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    Summary
    EudraCT Number:2021-002617-33
    Sponsor's Protocol Code Number:VS01IIa01
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-07-05
    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 ConcernedGermany - BfArM
    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) grades 1 and 2 and ascites
    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.
    A.3.2Name or abbreviated title of the trial where available
    UNVEIL-IT
    A.4.1Sponsor's protocol code numberVS01IIa01
    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+4144 500 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.
    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.
    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 evaluate the efficacy of VS-01 administered intraperitoneally (i.p.)
    daily over 4 days on top of standard of care (SOC) vs. SOC alone in patients with ACLF grades 1 and 2 as measured by Chronic Liver Failure Consortium Acute on-Chronic Liver Failure (CLIF-C ACLF) score at Day 7
    E.2.2Secondary objectives of the trial
    - To evaluate the efficacy of VS-01 administered i.p. daily over 4 days on top of SOC vs. SOC alone in patients with ACLF grades 1 and 2 with respect to:
    a. Mortality rate;
    b. Time to death;
    c. ACLF grade change and time to resolution of ACLF;
    d. Transplant-free survival;

    - To characterize the safety and tolerability of VS-01 in ACLF patients following i.p. administration of VS-01
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients with liver cirrhosis, diagnosed by standard clinical criteria, imaging findings and/or histology with any underlying etiology;
    2. Patients with liver cirrhosis and ACLF grade 1 or 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. Single kidney failure (serum creatinine ≥ 2 mg/dL) without RRT +/- liver, cerebral, coagulation, circulation or respiratory dysfunction;
    b. Liver failure (serum bilirubin ≥ 12.0 mg/dL) with either kidney dysfunction (serum creatinine ≥ 1.5 – < 2.0 mg/dL) and/or HE grade 1 or 2;
    c. Coagulation failure (International Normalized Ratio [INR] ≥ 2.5 - ≤ 3.0) with either kidney dysfunction (serum creatinine ≥ 1.5 - < 2.0 mg/dL) and/or HE grade 1 or 2;
    d. Circulatory failure (dopamine ≤15 µg/kg/min, or epinephrine ≤ 0.1 µg/kg/min, or norepinephrine ≤ 0.1 µg/kg/min) with either kidney dysfunction (serum creatinine ≥ 1.5 - < 2.0 mg/dL) and/or HE grade 1 or 2;
    e. Brain failure (HE West Haven grade 3) + kidney dysfunction (serum creatinine ≥ 1.5 - < 2.0 mg/dL).

    ACLF grade 2 patients meeting one of the following:
    f. Kidney failure (serum creatinine ≥ 2 mg/dL) without RRT + brain failure (HE West Haven grade 3);
    g. Liver failure (serum bilirubin ≥ 12.0 mg/dL) + brain failure (HE West Haven grade 3);
    h. Kidney failure (serum creatinine ≥ 2 mg/dL) without RRT + liver failure (serum bilirubin ≥ 12.0 mg/dL);
    i. Coagulation failure (INR ≥ 2.5 - ≤3.0) with either brain failure (HE West Haven grade 3), kidney failure without RRT, liver failure (serum bilirubin ≥ 12.0 mg/dL) or circulatory failure (dopamine <15 µg/kg/min, or epinephrine ≤ 0.1 µg/kg/min, or norepinephrine ≤ 0.1 µg/kg/min);
    j. Circulatory failure (dopamine ≤15 µg/kg/min, or epinephrine ≤ 0.1 µg/kg/min, or norepinephrine ≤ 0.1 µg/kg/min) with either kidney failure without RRT, liver failure (serum bilirubin ≥ 12.0 mg/dL), or brain failure (HE West Haven grade 3).

    3. Onset of ACLF not more than 96 h before SCR;
    4. Presence of ascites requiring paracentesis;
    5. Patients with body mass index (BMI) < 35 kg/m² (calculated on dry body weight);
    6. Men and women ≥ 18 and ≤ 69 years of age on the day of signing Patient Informed Consent Document (PICD);
    7. Informed consent:
    a. Ability to understand the PICD and comply with the protocol and sign the PICD or a legal representative can sign the PICD on behalf of the patient in accordance with local law and institutional policy
    b. Signed and dated PICD obtained prior to performing any study-related procedure, including SCR.
    E.4Principal exclusion criteria
    1. Patients with acute or sub-acute liver failure without underlying cirrhosis;
    2. Presence of the following organ failure(s) as per the EASL-CLIF criteria and/or adapted from CLIF-C OF/CLIF-SOFA scores:
    a. Respiratory failure as defined by Partial pressure of oxygen (PaO2)/Fraction of inspired oxygen (FiO2) ≤ 200, or oxygen saturation (SpO2)/FiO2 ≤ 214 or mechanical ventilation;
    b. Coagulation failure with an INR > 3.0 or platelet count ≤ 20 x 109/L;
    c. Severe cardiovascular failure requiring the use of vasopressors (dopamine >15 µg/kg/min, or epinephrine > 0.1 µg/kg/min, or norepinephrine > 0.1 µg/kg/min). It should be clarified that the use of terlipressin or low-dose norepinephrine in case of hepatorenal syndrome (HRS) is not an exclusion criterion;
    d. HE West Haven grade 4
    3. ACLF grade 3: Presence of three or more organ failures as per EASLCLIF criteria as described in the EASL-Clinical Practice Guideline on decompensated liver cirrhosis; organ failures will be calculated based on CLIF-C OF score);
    4. Presence of spontaneous or secondary bacterial peritonitis:
    a. presence of neutrophils in a normally sterile body fluid (i.e., neutrophil counts > 250/mm3 in ascitic fluid);
    5. Presence of spontaneous bacterial pleural empyema:
    a. 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 3 > 500/mm in the absence of pneumonia;
    6. Patients with medical history of spontaneous bacterial peritonitis over the past 4 weeks;
    7. Known active tuberculosis, or latent tuberculosis requiring treatment;
    8. Presence of uncontrolled severe infection at SCR or BL (patients may be enrolled provided anti-infectives have been administered for at least 24 h before SCR or 48 h before BL with an appropriate response prior to randomization):
    a. Infections with hemodynamic instability or septic shock, such as but not limited to UTI, pneumonia, and skin/soft tissue infection;
    b. 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;
    c. Patients with sepsis or septic shock of unknown source;
    9. Patients with known seizure disorder;
    10. Patients with medical history of gastro-intestinal bleeding over the past 2 weeks, acute bleeding or bleeding upon paracentesis at SCR or BL;
    11. Contraindication for paracentesis according to the EASL Clinical Practice Guidelines 2018, and AASLD guideline on the treatment of ascites, spontaneous bacterial peritonitis and HRS-AKI for the management of patients with decompensated cirrhosis;
    12. Coagulation disorders such as disseminated intravascular coagulation (DIC) or hemophilia;
    13. TIPS procedure or any major abdominal surgery having occurred in the past 4 weeks prior to SCR;
    14. Potential or known hypersensitivity to liposomes;
    15. Potential or known risk factors for allergic/anaphylactoid like reactions (e.g., mastocytosis/elevated basal tryptase) or multiple hypersensitivities;
    16. Patients with known porto-pulmonary hypertension (PPHT) and hepato-pulmonary syndrome;
    17. Patients after organ transplantation receiving immunosuppressive medication;
    18. 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, individuals formerly injecting drugs on substitution therapy;
    19. Need for RRT or any extracorporeal liver support device (e.g., MARS ® , Prometheus® , Plasmapheresis);
    20. Alfapump ® in place to manage ascites;
    21. ACLF due to severe alcoholic steatohepatitis in patients with ongoing excessive alcohol intake with a Maddrey Score ≥ 32 requiring steroid treatment (Score formula: Discriminant Function=4.6 * [Patient's Prothrombin time (sec) - Control Prothrombin time (sec)] + total bilirubin (mg/dl)
    22. ACLF due to acute viral hepatitis A, B, B+D, C or E requiring antiviral treatment;
    23. ACLF due to autoimmune hepatitis (AIH) requiring high-dose steroid treatment;
    24. Pregnancy and lactation;
    25. Women of child-bearing potential who are not willing to use
    adequate contraception;
    26. Patients who participate in another clinical trial at the time of SCR or within 4 weeks prior to SCR.
    E.5 End points
    E.5.1Primary end point(s)
    CLIF-C ACLF score at Day 7
    E.5.1.1Timepoint(s) of evaluation of this end point
    CLIF-C ACLF score Day 7
    E.5.2Secondary end point(s)
    1. Outcome:
    a) 90 day - mortality;
    b) 28 day - mortality;
    c) Time to death through Day 90;
    d) Time to death through Day 28;
    e) Change in ACLF grade through/at Days 7 and 28:
    - Rate of ACLF resolution;
    - Time to ACLF resolution;
    - Rate of ≥ one ACLF grade regression;
    -Time to ≥ one ACLF grade regression;
    f) Transplant-free survival through/at Day 90;
    g) Transplant-free survival through/at Day 28;

    2. Safety
    a) Incidence rate, severity, and relationship to VS-01 of adverse drug
    reactions and serious adverse drug reactions.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Outcome:
    a) 90 day - mortality;
    b) 28 day - mortality;
    c) Time to death through Day 90;
    d) Time to death through Day 28;
    e) Change in ACLF grade through/at Days 7 and 28:
    - Rate of ACLF resolution;
    - Time to ACLF resolution;
    - Rate of ≥ one ACLF grade regression;
    -Time to ≥ one ACLF grade regression;
    f) Transplant-free survival through/at Day 90;
    g) Transplant-free survival through/at Day 28;

    2. Safety
    - All AEs will be collected by the Investigator throughout the study period starting from the date of consent until the EOS visit on Day 90
    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
    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 EEA18
    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
    Belgium
    France
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    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: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Liver cirrhosis patients with ACLF grades 1 and 2 or grade 1 and grade 2 are enrolled. Patients with HE Grades 2-3 and require legal rep to give
    consent. Considering the rapid life-threatening evolution of ACLF they may be in ER situation.
    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 47
    F.4.2.2In the whole clinical trial 60
    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.
    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 Decision2021-11-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-08-17
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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