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    Summary
    EudraCT Number:2015-004572-30
    Sponsor's Protocol Code Number:GS-US-406-1840
    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:2016-02-24
    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 number2015-004572-30
    A.3Full title of the trial
    A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Tolerability of Entospletinib, a Selective SYK Inhibitor, in Combination with Systemic Corticosteroids as First-Line Therapy in Subjects with Chronic Graft Versus Host Disease (cGVHD)
    Estudio de fase 2, aleatorizado, con doble enmascaramiento y controlado con placebo para evaluar la eficacia y la tolerabilidad del Entospletinib, un inhibidor selectivo de SYK, en combinación con corticoesteroides sistémicos como tratamiento de primera línea en pacientes con enfermedad crónica de injerto contra huésped (EICHc)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study for Efficacy and Tolerability of Entospletinib in Combination with Corticosteroids as First-Line Therapy in (cGVHD)
    Estudio de eficacia y tolerabilidad de Entospletinib en combinación con corticosteroides para EICHC en primera línea
    A.4.1Sponsor's protocol code numberGS-US-406-1840
    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 SponsorGilead Sciences, 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 supportGilead Sciences, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGilead Sciences International Ltd.
    B.5.2Functional name of contact pointClinical Trials Mailbox
    B.5.3 Address:
    B.5.3.1Street AddressFlowers Building, Granta Park, Abington
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post codeCB21 6GT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number0034911142244
    B.5.5Fax number00441223897284
    B.5.6E-mailclinical.trials@gilead.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.3.2Product code GS-9973
    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 INNEntospletinib
    D.3.9.3Other descriptive nameENTOSPLETINIB
    D.3.9.4EV Substance CodeSUB178740
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Chronic Graft Versus Host Disease (cGVHD)
    Enfermedad crónica de injerto contra huésped (EICHc)
    E.1.1.1Medical condition in easily understood language
    Chronic Graft Versus Host Disease (cGVHD) is a disease observed in transplant recipients.
    Enfermedad crónica de injerto contra huésped (EICHc) es una enfermedad observada en receptores de trasplante.
    E.1.1.2Therapeutic area Body processes [G] - Immune system processes [G12]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10066261
    E.1.2Term Chronic graft versus host disease
    E.1.2System Organ Class 10021428 - Immune 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
    To evaluate the effect of ENTO on the best overall response rate (BORR) as assessed by the NIH cGVHD Activity Assessment (NCAA) by 24 weeks in the setting of add-on to systemic corticosteroids as part of first-line therapy for cGVHD
    Evaluar el efecto de ENTO en la tasa de mejor respuesta global (TMRG) según el resultado de la evaluación general de la actividad del NIH (NCAA) de EICHc durante 24 semanas en una situación de tratamiento complementario a los corticosteroides sistémicos como parte del tratamiento de primera línea para EICHc
    E.2.2Secondary objectives of the trial
    The key secondary objectives are:
    - To evaluate the effect of ENTO on the skin domain of the Lee Symptom Scale (LSS) at 24 weeks
    - To evaluate the effect of ENTO on the mouth domain of the LSS at 24 weeks
    - To evaluate the effect of ENTO on the eyes domain of the LSS at 24 weeks
    - To evaluate the effect of ENTO on the total score of the LSS at 24 weeks
    Los objetivos secundarios clave son:
    Evaluar el efecto de ENTO en el ámbito de la piel de la Escala de síntomas de Lee (ESL) a las 24 semanas
    Evaluar el efecto de ENTO en el ámbito de la boca de la ESL a las 24 semanas
    Evaluar el efecto de ENTO en el ámbito de los ojos de la ESL a las 24 semanas
    Evaluar el efecto de ENTO en la puntuación total de la ESL a las 24 semanas
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) The ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures
    2) 18-75 years of age, inclusive at Screening
    3) Newly diagnosed cGVHD defined by:
    a) At least 100 days after receiving any allogeneic hematopoietic stem cell transplant
    AND
    b) Receiving new course of systemic corticosteroids (1.0 mg/kg/day or prednisone equivalent) as first-line therapy for cGVHD within 10 days of screening
    AND
    c) Moderate to severe cGVHD as assessed by NCDSC with at least three organ systems involved OR one organ system with a score of 2 OR lung organ score = 1
    4) Subjects who have undergone transplantation for benign indications are eligible for the study. Complete remission is required for subjects who have undergone transplantations for hematologic malignancies.
    5) Have either a normal ECG or one with abnormalities that are considered clinically insignificant by the investigator in consultation with the Sponsor
    6) A negative serum pregnancy test is required for female subjects (unless permanently sterile or greater than two years post-menopausal)
    7) A female subject is eligible to enter the study if it is confirmed that she is:
    a) Not pregnant or nursing
    b) Of non-childbearing potential (i.e., women who have had a hysterectomy, have had both ovaries removed or medically documented ovarian failure, or are postmenopausal women > 54 years of age with cessation (for more than or equal to 12 months) of previously occurring menses), or
    c) Of childbearing potential and agrees to utilize a highly effective protocol-specified contraceptive method or be non-heterosexually active or practice sexual abstinence from Screening throughout the duration of study treatment and for 30 days following the last study drug dose
    d) Female subjects who utilize a hormonal contraceptive as one of their birth control methods must have used the same method for at least three months prior to study dosing
    8) Male subjects of childbearing potential who engage in heterosexual intercourse must agree to
    use protocol specified method(s) of contraception.
    1) Ser capaz de comprender y firmar un formulario de consentimiento informado por escrito, que debe obtenerse antes del inicio de los procedimientos del estudio.
    2) Tener entre 18 y 75 años inclusive durante la selección
    3) Diagnóstico reciente de EICHc definida por las siguientes características:
    a) Al menos 100 días después de recibir algún trasplante alogénico de células madre hematopoyéticas
    Y
    b) Que esté recibiendo un nuevo tratamiento con corticosteroides sistémicos (1,0 mg/kg al día o un equivalente de prednisona) como tratamiento de primera línea para EICHc en los 10 días anteriores a la selección
    Y
    c) EICHc de moderada a intensa evaluada por NCDSC con al menos tres sistemas de órganos implicados O un sistema de órganos con puntuación de 2 O con puntuación pulmonar = 1
    4) Los pacientes que se hayan sometido a un trasplante por indicación benigna son aptos para el estudio. Los pacientes que se hayan sometido a un trasplante por un proceso hematológico maligno deben estar en fase de remisión completa.
    5) Tener un ECG normal o un ECG con anomalías que el investigador, tras consultarlo con el promotor, considere clínicamente insignificantes
    6) Es necesaria una prueba de embarazo en suero negativa para las pacientes (salvo si son permanentemente estériles o llevan más de dos años en estado postmenopáusico)
    7) Una paciente es apta para participar en el estudio si se confirma que:
    a) No está embarazada ni amamantando
    b) No tiene capacidad para quedarse embarazada (p. ej., mujeres que se hayan sometido a una histerectomía, a las que se les hayan extraído ambos ovarios, con insuficiencia ovárica médicamente confirmada, o mayores de 54 años que estén en estado posmenopáusico con cese [de al menos 12 meses] de menstruación antes activa)
    c) Tiene capacidad para quedar embarazada (tal y como se define en Anexo 8) y acepta utilizar anticonceptivos de alta eficacia especificados por el protocolo, no mantener relaciones heterosexuales o practicar abstinencia sexual a partir del periodo de selección y durante toda la duración del tratamiento, así como en los 30 días posteriores a la última dosis de medicamento del estudio
    d) Las pacientes que utilicen anticonceptivos hormonales como uno de sus métodos de control anticonceptivo deberán haber utilizado el mismo método durante al menos 3 meses consecutivos antes de comenzar con las dosis del estudio
    8) Los pacientes con capacidad de procrear que mantengan relaciones heterosexuales deben aceptar el método anticonceptivo especificado en el protocolo.
    E.4Principal exclusion criteria
    1) Uncontrolled infection within 4 weeks of Screening
    2) History of the following therapies in the post-transplant period:
    a) B cell depleting biologic agents
    b) CD19 CAR-T cells based therapies
    c) BTK/SYK/JAK/PI3K inhibitors
    d) Phototherapy-unless administered for aGVHD
    3) Treatment of cGVHD with anti-thymocyte globulins (ATG), or campath within 60 days of Screening visit unless used for treatment of acute GVHD
    4) Severe organ dysfunction manifest during Screening period:
    a) Requiring supplemental oxygen at more than 2L/min
    b) Uncontrolled arrhythmia or heart failure
    c) Creatinine clearance (Cockroft-Gault) < 30 mL/min
    5) Known hypersensitivity to the Investigational Medicinal Product (IMP), the metabolites, or formulation excipient.
    6) Laboratory abnormalities including:
    a) Human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen or hepatitis C antibody positive (Subjects with positive HCV antibody and without detectable HCV RNA are permitted to enrol)
    b) Aspartate aminotrasferase (AST)/Alanine aminotransferase (ALT) ? 2 X upper limit of normal (ULN) unless deemed to be secondary to Liver GVHD
    c) Total bilirubin >= 2 X ULN unless deemed to be secondary to Liver GVHD
    7) Positive serum pregnancy test (for female subjects)
    8) Any other clinical condition or prior therapy that, in the opinion of the investigator, would make the subject unsuitable for the study or unable to comply with dosing requirements
    9) Participation in any other clinical trial without prior approval from the sponsor is prohibited while participating in this trial
    10) Current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance or subject safety
    11) Subjects receiving ongoing therapy with any of the medications from the following drug class: mTOR inhibitor, any cell depleting antibody, phototherapy, BTK agents, JAK inhibitors, strong and moderate CYP3A/2C9 inducers, strong CYP2C9 inhibitors, herbal/natural supplements
    1) Infección no controlada en las primeras 4 semanas del periodo de selección
    2) Antecedentes de los siguientes tratamientos en el periodo posterior al trasplante:
    a) Agentes biológicos de reducción de células B
    b) Tratamientos basados en células T de CAR CD19
    c) Inhibidores de BTK/SYK/JAK/PI3K
    d) Fototerapia a menos que se administre para EICH aguda
    3) Tratamiento de EICHc con globulina antitimocítica (GAT), o campath en los 60 días anteriores a la visita de selección a menos que se haya utilizado para el tratamiento de EICH aguda
    4) Disfunción de órganos intensa manifestada durante el periodo de selección:
    a) Necesita más de 2 l/min de oxígeno suplementario
    b) Fallo cardiaco o arritmia no controlada
    c) Aclaramiento de creatinina (Cockcroft-Gault) < 30 ml/min
    5) Hipersensibilidad conocida al MEI, a los metabolitos o al excipiente de la formulación.
    6) Anomalías analíticas, incluidas:
    a) Positivo en anticuerpos del virus de inmunodeficiencia humana (VIH), antígenos de superficie de la hepatitis B o anticuerpos de la hepatitis C (los pacientes que den positivo en anticuerpos del VHC y sin ARN del VHC se pueden inscribir)
    b) Aspartato aminotransferasa (AST)/alanina aminotransferasa (ALT) que como mínimo dupliquen el límite superior de la normalidad (LSN), salvo si se los considera secundarios respecto a la EICH hepática
    c) Bilirrubina total que como mínimo duplique el LSN, salvo si se la considera secundaria respecto a la EICH hepática
    7) Prueba de embarazo en sangre positiva (para mujeres)
    8) Cualquier otra afección clínica o tratamiento anterior que el investigador considere que le hace inadecuado para el estudio o incapaz de cumplir con los requisitos de las dosis.
    9) Se prohíbe la participación en cualquier otro ensayo clínico del promotor sin una autorización anterior mientras se participe en este ensayo
    10) Abuso de sustancias o de alcohol actual según el investigador si cree que puede interferir con la seguridad o con el cumplimiento del paciente
    11) Sujetos que reciben tratamiento constante con alguno de los siguientes medicamentos:inhibidor mTOR, cualquier anticuerpo de reducción de células, fototerapia ,agentes BTK, inhibidores JAK, inductores moderados y fuertes de CYP3A/2C9, inhibidores fuertes de CYP2C9 , suplementos herbales/naturales.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is BORR as assessed by the NCAA by 24 weeks in the setting of add-on to systemic corticosteroids as part of first-line therapy for cGVHD
    El objetivo principal es la tasa de mejor respuesta global (TMRG) según el resultado de la evaluación general de la actividad del NIH (NCAA) de EICHc durante 24 semanas en una situación de tratamiento complementario a los corticosteroides sistémicos como parte del tratamiento de primera línea para EICHc
    E.5.1.1Timepoint(s) of evaluation of this end point
    24 weeks
    24 semanas
    E.5.2Secondary end point(s)
    The key secondary endpoints are:
    Change from Baseline in the skin domain of the LSS at 24 weeks
    Change from Baseline in the mouth domain of the LSS at 24 weeks
    Change from Baseline in the eyes domain of the LSS at 24 weeks
    Change from Baseline in the total score of the LSS at 24 weeks
    Los objetivos secundarios clave son:
    Evaluar el efecto de ENTO en el ámbito de la piel de ESL a las 24 semanas
    Evaluar el efecto de ENTO en el ámbito de la boca de la ESL a las 24 semanas
    Evaluar el efecto de ENTO en el ámbito de los ojos de la ESL a las 24 semanas
    Evaluar el efecto de ENTO en la puntuación total de la ESL a las 24 semanas
    E.5.2.1Timepoint(s) of evaluation of this end point
    24 weeks
    24 semanas
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group 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) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA16
    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
    Canada
    France
    Germany
    Korea, Republic of
    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
    UVUP
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days27
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days27
    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: 5
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 49
    F.4.2.2In the whole clinical trial 100
    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)
    After the patient has completed/terminated their study participation, long term care of the participant will remain the responsibility of their primary treating physicians.
    Después de que el paciente haya completado/terminado su participación en el estudio, el cuidado a largo plazo del participante permanecerá como responsabilidad de sus médicos de atención primaria.
    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 Decision2016-03-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-03-10
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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