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    Summary
    EudraCT Number:2018-004449-18
    Sponsor's Protocol Code Number:HEP201
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-04-11
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2018-004449-18
    A.3Full title of the trial
    Multicenter, open-label, safety and tolerability study of ascending doses of HepaStem in patients with cirrhotic and pre-cirrhotic non-alcoholic steatohepatitis
    (NASH).
    Estudio multicéntrico, abierto, de seguridad y tolerabilidad de dosis ascendentes de HepaStem en pacientes con esteatohepatitis no alcohólica (EHNA) cirrótica y precirrótica.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    HEP201-PANASH is an interventional study of increasing doses of HepaStem for the treatment of patients with cirrhotic and pre-cirrhotic NASH. The population will be divided in 4 cohorts and a total of 2 doses are planned to be administered as single or repeated infusions in an ascending manner. The safety and tolerability of HepaStem in the treatment of NASH will be first evaluated as well as preliminary efficacy.
    HEP201-PANASH es un estudio intervencionista de dosis ascendentes de HepaStem para el tratamiento de pacientes con EHNA cirrótica y precirrótica.
    La población se dividirá en 4 cohortes y se planea administrar un total de 2 dosis como infusiones únicas o repetidas de manera ascendente.
    La seguridad y la tolerabilidad de HepaStem en el tratamiento de la EHNA se evaluarán primero, así como su eficacia preliminar.
    A.3.2Name or abbreviated title of the trial where available
    HEP201 - PANASH
    A.4.1Sponsor's protocol code numberHEP201
    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 SponsorPromethera Biosciences
    B.1.3.4CountryBelgium
    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 supportPromethera Biosciences
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPromethera Biosciences
    B.5.2Functional name of contact pointWelcome desk
    B.5.3 Address:
    B.5.3.1Street AddressRue Granbonpré, 11
    B.5.3.2Town/ cityMont-Saint-Guibert
    B.5.3.3Post codeB-1435
    B.5.3.4CountryBelgium
    B.5.4Telephone number32 10 394300
    B.5.5Fax number32 10 394301
    B.5.6E-mailRegulatory@promethera.com
    D. IMP Identification
    D.IMP: 1
    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 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 nameHepaStem
    D.3.2Product code HHALPC
    D.3.4Pharmaceutical form Suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHeterologous Human Adult Liver-derived Progenitor Cells
    D.3.9.2Current sponsor codeHepaStem
    D.3.9.3Other descriptive nameHHALPC
    D.3.9.4EV Substance CodeSUB122824
    D.3.10 Strength
    D.3.10.1Concentration unit million organisms/ml million organisms/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number10 to 50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    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) Yes
    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 Yes
    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 Yes
    D.3.11.3.5.1CAT classification and reference numberTissue engineered product (EMA/CAT/391889/2016) in the treatment of fibroinflammatory liver diseases.
    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
    NASH is characterized by steatosis, inflammation and cytological ballooning with varying amounts of fibrosis. Patients with NASH are at risk of cardiovascular morbidity and mortality. In chronic liver disease, changes in inflammatory components of the liver are not limited to the sole organ, but has a systemic influence. Disease evolution is characterized by increasing fibrosis and cirrhosis in a subset of patients, and a degree of fibrosis linked with increased risk of mortality.
    EHNA se caracteriza por esteatosis, inflamación y balonización citológico con fibrosis variable. Los pacientes con EHNA corren el riesgo de tener morbilidad y mortalidad cardiovascular. En las enfermedades crónicas del hígado, los cambios en los componentes inflamatorios del hígado tienen una influencia sistémica. La evolución de la enfermedad se caracteriza por un aumento de fibrosis y cirrosis en un subconjunto de pacientes y un grado de fibrosis relacionado con mayor riesgo de mortalidad.
    E.1.1.1Medical condition in easily understood language
    NASH is a chronic liver disease and a major health issue in association with obesity and diabetes. NASH patients are at risks of cardiovascular events, cirrhosis, cancer and mortality.
    EHNA es una enfermedad hepática crónica y un problema de salud importante con obesidad y diabetes. Pacientes con EHNA tienen riesgo de eventos cardiovasculares, cirrosis, cáncer y mortalidad.
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level SOC
    E.1.2Classification code 10019805
    E.1.2Term Hepatobiliary disorders
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10031743
    E.1.2Term Other chronic nonalcoholic liver disease
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10019708
    E.1.2Term Hepatic steatosis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10041970
    E.1.2Term Steatosis hepatic
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10019669
    E.1.2Term Hepatic fibrosis and cirrhosis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10019641
    E.1.2Term Hepatic cirrhosis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10009211
    E.1.2Term Cirrhosis liver
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10024667
    E.1.2Term Liver cirrhosis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10009213
    E.1.2Term Cirrhosis of liver
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10064704
    E.1.2Term Decompensated cirrhosis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10064844
    E.1.2Term Compensated cirrhosis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10053219
    E.1.2Term Non-alcoholic steatohepatitis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10076331
    E.1.2Term Steatohepatitis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    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 this trial is to determine the safety and tolerability of ascending single and repeated doses of HepaStem up to Day 28 administered to patients with cirrhotic and pre cirrhotic NASH.
    El principal objetivo de este estudio es de determinar la seguridad y tolerabilidad de dosis únicas y repetidas ascendentes de HepaStem hasta el día 28, administradas a pacientes con EHNA cirrótica y precirrótica
    E.2.2Secondary objectives of the trial
    1. Secondary safety objective
    - To assess the appearance of anti-HLA Antigen antibodies and identification of donor HLA specificity following infusion of HepaStem
    - To assess changes in levels of coagulation-related factors and coagulation efficiency up to 24 hours post-infusion
    - To determine the safety and tolerability of HepaStem up to 6 months post-infusion
    2. Preliminary efficacy objectives
    o assess changes composite scores for disease stage: MELD, Child-Pugh scores and CLIF-C AD (for F4 decompensated)
    - To assess changes in liver function tests
    - To assess changes in metabolic biomarkers and clinical signs
    - To assess changes in hepatic fibrosis by non-invasive methods
    3. Exploratory objectives:
    - To assess the effect of HepaStem on cellular immune response
    - To assess changes in inflammatory, apoptosis, and NASH biomarkers
    - To assess changes in non-invasive markers of portal hypertension
    - To assess the evolution to acute decompensation of cirrhosis
    1. Seguridad
    - aparición de anticuerpos contra HLA y especificidad HLA del donante después de HepaStem
    - cambios en los niveles de los factores relacionados con la coagulación y la eficacia de la coagulación hasta 24 horas después de la infusion
    - seguridad y tolerabilidad de HepaStem hasta 6 meses después de la infusión eficacia
    2. Eficacia:
    - cambios de las puntuaciones de la enfermedad: MELD, Child-Pugh y
    CLIF-C AD (F4 descompensado)
    - cambios de la función hepatica
    - cambios en los biomarcadores metabólicos y los signos clínicos
    - cambios en la fibrosis hepática (métodos no invasivos)
    3. Exploratorios
    - efecto de HepaStem sobre la respuesta inmunitaria cellular
    - cambios en los biomarcadores inflamatorios, apoptosis y EHNA
    - cambios en los marcadores de la hipertensión portal
    - evolución hacia la descompensación aguda de la cirrosis
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Title: Assessment of the changes in Histology and HVPG in pre-cirrhotic and Cirrhotic patients from HEP201 study, having received HepaStem
    Sub study exploratory efficacy objectives:
    - To assess changes in hepatic venous pressure gradient (HPVG) at 6 months post-infusion
    - To assess changes on fibrosis at 6 months post-infusion using histology scores based on biopsy.
    Título: Evaluación de los cambios en la histología y HVPG en pacientes
    pre-cirróticos y cirróticos del estudio HEP201, que recibieron HepaStem
    Objetivos exploratorios de eficacia del sub estudio:
    - Para evaluar los cambios en el gradiente de presión venosa hepática (HPVG) a los 6 meses después de la infusión
    - Para evaluar los cambios en la fibrosis a los 6 meses después de la infusión utilizando puntajes de histología basadas en biopsia.
    E.3Principal inclusion criteria
    Inclusion criteria:
    1. Able and willing to provide written informed consent and comply with the requirements of this study protocol
    2. Age 18 to 70-years old, inclusive
    3. Proven diagnosis of NASH based on histological evidence from biopsy performed within 6 months for F3 patients and within 2 years for F4 patients prior to Screening
    If no biopsy is available within these time windows, a biopsy should be performed at Screening
    NB: For F4 patients for whom the biopsy cannot confirm the diagnosis of NASH, any other causes of underlying liver diseases should be excluded.

    Infusion eligibility criteria
    1. Fibrinogen > 80 mg/dL
    2. And Platelets > 40.000/mm3
    3. Absence thrombosis of the portal vein
    4. No clinically significant reaction during previous infusions of IMP that, according to investigator, preclude the administration of HepaStem

    Inclusion criteria for sub-study
    1. Able and willing to provide written informed consent for the sub-study and comply the inclusion/exclusion of the study.
    Criterios de inclusión:
    1. Ser capaz y estar dispuesto a facilitar su consentimiento informado por escrito y a cumplir con los requisitos de este protocolo de estudio
    2. De 18 a 70 años de edad, inclusive
    3. Diagnóstico probado de EHNA basado en la evidencia histológica de la biopsia realizada en un plazo de 6 meses para los pacientes con F3 y en
    un plazo de 2 años para los pacientes con F4 antes de la selección.
    Si la biopsia no está disponible dentro de estos periodos de tiempo, se debe realizar una biopsia en la visita de selección.
    Nota: En el caso de pacientes F4 para los cuales la biopsia no pueda
    confirmar el diagnóstico de EHNA, debe excluirse cualquier otra causa de enfermedades hepáticas subyacentes.

    Criterios de elegibilidad para la infusión
    1. Fibrinógeno > 80 mg/dL
    2. Y plaquetas > 40.000/mm3
    3. Ausencia de trombosis de la vena porta
    4. Ninguna reacción clínicamente significativa durante infusiones previas del PMI que, según el investigador, impidan la administración de HepaStem

    Criterios de inclusión para el subestudio
    1. Ser capaz y estar dispuesto a facilitar un consentimiento informado por escrito para el subestudio y ser elegible considerando los criterios de
    inclusión y exclusión del estudio.
    E.4Principal exclusion criteria
    Exclusion criteria:
    1. Alanine aminotransferase (ALT) ≥ 8 x upper limit of normal (ULN)
    2. Alcoholic liver disease or alcohol consumption exceeding the daily intake of 140g/w (two doses) for women and of 210g/w (three doses) for men
    3. Other causes of liver disease including, but not limited to, alcoholic liver disease, active hepatitis B (HbsAg+), hepatitis C (PCR positive), autoimmune disorders, drug-induced hepatotoxicity, Wilson disease, hemochromatosis, and alpha-1-antitryspin deficiency based on medical history and/ or clinical and biological assessment
    4. Recent recurrent or ongoing thrombotic or bleeding events within 3 months prior the screening
    5. Patients considered at persistent risk of thrombosis or bleeding at the time of screening
    6. Patients with high risk of Gastro intestinal bleeding at time of the screening. Patients with liver stiffness ≥ 21 kPa at the time of the screening must have endoscopic assessment of variceal bleeding risk; presence of grade III or IV varices is an exclusion criterion, unless treated with primary prophylaxis
    7. Heart failure (grade III and IV of New York Heart Association (NYHA) classification)
    8. Major invasive procedure within 4 weeks prior to screening. The
    proper healing of the puncture site should be verified by the investigator
    9. Cerebrovascular, myocardial, or limb arterial thrombotic event within
    12 months prior to the screening and/or not considered stabilized by the
    investigator
    10. Bariatric surgery within 1 year prior to the screening
    11. Coagulation disturbances defined as (Drolz et al. 2016, Nadim et al. 2016, Stravitz et al. 2018, Green et al. 2018): fibrinogen at < 80 mg/dL and/or platelets at < 40 x 10³/mm3
    12. Severe hepatic encephalopathy (defined by West Haven grade > 2)
    13. Acute Decompensation of cirrhosis with Chronic Liver Failure Consortium Acute Decompensation (CLIF-C AD) score > 60
    14. Acute on Chronic liver failure (ACLF) grade 1, 2 ,3
    15. MELD score > 20
    16. Child Pugh score ≥ C
    17. Septic shock or serious – non-controlled bacterial or systemic fungal infection defined as persistent or recent (< 48hrs) clinical signs of infection despite adequate antibiotic therapy
    18. Circulatory failure defined as treated with vasoconstrictors to maintain arterial pressure or inotropes to improve cardiac output
    19. Respiratory disorders with pulse oximetry < 90% and related clinical signs
    20. Receiving one of the following treatments at the time of Screening:
    a. Vitamin E, thiazolidinediones (TZD), glucagon-like peptide-1 (GLP1) antagonists, unless the dose is stable for 3 months prior to Screening
    b. Drugs with any influence on coagulation: antiplatelet agents, anticoagulants (vitamin K antagonists, direct and parenteral anticoagulants, dual antiplatelet therapy)
    Prophylaxis treatment with aspirin is authorized
    21.Uncontrolled diabetes mellitus (HbA1c > 9.5 %) or/and known diabetic proliferative retinopathy
    22. Seropositive to Human Immunodeficiency Virus (HIV)
    23. Previous organ transplantation
    24. Patients receiving immunosuppressive drugs
    25. Malignancies, other than cured skin cancer, or cancer treated unless a complete remission over last 5 years is documented, or cancer considered as definitive cured by the investigator
    26. Current or a history of hepatocellular carcinoma or serum alphafetoprotein > 200 ng/mL (Bruix, Sherman and Practice Guidelines Committee 2005, Omata et al. 2010)
    27. Previous treatment with mesenchymal stem cells (MSCs) or other cell therapies beside blood products
    28. Known or suspected hypersensitivity or allergy to any of the components of the HepaStem diluent (human albumin, heparin sodium, sodium bicarbonate, dimethyl sulfoxide (DMSO)) or a history of multiple and/or severe allergies to drugs or foods or a history of severe anaphylactic reaction
    29. Pregnancy, breastfeeding or women with childbearing potential who decline to use reliable contraceptive method during the entire duration of the study
    30. Participation in any clinical study of an investigational agent at the time of screening
    31. Any other significant medical or social condition or disability that, in the investigator's opinion, may warrant a specific treatment, or may interfere with the patient's optimal participation or compliance with the study procedures
    Criterios de exclusión:
    1. Alanina aminotransferasa (ALT) ≥ 8 x límite superior de la normalidad (LSN)
    2. Enfermedad hepática alcohólica o consumo de alcohol superior a la ingesta diaria de 140 g/semana (dos dosis) para las mujeres y de 210 g/semana (tres dosis) para los hombres.
    3. Otras causas de enfermedad hepática, entre ellas la enfermedad hepática alcohólica, hepatitis B activa (HbsAg+), hepatitis C (PCR positiva),
    rastornos autoinmunes, hepatotoxicidad inducida por medicamentos, enfermedad de Wilson, hemocromatosis y deficiencia de alfa-1-antitrispina basada en el historial médico y/o evaluación clínica y biológica.
    4. Eventos trombóticos o hemorrágicos recientes, recurrentes o en curso, durante los 3 meses anteriores a la selección.
    5. Pacientes considerados en riesgo persistente de trombosis o hemorragia en el momento de la selección.
    6. Pacientes con alto riesgo de sangrado gastrointestinal en el momento del examen. Los pacientes con rigidez hepática ≥ 21 kPa en el momento de la selección deben pasar una evaluación endoscópica del riesgo de hemorragia de las varices; la presencia de varices de grado III o IV es un criterio de
    exclusión, a menos que se trate con profilaxis primaria.
    7. Insuficiencia cardiaca (grado III y IV de la clasificación de la New York Heart Association, NYHA)
    8. Procedimiento invasivo de gran envergadura durante las 4 semanas previas a la selección. El investigador debe comprobar la cicatrización adecuada del sitio de punción.
    9. Evento trombótico cerebrovascular, miocárdico o arterial de las extremidades durante los 12 meses anteriores de la selección y/o no se considera estabilizado por el investigador.
    10. Cirugía bariátrica durante el año anterior a la selección
    11. Trastornos de la coagulación definidos como: (Drolz et al. 2016, Nadim et al. 2016, Stravitz et al. 2018, Green et al. 2018)fibrinógeno a <80 mg/dl
    y/o plaquetas a < 40 x 10³/mm3
    12. Encefalopatía hepática grave (definida por el grado de West Haven >2)
    13. Descompensación aguda de la cirrosis con puntuación de descompensación aguda (CLIF-C AD) del Consorcio de Insuficiencia Hepática Crónica > 60
    14. Insuficiencia hepática crónica agudizada (IHCA) de grado 1, 2 ,3
    15. Puntuación MELD > 20
    16. Puntuación Child Pugh ≥ C
    17. Choque séptico o infección no controlada bacteriana o fúngica sistémica grave, definida como persistente o signos recientes (< 48 h) de infección a pesar de una terapia adecuada con antibióticos.
    18. Insuficiencia circulatoria definida como tratada con vasoconstrictores para mantener la presión arterial o inótropos para mejorar el gasto cardíaco
    19. Trastornos respiratorios con oximetría de pulso < 90% y signos clínicos relacionados
    20. Recibir uno de los siguientes tratamientos en el momento a la selección:
    a. Vitamina E, tiazolidinedionas (TZD), antagonistas del péptido-1 (GLP1) similares al glucagón, a menos que la dosis sea estable durante los 3 meses anteriores a la selección.
    b. Medicamentos con cualquier influencia en la coagulación: agentes antiplaquetarios, anticoagulantes (antagonistas de la vitamina K, anticoagulantes directos y parenterales, tratamiento antiplaquetario dual)
    Se autoriza el tratamiento profiláctico con aspirina.
    21. Diabetes mellitus no controlada (HbA1c > 9.5 %) o/y retinopatía diabética proliferativa conocida
    22. Seropositivo al virus de inmunodeficiencia humana (VIH)
    23. Trasplante de órganos previo
    24. Pacientes que reciben medicamentos inmunosupresores
    25. Malignidades, que no sean cáncer de piel curado, o cáncer tratado a menos que se documente una remisión completa en los últimos 5 años, o cáncer considerado como curado definitivamente por el investigador.
    26. Carcinoma hepatocelular o alfafetoproteína sérica actual o con antecedentes > 200 ng/ml (Bruix, Sherman and Practice Guidelines Committee 2005, Omata et al. 2010)
    27. Tratamiento previo con células madre mesenquimales (CMM) u otras terapias celulares además de los productos sanguíneos
    28. Hipersensibilidad o alergia conocida o sospechada a cualquiera de los componentes del diluyente HepaStem (albúmina humana, heparina sódica, bicarbonato de sodio, dimetil sulfóxido (DMSO)) o antecedentes de alergias múltiples y/o graves a medicamentos o alimentos o antecedentes de
    reacción anafiláctica grave.
    29. Embarazo, lactancia o mujeres con posibilidad de tener hijos que se niegan a usar métodos anticonceptivos fiables durante toda la duración del estudio
    30. Participación en cualquier estudio clínico de un agente bajo investigación en el momento a la selección
    31. Cualquier otra condición o discapacidad médica o social significativa que, en opinión del investigador, pueda justificar un tratamiento específico, o
    nueda interferir con la participación o el cumplimiento óptimo del paciente con los procedimientos del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint: dose-finding and safety
    - AEs reported up to Day 28 assessed for seriousness, severity, relationship to the investigational medicinal product (IMP) and/or IMP administration procedure. This includes but is not limited to clinically changes in clinical examinations, vital signs, laboratory tests and imaging.
    Criterio de valoración primario: determinación de la dosis y seguridad
    - Los EA notificados hasta el día 28 se evalúan en cuanto a gravedad, severidad, relación con el producto medicinal bajo investigación (PEI) y/o el procedimiento de administración del PEI. Esto incluye de manera no exhaustiva los cambios clínicos en los exámenes clínicos, signos vitales, pruebas de laboratorio e imágenes.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary endpoint: dose-finding and safety up to Day 28.
    Criterio de valoración primario: determinación de la dosis y seguridad hasta el día 28.
    E.5.2Secondary end point(s)
    Secondary safety endpoints:
    - Presence of anti-HLA Abs and identification for donor HLA specificity.
    - Coagulation tests
    - AEs reported up to Month 6 assessed for seriousness, severity, relationship to the IMP and/or IMP administration procedure. This includes but is not limited to clinically changes in clinical examinations, vital signs, laboratory tests and imaging
    Preliminary efficacy endpoints:
    - Composite score for disease stage: MELD, Child-Pugh scores and CLIF-C AD (for F4 decompensated)
    - Quantitative assessment of liver and metabolic function
    - Quantitative assessment of Liver fibrosis biomarkers
    - Quantitative assessment of Liver stiffness
    Exploratory endpoints:
    - Number of new/new onset of acute decompensation events
    - In vitro proliferative and cytokine secretion function of PBMC in response to TetT, PPD, and PHA
    - In vitro T cell response to HepaStem
    - Quantitative assessment of inflammatory, apoptosis, and NASH
    biomarkers from baseline to up to 6 months after last infusion
    - Quantitative assessment of Portal hypertension biomarkers
    - Day 28 assessed for seriousness, severity, relationship to the IMP and/or IMP administration procedure. This includes inflammation scores
    evaluated on Liver histology prior and 6 months post infusion
    Sub-study endpoints:
    - Quantitative assessment of HPVG prior and 6 months post infusion
    - Quantitative assessment of NAS, SAF score, METAVIR scores
    Criterios de valoración secundarios de seguridad:
    · Presencia de Ac anti-HLA y determinación de la especificidad HLA del donante.
    · Pruebas de coagulación
    · Los EA comunicados hasta el mes 6 se evalúan en cuanto a gravedad, severidad, relación con el PEI y/o el procedimiento de administración del PEI. Esto incluye de manera no exhaustiva los cambios clínicos en los exámenes clínicos, signos vitales, pruebas de laboratorio e imágenes.
    Criterios de valoración preliminares de la eficacia:
    · Puntuación compuesta por estadio de la enfermedad: Puntuaciones MELD, Child-Pugh y CLIF-C AD (para F4 descompensado)
    · Evaluación cuantitativa de la función hepática y metabólica
    · Evaluación cuantitativa de biomarcadores de fibrosis hepática
    · Evaluación cuantitativa de la rigidez hepática
    Criterios de valoración exploratorios:
    · Número de casos nuevos / nuevas apariciones de descompensación aguda
    · Función proliferativa in vitro y de secreción de citocinas de PBMC en respuesta a TetT, PPD y PHA
    · Respuesta in vitro de las células T a HepaStem
    · Evaluación cuantitativa de biomarcadores inflamatorios, apoptosis y EHNA desde el inicio hasta 6 meses después de la última infusión.
    · Evaluación cuantitativa de biomarcadores de hipertensión portal
    · Día 28, evaluación de la severidad, gravedad y relación con el PEI y/o el procedimiento de administración del PEI. Esto incluye las puntuaciones de inflamación evaluadas en histología hepática antes y 6 meses después de la infusión.
    Criterios de valoración del subestudio:
    · Evaluación cuantitativa de la HPVG antes y 6 meses después de la infusión
    · Evaluación cuantitativa de puntuaciones NAS, SAF y METAVIR
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Secondary safety endpoints, AEs reported up to Month 6
    - Preliminary efficacy endpoints: up to Month 6
    - Exploratory endpoints:
    - Quantitative assessment of inflammatory, apoptosis, and NASH biomarkers from baseline to up to 6 months after last infusion
    - Day 28 assessed for seriousness, severity, relationship to the IMP and/or IMP administration procedure. This includes inflammation scores evaluated on Liver histology prior and 6 months post infusion
    - Sub-study endpoints:
    - Quantitative assessment of HPVG prior and 6 months post infusion
    - Criterios de valoración secundarios de seguridad: Los EA comunicados hasta el mes 6
    - Criterios de valoración preliminares de la eficacia: hasta el mes 6 .
    - Criterios de valoración exploratorios:
    - Evaluación cuantitativa de biomarcadores inflamatorios, apoptosis y EHNA desde el inicio hasta 6 meses después de la última infusión.
    - Día 28, evaluación de la severidad, gravedad y relación con el PEI y/o el procedimiento de administración del PEI. Esto incluye las puntuaciones de inflamación evaluadas en histología hepática antes y 6 meses después de la infusión.
    Criterios de valoración del subestudio:
    - Evaluación cuantitativa de la HPVG antes y 6 meses después de la infusión
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    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 No
    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 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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA23
    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
    Switzerland
    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
    última visita del último sujeto
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months12
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months12
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 4
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 22
    F.4.2.2In the whole clinical trial 24
    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)
    Patients who receive at least one infusion of HepaStem will be eligible to enter a long-term safety follow up study for 5 years (PROLONGSTEM – EudraCT 2017-003989-27).
    Los pacientes que han recibido al menos una infusión de HepaStem serán elegibles para ingresar a un estudio de seguimiento de seguridad a largo plazo durante 5 años (PROLONGSTEM - EudraCT 2017-003989-27)
    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 Decision2019-04-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-04-12
    P. End of Trial
    P.End of Trial StatusOngoing
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