberE5501-G000-305
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01433978
    A.5.4Other Identifiers
    Name:ASTUTENumber:E5501-G000-305
    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 SponsorEisai Limited
    B.1.3.4CountryUnited Kingdom
    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 supportEisai Incorporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEisai Limited
    B.5.2Functional name of contact pointMedical Information
    B.5.3 Address:
    B.5.3.1Street AddressEuropean Knowledge Centre, Mosquito Way
    B.5.3.2Town/ cityHatfield
    B.5.3.3Post codeAL10 9SN
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+4408456761400
    B.5.5Fax number+4408456761401
    B.5.6E-mailLmedInfo@eisai.net
    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 nameE5501
    D.3.2Product code E5501
    D.3.4Pharmaceutical form Film-coated 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 INNAvatrombopag maleate
    D.3.9.1CAS number 1254322-84-3
    D.3.9.2Current sponsor codeE5501
    D.3.9.3Other descriptive nameAKR-501, YM-477
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 nameE5501
    D.3.2Product code E5501
    D.3.4Pharmaceutical form Film-coated 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 INNAvatrombopag maleate
    D.3.9.1CAS number 1254322-84-3
    D.3.9.2Current sponsor codeE5501
    D.3.9.3Other descriptive nameAKR-501, YM-477
    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 nameE5501
    D.3.2Product code E5501
    D.3.4Pharmaceutical form Film-coated 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 INNAvatrombopag maleate
    D.3.9.1CAS number 1254322-84-3
    D.3.9.2Current sponsor codeE5501
    D.3.9.3Other descriptive nameAKR-501, YM-477
    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.IMP: 4
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Revolade 25 mg film-coated tablets
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxoSmithKline Trading Services 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 Yes
    D.2.5.1Orphan drug designation numberEU/3/07/467 (removed by sponsor January 2012)
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Film-coated 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 INNeltrombopag
    D.3.9.1CAS number 496775-62-3
    D.3.9.2Current sponsor codeN/A
    D.3.9.3Other descriptive nameeltrombopag olamine, Revolade, Promacta
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Revolade 50 mg film-coated tablets
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxoSmithKline Trading Services 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 Yes
    D.2.5.1Orphan drug designation numberEU/3/07/467 (removed by sponsor January 2012)
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Film-coated 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 INNeltrombopag
    D.3.9.1CAS number 496775-62-3
    D.3.9.2Current sponsor codeN/A
    D.3.9.3Other descriptive nameeltrombopag olamine, Revolade, Promacta
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 3
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 4
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 5
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Chronic Immune Thrombocytopenia (Idiopathic Thrombocytopenic Purpura)
    Trombocitopenia inmunitaria crónica (púrpura trombocitopénica idiopática)
    E.1.1.1Medical condition in easily understood language
    Low platelet count, which has lasted for more than a year, caused because platelets (and the cells that produce platelets in the bone marrow) are destroyed by antibodies in the blood.
    Los niveles bajos de recuento de plaquetas, alcanzados en mas de un año, debido a que las plaquetas (y las células que producen plaquetas en la médula ósea) se destruyen en la sangre por anticuerpos.
    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 14.1
    E.1.2Level PT
    E.1.2Classification code 10043554
    E.1.2Term Thrombocytopenia
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level HLGT
    E.1.2Classification code 10035534
    E.1.2Term Platelet disorders
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level SOC
    E.1.2Classification code 10005329
    E.1.2Term Blood and lymphatic system disorders
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10036735
    E.1.2Term Primary thrombocytopenia
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Core study
    To compare the efficacy of E5501 (in addition to standard of care) to eltrombopag (in addition to standard of care) for the treatment of adult subjects with chronic immune thrombocytopenia (idiopathic thrombocytopenic purpura [ITP]) as measured by durable platelet response

    Extension study
    To evaluate the safety and tolerability of long-term therapy with
    E5501 in subjects with chronic ITP (cITP)
    Estudio basico Comparar la eficacia de E5501 (sumado a la atención médica
    habitual) con la de eltrombopag (sumado a la atención médica habitual) en el
    tratamiento de sujetos adultos que sufren trombocitopenia inmunitaria crónica
    (púrpura trombocitopénica idiopática [PTI]), cuantificada en función de la
    presentación de una respuesta plaquetaria duradera. Estudio de ampliación Evaluar
    la seguridad y la tolerabilidad del tratamiento a largo plazo con E5501 en sujetos
    aquejados de PTI crónica (PTIc).
    E.2.2Secondary objectives of the trial
    Core study
    ? To demonstrate that the efficacy of E5501 (in addition to standard of care) is superior to the efficacy of eltrombopag (in addition to standard of care) as measured by platelet response rate at Day 8
    ? To evaluate the safety of E5501 compared with eltrombopag

    Extension study

    ? To demonstrate the effectiveness of long-term therapy with E5501 as measured by platelet response, bleeding, and the use of rescue therapy
    ? To assess the reduction in use of steroids and concomitant ITP
    medication in subjects receiving E5501
    Estudio básico
    Demostrar que la eficacia de E5501 (sumado a la atención médica
    habitual) es superior a la de eltrombopag (sumado a la atención médica habitual),
    cuantificada en función de la presentación de una respuesta plaquetaria duradera
    en el día 8. ?Evaluar la seguridad de E5501 comparado con eltrombopag Estudio
    de ampliación ?Demostrar la eficacia del tratamiento a largo plazo con E5501
    según las mediciones de la respuesta plaquetaria, el sangrado y el empleo de un
    tratamiento de rescate ?Evaluar la disminución del uso de esteroides y medicación
    concomitante para la PTI en sujetos que reciban E5501.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Core study
    1. Men and women ? 18 years of age
    2. Subjects diagnosed with cITP (?12 months duration) according to the American Society for Hematology/British Committee for Standards in Hematology (ASH/BCSH) guidelines, and an average of two platelet counts < 30 × 109/L (no single count may be >35 × 109/L). In addition, a peripheral blood smear should support the diagnosis of ITP with no evidence of other causes of thrombocytopenia (e.g., pseudothrombocytopenia, myelofibrosis). The physical examination should not suggest any disease which may cause thrombocytopenia other than ITP.
    3. Subjects who previously received one or more ITP therapies (including, but not limited to, corticosteroids, immunoglobulins,
    azathioprine, danazol, cyclophosphamide and/or rituximab)
    4. Subjects must have had either initially responded (platelet count
    >50 × 109/L) to a previous ITP therapy or have had a bone marrow examination consistent with ITP within 3 years to rule out
    myelodysplastic syndrome (MDS) or other causes of thrombocytopenia.
    5. Prothrombin time/International Normalized Ratio (PT/INR) and
    activated partial thromboplastin time (aPTT) must have been within
    80% to 120% of the normal range with no history of hypercoagulable state.
    6. A complete blood count within the reference range (including WBC differential not indicative of a disorder other than ITP), with the following exceptions:
    ? Hemoglobin: Subjects with hemoglobin levels between 10 g/dL
    (100 g/L) and the lower limit of normal (LLN) are eligible for inclusion, if anemia was clearly attributable to ITP (excessive blood loss).
    ? Absolute neutrophil count (ANC) ? 1500/?L (1.5 x 109/L)
    (elevated WBC/ANC due to corticosteroid treatment is acceptable).

    Extension study
    1. Subjects who have completed 6 months of study treatment in the Randomization Phase or
    2. Subjects who discontinue the Core Study early due to lack of treatment effects (see Study Drug Discontinuation)
    3. No significant safety or tolerability concerns with the subject?s
    participation of Randomization Phase as determined by the investigator
    Estudio básico 1. Hombres y mujeres de edad igual o superior a 18 años.
    2.Pacientes a quienes se les haya diagnosticado PTIc (de duración igual o superior
    a 12 meses), de acuerdo con las pautas establecidas por la American Society for
    Hematology (Sociedad Estadounidense de Hematología) y el British Committee for
    Standards in Haematology (Comité Británico de Normas en Hematología)
    (ASH/BCSH), y que presenten una media de dos recuentos de plaquetas que sea
    inferior a 30 × 109/L (ninguno de estos recuentos podrá ser, por sí solo, superior a
    35 × 109/L).Asimismo, habrá de corroborarse el diagnóstico de PTI, sin evidencias
    de otras causas de trombocitopenia (por ejemplo, pseudotrombocitopenia o
    mielofibrosis), mediante un frotis de sangre periférica. La exploración física no
    deberá mostrar indicios de otras enfermedades, aparte de la PTI, que puedan
    causar trombocitopenia. 3.Sujetos que hayan recibido previamente uno o más
    tratamientos para la PTI (como, a título meramente indicativo, corticosteroides,
    inmunoglobulinas, azatioprina, danazol, ciclofosfamida o rituximab, o una
    combinación de éstos). 4.Los sujetos deberán haber respondido inicialmente a un
    tratamiento anterior para la PTI (recuento de plaquetas superior a 50 × 109/L), o
    bien se les deberá haber practicado en los tres años precedentes un examen de
    médula ósea cuyos resultados sean compatibles con la existencia de PTI, con el fin
    de descartar la presencia de un síndrome mielodisplásico (SMD) u otras causas de trombocitopenia. 5.El tiempo de protrombina y la relación internacional normalizada,
    por una parte (TP/RIN), y el tiempo de tromboplastina parcial activado (TTPA), por
    otra, tendrán que haberse mantenido entre el 80 y el 120 % del rango normal, sin
    antecedentes de estado hipercoagulable. 6.Hemograma que muestre valores
    incluidos dentro del rango de referencia (comprendido un diferencial leucocitario no
    indicativo de un trastorno que no sea la PTI), con las siguientes excepciones: ?
    Hemoglobina: Los sujetos que presenten niveles de hemoglobina situados entre los
    10 g/dL (100 g/L) y el límite inferior de la normalidad (LIN) se considerarán
    candidatos aptos si la anemia pudiera atribuirse claramente a la PTI (por pérdida de
    sangre excesiva). ? Recuento absoluto de neutrófilos (RAN) igual o superior a
    1500/?L (1,5 x 109/L) (se considera aceptable un nivel leucocitario y un RAN
    elevados cuando se deban a un tratamiento con corticosteroides). Estudio de
    ampliacion 1. Sujetos que hayan completado seis meses de tratamiento de estudio
    en la fase de aleatorización, o bien 2. sujetos que abandonen el estudio de manera
    temprana por falta de efecto del tratamiento (véase la sección «Abandono del
    fármaco del estudio»); 3. inexistencia de motivos de preocupación significativos
    relacionados con la inocuidad o la tolerabilidad que afecten a la participación del
    sujeto en la fase de aleatorización, según determine el investigador.
    E.4Principal exclusion criteria
    Core Study
    1.Subjects with known secondary immune thrombocytopenia (e.g., known H.pylori-induced ITP, known HIV or hepatitis C virus infection or subjects with known systemic lupus erythematosus)
    2.Subjects unable, or unwilling to comply with the protocol requirements or give informed consent
    3.Subjects with significant medical conditions that may impact the safety of the subject or interpretation of the study results (e.g., acute hepatitis, active chronic hepatitis; lymphoproliferative disease; myeloproliferative disorders, leukemia)
    4.History of MDS
    5.History of pernicious anaemia
    6.Any prior history of arterial or venous thrombosis (stroke, transient ischemic attack, myocardial infarction, deep vein thrombosis, or pulmonary embolism), and more than 2 of the following risk factors: estrogen containing hormone replacement or contraceptive therapies, smoking, diabetes, hypercholesterolemia, hypertension medication, cancer, hereditary thrombophilic disorders (e.g., Factor V Leiden, antithrombin III deficiency), or any other family history of arterial or venous thrombosis
    7.History of significant cardiovascular disease (e.g., congestive heart failure New York Heart Association Grade III/IV), arrhythmia known to increase the risk of thromboembolic events [e.g., atrial fibrillation], subjects with a QT interval corrected for heart rate of > 450 msec, angina, unstable angina, coronary artery stent placement, angioplasty, coronary artery bypass grafting)
    8.History of cirrhosis, portal hypertension, and chronic active hepatitis
    9.Subjects with concurrent malignant disease
    10.Use of IVIg and anti-D within 1 week of randomization
    11.Splenectomy or use of rituximab within 12 weeks of randomization
    12.Use of romiplostim or eltrombopag within 4 weeks of randomization
    13.Subjects who have not been on a stable dose of corticosteroids or azathioprine for at least 4 weeks prior to randomization, or had not stopped these > 4 weeks before
    14.Subjects who have not been on a stable dose of MMF, CsA, or danazol for at least 12 weeks prior to randomization or had not stopped these > 4 weeks before
    15.Use of cyclophosphamide or vinca alkaloid regimens within 4 weeks of randomization.
    16.Subjects who have not been on a stable dose of PPIs or H2 antagonist therapy for at least 6 weeks prior to randomization or had not stopped these > 2 weeks before
    17.Screening Fasting gastrin 17 blood levels > the ULN
    18.Blood creatinine exceeding the ULN by more than 20% or total albumin below the LLN by10%.
    19.ALT and AST levels > 2 times the ULN. Total bilirubin > 1.5 times the ULN.
    20.History of cancer treatment with cytotoxic chemotherapy and/or radiotherapy. (cytotoxic chemotherapy for ITP treatment is permitted)
    21.Females who are pregnant (positive ?-hCG test) or breastfeeding
    22.Subjects with a known allergy to E5501 or eltrombopag
    23.Subjects with a history of significant aminotransferase elevations while receiving eltrombopag (ALT and/or AST >3 x ULN)
    24.Subjects who are known nonresponders to previous TPO agonist therapy (including E5501 therapy) who do not have a bone marrow examination consistent with ITP
    Extension Phase
    1.Subjects for whom participation in the Extension is considered unsafe, in the investigator?s judgment
    2.Subjects unable or unwilling to comply with the study protocol requirements or give informed consent
    3.Subjects unwilling to undergo an endoscopy at time of enrollment into Extension
    4.Subjects requiring the following at time of enrollment into the Extension
    ?Rituximab
    ?Splenectomy
    ?Other TPO agonists
    Estudio básico
    1. Sujetos que presenten una trombocitopenia inmunitaria secundaria conocida (es decir, pacientes
    aquejados de PTI inducida por H. pylori, que se sepa que están infectados con VIH o de la hepatitis C, o afectados por lupus eritematoso sistémico.
    2. Sujetos que se entienda que no pueden o no quieren ajustarse a lo exigido por el protocolo del
    estudio o prestar su consentimiento informado.
    3. Sujetos que presenten afecciones significativas que puedan comprometer su integridad o influir
    en la interpretación de los resultados del estudio (por ejemplo, hepatitis aguda o hepatitis
    crónica activa; enfermedad linfoproliferativa; trastornos mieloproliferativos o leucemia).
    4. Antecedentes de SMD.
    5. Antecedentes de anemia perniciosa
    6. Cualquier antecedente de trombosis arterial o venosa (ictus, accidente isquémico transitorio,
    infarto de miocardio, trombosis venosa profunda o embolia pulmonar) y presencia de más de
    dos de los siguientes factores de riesgo: tratamientos de sustitución hormonal con estrógenos o
    anticonceptivos, tabaquismo, diabetes, hipercolesterolemia, medicación antihipertensiva, cáncer,
    trastornos trombofílicos hereditarios (por ejemplo, factor V Leiden, deficiencia de antitrombina
    III, etc.) o cualesquiera otros antecedentes familiares de trombosis arterial o venosa.
    7. Sujetos que tengan antecedentes de enfermedad cardiovascular significativa (por ejemplo,
    insuficiencia cardíaca congestiva de grado III/IV, según lo establecido por la New York
    Heart Association) una arritmia que se sepa que aumenta el riesgo de sufrir acontecimientos
    tromboembólicos ?por ejemplo, fibrilación auricular?, sujetos que presenten un intervalo QTc
    superior a 450 ms, angina, angina inestable, colocación de endoprótesis en la arteria coronaria,
    angioplastia o injerto de derivación aortocoronaria).
    8. Antecedentes de cirrosis, hipertensión portal y hepatitis activa crónica.
    9. Sujetos que presenten una enfermedad maligna concurrente.
    10. Utilización de IgIV y anti-D en la semana anterior a la aleatorización.
    11. Esplenectomía o uso de rituximab dentro de las 12 semanas anteriores a la aleatorización.
    12. Utilización de romiplostim o eltrombopag dentro de las cuatro semanas anteriores a la
    aleatorización.
    13. Sujetos que no hayan estado con dosis estable corticosteroides o azatioprina al menos en las cuatro semanas anteriores a la aleatorización, o que no hayan finalizado estos tratamientos en un plazo superior a cuatro semanas antes de ser aleatorizados.
    14. Sujetos que no hayan estado con dosis estables de MMF, CsA o danazol al menos en las 12 semanas anteriores a la aleatorización, o que no hayan finalizado estos tratamientos en un plazo superior a cuatro semanas antes de la aleatorización.
    15. Uso de regímenes de ciclofosfamida o alcaloides de la vinca en las cuatro semanas anteriores a la aleatorización.
    16. Sujetos que no hayan recibido una dosis estable de IBP o antagonistas H2 al menos en las seis semanas anteriores a la aleatorización, o que no hayan finalizado estos tratamientos en un plazo superior a dos semanas antes de ser aleatorizados.
    17. Niveles en sangre de gastrina 17 en ayunas que sobrepasen el límite superior a LSN
    18. Niveles de creatinina en sangre que supere el LSN en más del 20% o albúmina total inferior al LIN en más del 10%.

    19. Niveles de ALT y AST que multipliquen por dos el LSN; bilirrubina total que multiplique por 1,5 dicho límite.
    20. Sujetos que tengan antecedentes de tratamientos contra el cáncer con quimioterapia o
    radioterapia citotóxicas, o ambas. (Tratamiento con quimitorapia citotoxica para la PTI está permitido)
    21. Mujeres embarazadas (prueba de GCH-? con resultado positivo) o que estén dando el pecho.
    22. Sujetos que tengan una alergia conocida a E5501 o a eltrombopag
    23. Sujetos que presenten antecedentes de aumentos significativos de la aminotransferasa mientras
    recibían eltrombopag (ALT o AST, o ambas, que superen el triple del LSN).
    24. Los sujetos de los que se sepa que no han respondido a ningún tratamiento anterior con agonistasde la TPO (incluido tratamiento con E5501), y a los que no se les haya realizado un
    examen de la médula ósea compatible con la existencia de PTI.

    Fase de ampliación
    1. Sujetos cuya participación en la fase de ampliación se considere no exenta de peligros, a juicio
    del investigador.
    2. Sujetos que se entienda que no pueden o no quieren ajustarse a lo exigido por el protocolo del
    estudio o prestar su consentimiento informado.
    3. Sujetos que no deseen someterse a una endoscopia al inscribirse para pasar a la fase de
    ampliación.
    4. Sujetos que, en el momento de inscribirse para la fase de ampliación, necesiten los siguientes
    fármacos o tratamientos:
    ? Rituximab
    ? Esplenectomía
    ? Otros agonistas de la TPO
    E.5 End points
    E.5.1Primary end point(s)
    Core study
    Durable platelet response rate as defined by:
    ? Proportion of subjects who have at least 6 of 8 (i.e., ?75%) weekly platelet responses during the last 8 weeks of treatment (i.e., at Visits 15 through 22, inclusive) over the 6-month treatment period in absence of rescue therapy
    ? Subjects using rescue therapy at any time during the 6-month
    treatment period will be considered to not have a durable platelet
    response
    ? A platelet response will be defined as a platelet count of ? 50 x 109/L and nonresponse will also be defined as a platelet count of
    < 50 x 109/L
    ? Missing platelet assessments at any given time point will be
    considered to be a nonresponse at that time point. Subjects who
    discontinue the study or who are lost to follow-up before 6 months will have all subsequent unobserved scheduled platelet assessments at the scheduled time points as having ?missing? platelet values.
    ? All analyses of platelet counts will be based on local laboratory
    results.

    Extension study
    Effectiveness will be assessed by measuring platelet counts, reduction of concomitant ITP medication, and bleeding events. Specifically:
    ? Time that subjects maintained a platelet count ? 50 x 109/L during the study
    ? Median platelet count of all subjects at selected time points (monthly)
    ? Maximum duration (in months) of continuous platelet response
    (?50 x 109/L)
    ? Proportion of subjects with a reduction in use of concomitant ITP
    medications from baseline
    ? Proportion of subjects with a discontinuation in use of concomitant ITP medications from baseline
    ? Proportion of subjects needing rescue treatment
    ? Incidence and severity of bleeding (in accordance with the WHO
    Bleeding Scale)
    EStudio básico Índice de respuesta plaquetaria duradera, que se establecerá en
    función de los siguientes factores: ? Proporción de sujetos que presenten al menos
    seis de ocho (es decir, ? 75 %) respuestas plaquetarias semanales durante las
    últimas ocho semanas de tratamiento (en otras palabras, de la visita 15 a la 22,
    ambas incluidas) a lo largo del período de seis meses de tratamiento y en ausencia
    de tratamiento de rescate. ? Se considerará que los sujetos que reciban un
    tratamiento de rescate en algún momento del período de seis meses de tratamiento
    no presentan una respuesta plaquetaria duradera. ? La respuesta plaquetaria se
    definirá como un recuento de plaquetas igual o superior a 50 x 109/L; de igual
    modo, la falta de respuesta se referirá a un recuento de plaquetas inferior a 50 x
    109/L. ? La inexistencia de evaluaciones plaquetarias en algún punto temporal se
    considerará una falta de respuesta en dicho punto. En el caso de los sujetos que
    abandonen el estudio o a los que no se les realice un seguimiento antes de seis
    meses, se entenderá que todas las demás evaluaciones plaquetarias posteriores
    planificadas y no respetadas arrojan una «ausencia» de valores de plaquetas
    ?Todos los análisis de los recuentos de plaquetas se basarán en los resultados
    obtenidos en los laboratorios locales Fase de ampliación La eficacia se evaluará en
    función de los recuentos de plaquetas, la reducción de la medicación concomitante
    para la PTI y los acontecimientos hemorrágicos, concretamente como sigue: ?
    tiempo durante el que los sujetos hayan mantenido un recuento de plaquetas igual
    o superior a 50 x 109/L a lo largo del estudio; ? mediana del recuento de plaquetas
    de todos los sujetos en los puntos temporales establecidos (de manera mensual); ?
    duración máxima (en meses) de respuesta plaquetaria continua (? 50 x 109/L); (?50
    x 109/L) ? proporción de sujetos a los que se les aplique una reducción en el uso
    de medicaciones concomitantes para la PTIc a partir del momento inicial; ?
    proporción de sujetos que dejen de emplear medicaciones concomitantes para la
    PTIc a partir del momento inicial; ? proporción de sujetos que necesiten tratamiento
    de rescate; e ? incidencia e intensidad del sangrado (evaluadas de acuerdo con la
    escala de sangrado de la OMS).
    E.5.1.1Timepoint(s) of evaluation of this end point
    During the last 8 weeks of treatment (i.e., at Visits 15 to 22, inclusive) over the 6-month treatment period in absence of rescue therapy.
    Durante las 8 semanas de tratamiento ( ej desde las visitas 15 a la 22, ambas
    incluidas)y a lo largo del período de seis meses de tratamiento, en ausencia de
    tratamiento de rescate.
    E.5.2Secondary end point(s)
    ? Platelet response rate at Day 8 (as defined by the proportion of subjects with a platelet response ?50 x 109/L at Day 8). Subjects with missing platelet counts at Day 8 or use of a rescue therapy before or on Day 8, will be considered platelet nonresponders.
    ? Alternative durable platelet response as defined by: proportion of subjects with at least 75% of platelet assessments between ? 50 x 109/L and ? 400 x 109/L from the time of first response over a 6-month treatment period in the absence of rescue therapy (durability by flexible period)
    ? Proportion of subjects with a reduction in use of concomitant ITP medications from baseline
    El índice de respuesta plaquetaria en el día 8, establecido en función de la proporción de sujetos que ofrezcan un nivel de respuesta igual o superior a 50 x 109/L en dicho día 8. Se considerará que no muestran respuesta plaquetaria los sujetos que ese día presenten una ausencia de recuento de plaquetas o reciban tratamiento de rescate en dicha fecha o antes. ?Respuesta duradera alternativa, establecida en función de la proporción de sujetos en los que un número igual o superior al 75 % de las evaluaciones plaquetarias sea igual o superior a 50 x 109/L e igual o inferior a 400 x 109/L a partir del momento de producirse la primera
    respuesta y a lo largo de un período de seis meses de tratamiento, en ausencia de
    tratamiento de rescate (durabilidad con arreglo a un período flexible). ?Proporción
    de sujetos a los que se les aplique una reducción en el uso de medicaciones
    concomitantes para la PTIc a partir del momento inicial
    E.5.2.1Timepoint(s) of evaluation of this end point
    ? Day 8
    ? From the time of first response over a 6-month treatment period (in the absence of rescue therapy).
    Dia 8
    A partir del momento de producirse la primera respuesta y a lo largo de 6
    meses del periodo de tratamiento, (en ausencia de tratamiento de rescate)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Open label extension
    periodo de ampliacion abierto
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Open-label extension
    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 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
    Australia
    Austria
    Belgium
    Canada
    France
    Germany
    Ireland
    Israel
    Italy
    Korea, Republic of
    Netherlands
    Russian Federation
    Spain
    Sweden
    Switzerland
    Taiwan
    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
    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 months0
    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 Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 230
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 56
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 145
    F.4.2.2In the whole clinical trial 286
    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)
    Standard of care
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-05-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-05-11
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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