A Novel Extracorporeal Liver Support Therapy In ALCF and to Evaluate the Efficacy of DIALIVE 2.0, a Liver Dialysis Device.

This study is intended to demonstrate the efficacy and safety of the DIALIVE Liver Dialysis Device when incorporated into the standard management plan for participants with A-TANGO ACLF grade 2-4. A total of 72 evaluable participants, aged 18-70, will be enrolled in up to 12 clinical centres in the United Kingdom. Participants must have a history of liver cirrhosis and a deterioration within four weeks due to a precipitating event, leading to A-TANGO ACLF grade 2-4. Multicenter, individually randomised, controlled, open-label, parallel group trial using double-arm design. The control group will receive SoC for participants with ACLF. The DIALIVE 2.0 treatment group will receive SoC with the addition of up to 7 (seven) daily DIALIVE 2.0 treatment sessions within the 10-day treatment window. Seventy-two participants with ACLF (60% A-TANGO ACLF grade 2 at randomisation, and 40% A-TANGO ACLF grade 3 \& 4 at randomisation) will be randomised 1:1 to receive either SoC or SoC + DIALIVE 2.0. This allows for 5% loss due to drop-out, and 5% censoring due to liver transplantation within 28 days. All randomised participants will be included in the intention to treat (ITT) analysis while all participants that receive at least one treatment cycle will be used for the safety population. For each participant, the study duration will be up to 105 days (screening: 5 days; treatment up to 10 days; follow up 90 days). The total study duration is estimated to be approximately 18 months from screening of first participant until study completion of the last participant.

Inclusion Criteria: * Adults aged 18-70 years, with a diagnosis of ACLF grade 2-4 (according to A-TANGO ACLF criteria, APPENDIX 1) * ACLF non-responsive to SoC for up to 48 hours prior to developing grade 2-4 ACLF. * Inclusion within 10 days from the onset of A-TANGO ACLF grade ≥ 2. Exclusion Criteria: * A-TANGO ACLF grade ≥2 for more than 10 days prior to inclusion * Pregnancy * Co-infection with HIV and AIDS defining illness i.e. CD4+ T-cell count below 200 cells/µL, a CD4+ T-cell percentage of total lymphocytes of less than 15%, or one of the defining illnesses such as PCP, Kaposi's sarcoma, CMV, Candidiasis etc. * Bacterial infection or sepsis unresponsive to treatment with antimicrobials for 48 hours indicated by (a) persistent pyrexia (b) rising white cell count, creactive protein and lactate (c) persistently positive cultures for bacteria or fungi and/or (d) worsening clinical state indicated by escalating requirement for fluid resuscitation, increasing vasopressors requirements or increasing organ support. * Invasive fungal infection (clinical or radiological evidence, not solely biomarker positivity such as BDG or galactomannan) * Acute or sub-acute liver failure in the absence of cirrhosis * Post-hepatectomy liver failure or primary non-function following transplantation * Previous liver transplant * Severe thrombocytopaenia (absolute platelet count \ 50% reduction within the preceding 24 hrs) * INR \>3.0, unless sustained correction for \>24 hours following FFP/PCC treatment * Severe disseminated intravascular coagulopathy (DIC) * Persistent haemodynamic instability as defined by: (i) Norepinephrine(NE) dose \>0.5µg/kg/min, or, (ii) If a second pressor is used, a composite Norepinephrine equivalence index (NEEI) of dose \>0.5µg/kg/min (iii) Arterial lactate level \>4mmol/L despite 24 hours of adequate fluid resuscitation and pressor therapy * Severe respiratory failure: PaO2/FiO2 (P/F) ≤ 200 mmHg or 27kPa * Established on renal replacement therapy for longer than 24 hours prior to inclusion * A-TANGO WCC ACLF score \>64 (APPENDIX 1) * Significant and/or uncontrolled bleeding (participants can be enrolled 48 hours after bleeding is controlled) * Active or prior history of non hepatic malignancy unless adequately treated or in complete remission for five or more years * HCC outside of Milan criteria. * Acute, extensive, portal vein thrombosis extending to and occluding superior mesenteric vein * Major systemic illness, aside from liver disease, that in the opinion of the investigator would preclude the participant from participating in the study (e.g. coronary artery disease, cerebrovascular disease, chronic pulmonary disease, chronic kidney disease, serious psychiatric disease) * Pre-existing chronic kidney disease (CKD) defined as eGFR (estimated glomerular filtration rate) \5) * Severe malnourishment (BMI\