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.

Phase 1

Conditions: Acute-on-chronic liver failure (ACLF) is characterized by hepatic andextrahepatic organ dysfunction and/or failure and highly activatedsystemic inflammation. It leads to an accumulation of different metabolites, interalias ammonia, which cannot be metabolized.Hyperammonemia leads to Hepatic Encephalopathy (HE). ACLF is amajor 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-DE

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. 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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 50
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 10

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, extrahe

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 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;Secondary Objective: - 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:<br>a. Mortality rate;<br>b. Time to death;<br>c. ACLF grade change and time to resolution of ACLF;<br>d. Transplant-free survival;<br><br>- To characterize the safety and tolerability of VS-01 in ACLF patients following i.p. administration of VS-01<br> ;Primary end point(s): CLIF-C ACLF score at Day 7 ;Timepoint(s) of evaluation of this end point: CLIF-C ACLF score Day 7

Secondary Outcome Measures