E.1 Medical condition or disease under investigation |
E.1.1 | Medical 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. |
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E.1.1.1 | Medical 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. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 24.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10077305 |
E.1.2 | Term | Acute on chronic liver failure |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main 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 |
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E.2.2 | Secondary 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
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. |
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E.4 | Principal 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
CLIF-C ACLF score at Day 7 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary 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.
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E.5.2.1 | Timepoint(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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Controlled study on top of standard of care |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If 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 |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |