A clinical study to evaluate a new medicinal product VS-01 in patients withan acute episode on top of a chronic liver disease (called acute-on-chronicliver failure) who experience accumulation of fluid in the abdominal cavity(called ascites) as well as intellectual, behavioral decay and physicaldecay.

Phase 1

Conditions: 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.
MedDRA version: 24.0Level: PTClassification code 10077305Term: Acute on chronic liver failureSystem Organ Class: 10019805 - Hepatobiliary disorders
Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]

Registration Number: EUCTR2021-002617-33-FR

Lead Sponsor: Versantis AG

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 60

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 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 or 4) + kidney dysfunction
(serum creatinine = 1.5 - < 2.0 mg/dL).
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 or 4) + 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 or 4);
g. Liver failure (serum bilirubin = 12.0 mg/dL) + brain failure (HE
West Haven grade 3 or 4);
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) + Brain failure (HE West Haven
grade 3 or 4);
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, liver failure, or brain failure.
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 (calculated on dry body
weight);
6. Men and women = 18 and = 64 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 PICD. If the patients
are temporarily unable to consent and are considered in an
emergency situation, they will be included according to local law and EC requirements and need to consent as soon as they are able again to do so themselves or by legal representative who can sign the PICD
on behalf of the patient. If legal representative consented on behalf of the patient, consent must also

Exclusion Criteria

1. Patients with acute or sub-acute liver failure without underlying
cirrhosis;
2. Presence of the following organ(s) failure(s) as per the EASL definitions and CLIF-C OF score:
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 09/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;
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. History of active tuberculosis, or latent tuberculosis requiring
treatment;
8. Presence of uncontrolled and severe infection at SCR or BL (patients may be enrolled provided antibiotics 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. History of colonization (> 2 sites) or known invasive fungal infection;
d. Patients with sepsis or septic shock of unknown source;
9. Patients with epilepsy;
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, 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), hemophilia, congenital or acquired Von Willebrand
disease or platelet function defects;
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 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)

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the efficacy of VS-01 administered intraperitoneally (i.p.)<br>daily over 4 days on top of standard of care (SOC) vs. SOC alone in<br>patients with ACLF grades 1 and 2 as measured by Chronic Liver Failure<br>Consortium Acute on-Chronic Liver Failure (CLIF-C ACLF) score at Day 7;Secondary Objective: - To evaluate the efficacy of VS-01 administered i.p. daily over 4 days on<br>top of SOC vs. SOC alone in patients with ACLF grades 1 and 2 with<br>respect to:<br>a. Time to death through/at Days 28 and 90;<br>b. ACLF grade change and time to resolution of ACLF;<br>c. 28-day and 90-day mortality;<br>d. Transplant-free survival;<br>- To characterize the safety and tolerability of VS-01 in ACLF patients<br>following i.p. administration of VS-01;Primary end point(s): CLIF-C ACLF score at Day 7 ;Timepoint(s) of evaluation of this end point: CLIF-C ACLF scores on Day 1 pre-dose and Day 7.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): 1. Outcome:<br>a) Time to death through/at Days 28 and 90;<br>b) Change in ACLF grade through/at Days 7 and 28:<br>- Time to and rate of ACLF resolution;<br>-Time to and rate of = one ACLF grade regression;<br>c) 28-day and 90-day mortality;<br>d) Transplant-free survival through/at Days 28 and 90;<br>2. Safety<br>a) Incidence rate, severity, and relationship to VS-01 of adverse drug<br>reactions and serious adverse drug reactions.;Timepoint(s) of evaluation of this end point: 1. Outcome:<br>- Time to death: through/at Days 28 and 90;<br>- Change in ACLF grade: through/at Days 7 and 28<br>- 28-day and 90-day mortality;<br>- Transplant-free survival: through/at Days 28 and 90<br>2. Safety<br>- All AEs will be collected by the Investigator throughout the study<br>period starting from the date of consent until the EOS visit on Day 90