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    Summary
    EudraCT Number:2021-002617-33
    Sponsor's Protocol Code Number:VS01-IIa-01
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-03-18
    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 number2021-002617-33
    A.3Full title of the trial
    A Phase 2a, open-label, randomized, controlled, multi-center, proof of concept study, to assess the efficacy, safety and tolerability of VS-01 on top of standard of care, compared to standard of care alone, in adult patients with acute-on-chronic liver failure (ACLF) Grade 1-2 and ascites
    Estudio demostrativo preliminar de fase IIa, multicéntrico, aleatorizado, abierto y controlado para evaluar la eficacia, seguridad y tolerabilidad de VS-01 además del tratamiento estándar, en comparación con el tratamiento estándar solo, en pacientes adultos con insuficiencia hepática crónica agudizada (IHCA) de grado 1-2 y ascitis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to evaluate a new medicinal product VS-01 in patients with an acute episode on top of a chronic liver disease (called acute-on-chronic liver failure) who experience accumulation of fluid in the abdominal cavity (called ascites) as well as intellectual, behavioral decay and physical decay.
    Un estudio clínico para evaluar un nuevo medicamento VS-01 en pacientes con episodio agudo además de enfermedad hepática crónica (llamada insuficiencia hepática aguda sobre crónica) que experimentan tanto acumulación de líquido en la cavidad abdominal (llamado ascitis) como deterioro intelectual, conductual y físico.
    A.3.2Name or abbreviated title of the trial where available
    UNVEIL
    UNVEIL
    A.4.1Sponsor's protocol code numberVS01-IIa-01
    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 SponsorVersantis AG
    B.1.3.4CountrySwitzerland
    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 supportVersantis AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationVersantis AG
    B.5.2Functional name of contact pointHead of Clinical Operations
    B.5.3 Address:
    B.5.3.1Street AddressTechnoparkstrasse 1,
    B.5.3.2Town/ cityZuerich
    B.5.3.3Post code8005
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+41792329073
    B.5.5Fax number+4144500 8829
    B.5.6E-mailclinical@versantis.ch
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/16/1675
    D.3 Description of the IMP
    D.3.2Product code VS-01
    D.3.4Pharmaceutical form Suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntraperitoneal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCitric Acid
    D.3.9.1CAS number 77-92-9
    D.3.9.3Other descriptive nameCITRIC ACID, ANHYDROUS PH. EUR.
    D.3.9.4EV Substance CodeSUB171902
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3.54
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acute-on-chronic liver failure (ACLF) is characterized by hepatic and extrahepatic organ dysfunction and/or failure and highly activated systemic inflammation. It leads to an accumulation of different metabolites, interalias ammonia, which cannot be metabolized. Hyperammonemia leads to Hepatic Encephalopathy (HE). ACLF is a major cause of death in cirrhosis, with an approximately 50% mortality rate. The selected patient population is ACLF grade 1 and 2 patients with ascites.
    La insuficiencia hepática crónica agudizada (IHCA) se caracterizada por una disfunción y/o fallo orgánico extrahepático y por inflamación sistémica altamente activada.Esto conlleva a una acumulacion de matabolitos,entre ellos amoniaco,que no pueden ser metabolizados.La hiperamonemia conduce a Encefalopatía Hepática(EH).IHCA es una de las principales causas de muerte en cirrosis,con una tasa de mortalidad de alrededor del 50%.La población de pacientes seleccionada es IHCA grado 1 o 2 con ascitis
    E.1.1.1Medical condition in easily understood language
    Acute-on-chronic liver failure is an acute complication of a chronic liver disease affecting other organs (e.g., kidney & brain) and leading to
    physical, intellectual and behavioral decay or death.
    La Insuficiencia hepática crónica agudizada es una complicación aguda de enfermedad hepática crónica que afecta órganos (ej riñón&cerebro) y conduce a deterioro físico,intelectual,conductual o muerte.
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 24.0
    E.1.2Level PT
    E.1.2Classification code 10077305
    E.1.2Term Acute on chronic liver failure
    E.1.2System Organ Class 10019805 - Hepatobiliary 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 compare the efficacy of VS-01 administered intraperitoneally (i.p.) daily over 4 days in patients with ACLF Grades 1-2 between VS-01 on top of standard of care and standard of care alone.
    Comparar la eficacia del VS-01 administrado por vía intraperitoneal (i.p.) una vez al día durante 4 días en pacientes con IHCA de grado 1 y 2 además del tratamiento estándar con la administración del tratamiento estándar solo.
    E.2.2Secondary objectives of the trial
    1. To characterize the safety and tolerability of VS-01 in ACLF patients following administration of VS-01 i.p. daily for 4 days
    2. To evaluate the efficacy of VS-01 in ACLF patients following administration of VS-01 i.p. daily for 4 days on top of standard of care and standard of care alone:
    a. Effect on CLIF-C ACLF score on Day 5
    b. Evolution of CLIF-C ACLF score
    c. Evolution of ACLF grade
    d. Effect on organ failures (CLIF-C OF score)
    e. Effect on organ dysfunctions (CLIF-SOFA score)
    f. Effect on CPS, MELD and MELD-Na
    3. To evaluate the effect of VS-01 on HE in ACLF patients following administration of VS-01 i.p. daily for 4 days on top of standard of care and standard of care alone:
    a. Effect on West Haven grade
    b. Evolution of West Haven grade
    c. Effect on covert HE
    d. Effect on overt HE
    e. Evolution of overt HE
    4. To characterize the PK and the PD profiles of VS-01 in ACLF patients following administration of VS-01 i.p. daily for 4 days.
    1.Caracterizar seguridad y tolerabilidad de VS-01 en pacientes con IHCA tras administración ip de VS-01 1 vez al día durante 4 días
    2.Evaluar eficacia de VS-01 en pacientes con IHCA tras administración ip de VS-01 1 vez al día durante 4 días además de tratamiento estándar y tratamiento estándar solo:
    a.Efecto de puntuación CLIF-C ACLF en Día 5
    b.Evolución de puntuación CLIF-C ACLF
    c.Evolución grado IHCA
    d.Efecto en insuficiencias orgánicas(puntuación CLIF-C OF)
    e.Efecto en disfunciones orgánicas(puntuación CLIF-SOFA)
    f.Efecto en CPS,MELD y MELD-NA
    3.Evaluar efecto de VS-01 en EH en pacientes con IHCA tras administración ip de VS-01 1 vez al dia durante 4 días además de tratamiento estándar y tratamiento estándar solo:
    a.Efecto grado West Haven
    b.Evolución grado West Haven
    c.Efecto en EH encubierta
    d.Efecto en EH manifiesta
    e.Evolución EH manifiesta
    4.Caracterizar perfiles FC y FD de VS-01 en pacientes con IHCA tras administración de VS-01 ip 1 vez al dia durante 4 dias
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Cirrhotic patients diagnosed by standard clinical criteria, imaging findings and/or histology with any underlying etiology;
    2. Cirrhotic patients with ACLF Grade 1 to 2 (according to EASL-CLIF criteria as described in the EASL-Clinical Practice Guideline on decompensated liver cirrhosis (EASL Clinical Practice Guidelines, 2018); organ failures will be calculated based on the CLIF-C OF score) triggered by any acute insult other than those listed in the exclusion criteria:
    ACLF Grade 1 patients meeting one of the following:
    a. Kidney failure (serum creatinine ≥ 2 mg/dL without renal replacement therapy [RRT]) + HE West Haven Grade 2;
    b. Liver failure (serum bilirubin ≥ 12.0 mg/dL) + HE West Haven Grade 2 with or without kidney dysfunction (serum creatinine ≥ 1.5 – < 2.0 mg/dL);
    c. Corrected Coagulation failure (International Normalized Ratio [INR] ≥ 2.5), i.e., not requiring continuous transfusion + HE West Haven Grade 2 with or without kidney dysfunction (serum creatinine ≥ 1.5 - < 2.0 mg/dL);
    d. HE West Haven Grade 3 + kidney dysfunction (serum creatinine ≥ 1.5 - < 2.0 mg/dL).
    ACLF Grade 2 patients meeting one of the following:
    e. Kidney failure (serum creatinine ≥ 2 mg/dL without RRT) + HE West Haven Grade 3;
    f. Liver failure (serum bilirubin ≥ 12.0 mg/dL) + HE West Haven Grade 3;
    g. Corrected Coagulation failure (INR ≥ 2.5), i.e., not requiring continuous transfusion + HE West Haven Grade 3.
    3. Same ACLF Grade 1 or 2, for at least 24 h of hospitalization before Screening;
    4. Diagnosis of ACLF not more than 96 h before Screening;
    5. Presence of ascites with clinical decision for paracentesis;
    6. Fasting venous ammonia plasma levels above the upper limit of normal;
    7. Patients with body mass index (BMI) < 35 (calculated on dry weight);
    8. Men and women ≥ 18 and ≤ 64 years of age on the day of signing Patient Informed Consent Document (PICD);
    9. Informed consent:
    a. Ability to understand the PICD and comply with the protocol and sign the PICD or a legal representative can sign PICD. If patients are temporarily unable to consent and are considered in an emergency situation, they will be included according to local law and Ethics Committees (EC) requirements and need to consent as soon as they are able again to do so;
    b. Signed and dated PICD obtained prior to performing any study procedure, including Screening, except for patients who are considered in an emergency situation and for whom the PICD will be obtained as soon as it is possible and reasonable by the patient themselves or by a legal representative who can sign the PICD on behalf of the patient.
    1. Pacientes cirróticos diagnosticados por criterios clínicos estándar, hallazgos de imagen y/o histología con alguna etiología subyacente.
    2. Pacientes cirróticos con IHCA de Grado 1 a 2 (de acuerdo con los criterios EASL-CLIF descritos en la Guía de práctica clínica de la EASL para la cirrosis hepática descompensada [Guía de práctica clínica de la EASL, 2018]; las insuficiencias orgánicas serán calculadas en base a la puntuación CLIF-C OF desencadenada por alguna otra lesión aguda de las enumeradas en los criterios de exclusión:
    Pacientes con IHCA de grado 1 que cumplan uno de los siguientes criterios:
    a. Insuficiencia renal (creatinina sérica ≥2 mg/dl sin tratamiento de reemplazo renal [TRR]) + EH de grado 2 de West Haven;
    b. Insuficiencia hepática (bilirrubina sérica ≥12,0 mg/dl) + EH de grado 2 de West Haven con o sin disfunción renal (creatinina sérica ≥1,5 – <2,0 mg/dl);
    c. Insuficiencia de coagulación corregida (índice internacional normalizado [INR] ≥2,5), es decir, que no requiere transfusión continua + EH de grado 2 de West Haven con o sin disfunción renal (creatinina sérica ≥1,5 – <2,0 mg/dl);
    d. EH de grado 3 de West Haven + disfunción renal (creatinina sérica ≥1,5 – <2,0 mg/dl).
    Pacientes con IHCA de grado 2 que cumplan uno de los siguientes criterios:
    e. Insuficiencia renal (creatinina sérica ≥2 mg/dl sin TRR) + EH de grado 3 de West Haven;
    f. Insuficiencia hepática (bilirrubina sérica ≥12,0 mg/dl) + EH de grado 3 de West Haven;
    g. Insuficiencia de coagulación corregida (INR ≥2,5), es decir, que no requiere transfusión continua + EH de grado 3 de West Haven.
    3. IHCA del mismo grado 1 o 2, durante una hospitalización de al menos 24 h antes de la selección.
    4. Diagnóstico de IHCA obtenido como máximo 96 h antes de la selección.
    5. Presencia de ascitis con decisión clínica de paracentesis.
    6. Niveles plasmáticos de amoníaco venoso en ayunas por encima del límite superior de la normalidad.
    7. Pacientes con un índice de masa corporal (IMC) <35 (calculado con el peso en seco).
    8. Varones y mujeres de ≥18 y ≤64 años el día de la firma del documento de consentimiento informado (DCI).
    9. Consentimiento informado:
    a. capacidad para comprender el DCI, cumplir con el protocolo y para firmar el DCI o que lo firme un representante legal. Si el paciente está temporalmente incapacitado para otorgar su consentimiento y se considera que se encuentra en una situación de emergencia, se le incluirá de conformidad con lo que establezca la legislación local y los requisitos del CEIm, y deberá dar su consentimiento en cuanto esté nuevamente capacitado. Si fue el representante legal quien otorgó consentimiento en nombre del paciente, también se deberá obtener lo antes posible el consentimiento del paciente para continuar su participación;
    b. Recabar el DCI firmado y fechado antes de realizar cualquier procedimiento del estudio, incluida la selección, excepto en el caso de los pacientes que se consideren en una situación de emergencia y de quienes se obtendrá su consentimiento tan pronto como sea posible y razonable, ya sea en nombre propio o a través de un representante legal que pueda firmar el DCI en su nombre.
    E.4Principal exclusion criteria
    1. Presence of the following organ(s) failure(s) as per the EASL (EASL Clinical Practice Guidelines, 2018) definitions and CLIF-C OF score:
    a. Respiratory failure as defined by PaO2/ FiO2 ≤ 200, or SpO2/ FiO2 ≤ 214 or mechanical ventilation;
    b. Uncorrected coagulation failure as defined by INR (INR ≥ 2.5 or platelet count ≤ 20 x 109/L);
    c. Severe cardiovascular failure requiring the use of vasopressors. It should be clarified that the use of terlipressin or low-dose norepinephrine in case of hepatorenal syndrome (HRS) or bleeding is not an exclusion criterion;
    2. ACLF Grade 3: Presence of three or more organ failures as per EASL-CLIF criteria as described in the EASL-Clinical Practice Guideline on decompensated liver cirrhosis ((EASL Clinical Practice Guidelines, 2018); organ failures will be calculated based on CLIF-C OF score);
    3. Presence of uncontrolled and severe infection at Screening:
    a. Criteria for diagnosis of infections will be the presence of clinical signs of infection according to criteria adapted from the EASL Clinical Practice Guidelines 2018 (EASL Clinical Practice Guidelines, 2018) for the management of patients with decompensated cirrhosis:
    i. Any spontaneous or secondary bacterial peritonitis: presence of neutrophils in a normally sterile body fluid (e.g., neutrophil counts > 250/mm3 ascitic fluid);
    ii. Any spontaneous bacterial pleural empyema: In case of pleural effusion, positive pleural fluid culture and increased neutrophil count of > 250/mm3 or negative pleural fluid culture and a neutrophil count of > 500/mm3 in the absence of pneumonia;
    b. UTIs with hemodynamic instability or septic shock;
    c. Pneumonia with hemodynamic instability or septic shock;
    d. Documented or active tuberculosis;
    e. Skin/soft tissue infection: physical examination findings of swelling, erythema, heat and tenderness in the skin with hemodynamic instability or septic shock;
    f. Acute obstructive cholangitis in the presence of cholestasis, compatible symptoms (right upper quadrant pain and jaundice) and radiological data of biliary obstruction with hemodynamic instability or septic shock;
    g. Patients with colonized (> 2 sites) or invasive fungal infection;
    h. Patients with sepsis or septic shock of unknown source;
    4. Patients with medical history of spontaneous bacterial peritonitis over the past 4 weeks;
    5. Patients with epilepsy;
    6. Presence of on-going gastro-intestinal bleeding or bleeding upon paracentesis at Screening;
    7. Contraindication for paracentesis according to the EASL Clinical Practice Guidelines 2018 (EASL Clinical Practice Guidelines, 2018) for the management of patients with decompensated cirrhosis;
    8. Other known coagulation disorders such as hemophilia, congenital or acquired Von Willebrand disease or platelets function defects;
    9. For any of the following having occurred in the past 4 weeks prior to screening: TIPS procedure, banding of an esophageal varix or any major abdominal surgery;
    10. Potential or known hypersensitivity to liposomes;
    11. Potential or known risk factors for allergic/anaphylactoid like reactions (e.g., mastocytosis/elevated basal tryptase), increased complement activation; previous reactions to medicinal products; multiple hypersensitivities;
    12. Patients with known PPHT and hepato-pulmonary syndrome;
    13. Any transplanted patients receiving immunosuppressant medication;
    14. Any severe disease considered to be potentially detrimental at the discretion of the PI. This includes but is not limited to hepatocellular carcinoma (HCC) outside Milan criteria, cholangiocarcinoma, extrahepatic cancer over the past 2 years, drug abusers (excluding alcohol and marijuana) and former drug abusers under substitution therapy (e.g., methadone-maintained);
    15. The need for RRT or any extracorporeal liver support device (e.g., MARS, Prometheus, Plasmapheresis) at study inclusion;
    16. Patients with Alfapump® in place to manage ascites;
    17. Patients with severe alcoholic hepatitis with a Maddrey Score above 32;
    18. Pregnancy and lactation;
    19. Women of child-bearing potential who are not willing to use adequate contraception during the study period until Day 90;
    20. Patients who participate in another clinical trial at the time of screening or within 4 weeks prior to Screening.
    1. Presencia de la(s) siguiente(s) insuficiencia(s) orgánicas según las definiciones del EASL (EASL Guía de Práctica Clínica, 2018) y la puntuación CLIF-C OF:
    a. Insuficiencia respiratorio definida por PaO2/FiO2≤214 o ventilación mecánica;
    b. Insuficiencia de coagulación corregida definida por INR (INR≥2.5 o recuento de plaquetas ≤ 20 x 109/L);
    c. Insuficiencia cardiovascular severa que requiere el uso de vasopresores. Debe ser aclarado que el uso de terlipresson o dosis bajas de norepinefrina en caso de síndrome hepatorenal (SHE) o sangrado no es un criterio de exclusión;
    2. IHCA Grado 3: Presencia de tres o más insuficiencias orgánicas según los criterios EASL-CLIF descritos en la Guía de Práctica Clínica EASL o cirrosis hepática descompensada ((EASL Guía de Práctica Clínica, 2018); la insuficiencia orgánica será calculada en base a la puntuación CLIF-C OF);
    3. Presencia de infección grave y no controlada en la Selección:
    a. Será criterio para el diagnóstico de infecciones la presencia de signos clínicos de infección según criterios adaptados de las EASL Guía de Práctica Clínica 2018 (EASL Clinical Practice Guidelines, 2018) para el manejo de pacientes con cirrosis descompensada:
    i. Cualquier peritonitis bacteriana espontánea o secundaria: presencia de neutrófilos en un líquido corporal normalmente estéril (p. ej., recuento de neutrófilos > 250/mm3 en líquido ascítico);
    ii. Cualquier empiema pleural bacteriano espontáneo: en caso de derrame pleural, cultivo de líquido pleural positivo y aumento del recuento de neutrófilos > 250/mm3 o cultivo de líquido pleural negativo y recuento de neutrófilos 500/mm3 en ausencia de neumonía;
    b. ITU con inestabilidad hemodinámica o shock séptico;
    c. Neumonía con inestabilidad hemodinámica o shock séptico;
    d. Tuberculosis documentada o activa;
    e. Infección de piel/tejidos blandos: hallazgos en el examen físico de hinchazón, eritema, calor y sensibilidad en la piel con inestabilidad hemodinámica o choque séptico;
    f. Colangitis obstructiva aguda en presencia de colestasis, síntomas compatibles (dolor en hipocondrio derecho e ictericia) y datos radiológicos de obstrucción biliar con inestabilidad hemodinámica o shock séptico;
    g. Pacientes con infección fúngica colonizada (> 2 sitios) o invasiva;
    h. Pacientes con sepsis o shock séptico de origen desconocido;
    4. Pacientes con antecedentes médicos de peritonitis bacteriana espontánea en las últimas 4 semanas;
    5. Pacientes con epilepsia;
    6. Presencia de sangrado gastrointestinal en curso o sangrado en la paracentesis en la Selección;
    7. Contraindicación para la paracentesis según las Guía de Práctica Clínica EASL 2018 (EASL Clinical Practice Guidelines, 2018) para para el manejo de pacientes con cirrosis descompensada;
    8. Otros trastornos de la coagulación conocidos, como la hemofilia, la enfermedad de Von Willebrand congénita o adquirida o defectos en la función de las plaquetas;
    9. Por cualquiera de los siguientes que hayan ocurrido en las últimas 4 semanas antes de la selección: procedimiento TIPS, vendaje de variz esofágica o cualquier cirugía abdominal mayor;
    10. Hipersensibilidad potencial o conocida a los liposomas;
    11. Factores de riesgo conocidos o potenciales de reacciones alérgicas/anafilactoides (p. ej. mastocitosis/triptasa basal elevada), aumento de la activación del complemento; reacciones previas a medicamentos; hipersensibilidades múltiples;
    12. Pacientes con PPHT conocido y síndrome hepatopulmonar;
    13. Cualquier paciente trasplantado que reciba medicación inmunosupresora
    14. Cualquier enfermedad grave que se considere potencialmente perjudicial a criterio del IP. Esto incluye, entre otros, carcinoma hepatocelular (CHC) fuera de los criterios Milán, colangiocarcinoma, cáncer extrahepático en los últimos 2 años, drogodependientes (excluyendo alcohol y marihuana) y ex drogodependientes bajo terapia de sustitución (P.ej mantenimiento con metadona).
    15. Necesidad e RRT o cualquier dispositivo extracorpóreo de soporte hepático (p.ej MARS, Prometheus, plasmaféresis) en el momento de la inclusión en el estudio;
    16. Pacientes con Afapump para controlar la ascitis;
    17. Pacientes con hepatitis alcohólica grave con Maddrey Score superior a 32;
    18. Embarazo y lactancia;
    19. Mujeres en edad fértil que no estén dispuestas a utilizar métodos anticonceptivos adecuados durante el periodo de estudio hasta el día 90;
    20. Pacientes que participen en otro ensayo clínico en el momento de la selección o dentro de las 4 semanas anteriores a la selección.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in mean CLIF-C ACLF score on Day 7.
    Cambio en la puntuación media de CLIF-C ACLF en Día 7.
    E.5.1.1Timepoint(s) of evaluation of this end point
    CLIF-C ACLF scores on Day 1 pre-dose and Day 7.
    Puntuaciones CLIF-C ACFL en Día 1 pre-dosis y Día 7.
    E.5.2Secondary end point(s)
    1. To determine the incidence rate, severity and relationship to VS-01 of adverse drug reactions and serious adverse drug reactions, safety laboratory, vital signs and Electrocardiogram (ECG) assessments;
    2. ACLF
    a) Change from baseline in mean CLIF-C ACLF score on Day 5;
    b) Time from randomization to worsening or improvement of CLIF-C ACLF;
    c) Evolution of ACLF grade from baseline to Day 5 and to Day 7:
    - Percentage of patients with a regression to a lower ACLF grade;
    • Percentage of patients with a 1 or 2 ACLF grade regression;
    - Percentage of patients with a progression to a higher ACLF grade;
    • Percentage of patients with a 1 or 2 ACLF grade progression;
    - Percentage of patients with no change in ACLF grade;
    d) Organ failures assessed by CLIF-C OF score:
    - Number of organ failures at baseline, Day 5 and Day 7 (kidney: serum creatinine ≥ 2 mg/dL or use of Renal Replacement Therapy (RRT); cerebral: HE West Haven Grade ≥ 3; liver: serum bilirubin ≥ 12 mg/dL; coagulation: International Normalized Ratio (INR) ≥ 2.5;
    - Change from baseline in mean CLIF-C OF score on Day 5 and Day 7;
    e) Organ dysfunctions assessed by CLIF - SOFA score:
    - Number of organ dysfunction at baseline, Day 5 and Day 7 (kidney: serum creatinine ≥ 1.2 – < 2.0 mg/dL; brain: HE West Haven Grade 1 2; liver: serum bilirubin ≥ 1.2 – < 12 mg/dL; coagulation: INR ≥ 1.1 – < 2.5;
    - Change from baseline in mean CLIF-SOFA score on Day 5 and Day 7;
    f) Change from baseline in CPS, MELD and MELD-Na scores on Day 5 and Day 7;
    3. HE
    a) Change from baseline in West Haven grade on Day 5 and Day 7;
    b) Evolution of West Haven grade from baseline on Day 5 and Day 7:
    - Percentage of patients with a regression to a lower West Haven grade;
    • Percentage of patients with a 1, 2 or 3 West Haven grade regression;
    - Percentage of patients with a progression to a higher West Haven grade;
    • Percentage of patients with a 1, 2 or 3 West Haven grade progression;
    - Percentage of patients with no change in West Haven grade;
    c) Change from baseline on Day 5 and Day 7 in:
    - Psychometric hepatic encephalopathy score (PHES);
    - Animal Naming test;
    - Stroop test;
    d) Change from baseline in Glasgow Coma Scale on Day 5 and Day 7;
    e) Time to resolution of overt HE
    4. PK / PD
    a) To evaluate plasma concentration-time profile of baseline-corrected citric acid and lipids on Days 1 and 4: Cmax, Tmax, AUC (AUC0-3, AUC0-24, AUCt, and AUCinf), t1/2, apparent CL, Vd and accumulation ratio;
    b) To calculate the change from baseline in fasting plasma ammonia levels on Day 5 and Day 7, the maximum reduction in plasma ammonia from baseline (Emax) and the time to normalization of plasma ammonia (if it occurs) over the dosing period.
    1. Determinar la tasa de incidencia, severidad y relación con VS-01 de reacciones adversas a medicamentos y reacciones adversas graves a medicamentos, laboratorio de seguridad, evaluaciones de signos vitales y electrocardiograma (ECG);
    2. IHCA
    a) Cambio desde el inicio en la puntuación CLIF-C ACLF media en el día 5;
    b) Tiempo desde la aleatorización hasta el empeoramiento o mejora de CLIF-C ACLF;
    c) Evolución del grado ACLF desde el inicio hasta el Día 5 y hasta el Día 7:
    - Porcentaje de pacientes con regresión a un grado IHCA inferior;
    • Porcentaje de pacientes con una regresión de grado 1 o 2 IHCS;
    - Porcentaje de pacientes con progresión a un grado superior de IHCA;
    • Porcentaje de pacientes con progresión de grado 1 o 2 IHCA;
    - Porcentaje de pacientes sin cambios en el grado IHCA;
    d) Insuficiencia orgánica evaluada por CLIF-C OF
    - Número de insuficiencias orgánicas al inicio, Día 5 y Día 7 (riñón: creatinina sérica ≥ 2 mg/dL o uso de Terapia de Reemplazo Renal (TRR); cerebral: Grado HE West Haven ≥ 3; hígado: bilirrubina sérica ≥ 12 mg/ dL, coagulación: Razón Internacional Normalizada (INR) ≥ 2,5; - Cambio desde el inicio en la puntuación media de CLIF-C OF en el día 5 y el día 7;
    e) Disfunciones de órganos evaluadas por CLIF - Puntaje SOFA:
    - Número de disfunción orgánica al inicio, Día 5 y Día 7 (riñón: creatinina sérica ≥ 1,2 – < 2,0 mg/dL; cerebro: HE West Haven Grado 1 2; hígado: bilirrubina sérica ≥ 1,2 – < 12 mg/dL; coagulación : INR ≥ 1,1 – < 2,5;
    - Cambio desde el inicio en la puntuación CLIF-SOFA media en el Día 5 y el Día 7;
    f) Cambio desde el inicio en las puntuaciones de CPS, MELD y MELD-Na en el Día 5 y el Día 7;
    3. EH
    a) Cambio desde la línea de base en el grado de West Haven el día 5 y el día 7;
    b) Evolución del grado de West Haven desde la línea de base en el Día 5 y el Día 7:
    - Porcentaje de pacientes con regresión a un grado inferior de West Haven;
    • Porcentaje de pacientes con una regresión de grado West Haven de 1, 2 o 3;
    - Porcentaje de pacientes con progresión a un grado superior de West Haven;
    • Porcentaje de pacientes con una progresión de grado West Haven 1, 2 o 3;
    - Porcentaje de pacientes sin cambios en el grado de West Haven;
    c) Cambio desde la línea de base en el Día 5 y el Día 7 en:
    - Puntuación psicométrica de encefalopatía hepática (PHES);
    - Prueba de denominación de animales;
    - Prueba de Stroop;
    d) Cambio desde el inicio en la escala de coma de Glasgow en el día 5 y el día 7;
    e) Tiempo de resolución de HE manifiesto 4. PK / PD
    4. FC/FD
    a) Para evaluar el perfil de concentración plasmática-tiempo del ácido cítrico y los lípidos corregidos al valor inicial en los días 1 y 4: Cmax, Tmax, AUC (AUC0-3, AUC0-24, AUCt y AUCinf), t1/2, CL aparente, Vd y relación de acumulación;
    b) Para calcular el cambio desde el valor inicial en los niveles de amoníaco plasmático en ayunas en el Día 5 y el Día 7, la reducción máxima en el amoníaco plasmático desde el valor inicial (Emax) y el tiempo hasta la normalización del amoníaco plasmático (si ocurre) durante el período de dosificación.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) AE/SAE: study start - Day (D) 90; safety lab: Screening (SCR), D 1&4
    pre-&post-dose, D 2&3 pre-dose, D 5,6,7,14,28,90,Early Termination
    (ET); Vital Signs: SCR, D 1-4 pre-&post-dose (treatment group only), D 5,6,7,14, 28, 90, ET; ECG:
    SCR, D 1&4 pre-&post-dose (treatment group only), D 2&3 pre-dose, D 5,6,7,ET
    2) CLIF-C ACLF: SCR, D 1-4 (pre-dose), 5,6,7,14,28,90,ET
    3) West Haven: SCR, D 1-4 (pre-dose), 5,6,7,14,28,90,ET; PHES, Animal Naming, Stroop, Glasgow Coma: D 1 (pre-dose), 5, 7, ET
    4) Blood PK (treatment group only): D 1&4 pre-dose and 1,2,3, 6 h after dosing start, D 2&3 (predose), D5, 6, 7, ET
    Blood PD: SCR, D 1&4 pre-dose and 1,2,3, 6 h after dosing start (treatment group only), D 2&3 (predose), D5, 6, 7, ET
    1. AE/SAE: inicio estudio-Día(D)90;
    Seguridad de laboratorio: Basal(BS),D1 y 4 pre y tras dosis,D2 y 3 pre y tras dosis,D5,6,7,14,28,90,Terminación anticipada(TA);
    -Signos vitales: BS,D1-4 pre y tras dosis(solo grupo tratamiento),D5,6,7,14,28,90,TA;
    -electrocardiograma:BS, D1 y 4 pre y tras dosis(solo grupo tratamiento),D2 y 3 pre dosis,D5,6,7,TA;
    2) CLIF-C ACLF: BS,D1-4(pre dosis),5,6,7,14,28,90,TA;
    3)West Haven:BS,D1-4(pre dosis),5,6,7,14,28,90,TA
    PHES,Animal Naming,Stroop,Glasgow Coma:D1(pre dosis),5,7,TA
    4) FC en sangre(solo grupo tratamiento):D1 y 4 pre dosis y 1,2,3,6h tras inicio de dosis,D2 y 3(pre dosis),D5,6,7,TA;
    FD en sangre:BS,D1 y 4 pre dosis y 1,2,3,6h tras inicio de dosis(solo grupo tratamiento),D2 y 3 (pre dosis),D5,6,7,TA
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic 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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Estudio controlado además del cuidado estándar
    Controlled study on top of standard of care
    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 EEA10
    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
    United States
    Austria
    Germany
    Spain
    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 years2
    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 years2
    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 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: 70
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Cirrhotic patients with ACLF Grade 1-2 are enrolled in VS01-IIa-01. They present with HE Grade 2-3 and require a legal representative to give consent. Considering the rapid, life-threatening evolution of ACLF, they may be in an emergency situation.
    Los pacientes cirróticos con IHCA Grado 1-2 son incluidos en VS01-IIa-01. Presentan EH Grado 2-3 y requieren representante legal para dar consentimiento. Por la rápida evolución y amenaza para la vida del IHCA, pueden estar en situación de emergencia
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state19
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 55
    F.4.2.2In the whole clinical trial 70
    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 participating in VS01-IIa-01 will remain on standard of care during and after the study ends.
    Los pacientes participantes en VS01-IIa-01 mantendrán el estandar de cuidado durante y después de que el estudio finalice.
    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 Decision2023-03-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-05-17
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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