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

Phase 3Not Yet RecruitingNCT07347275

Yaqrit Ltd72 enrolled

Overview

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.

DIALIVE 2.0 is an innovative liver dialysis device that specifically targets the underlying mechanisms of acute-on-chronic liver failure. The novelty of DIALIVE 2.0 lies in the combined use of a commercially available high cutoff filter and an extracorporeal endotoxin adsorber integrated into a hemofiltration and plasmapheresis platform. This allows controlled extracorporeal circulation of the participant's blood, during which the system removes dysfunctional, toxin-bound albumin and circulating endotoxins, while simultaneously replenishing functional albumin. The result is a comprehensive therapeutic approach that addresses both immune dysregulation and impaired albumin detoxification capacity in acute-on-chronic liver failure. This treatment concept is referred to as Selective Plasma filtration, Endotoxin Adsorption, and Albumin Replacement (SPEAR), reflecting the three core processes that underpin DIALIVE 2.0's mode of action. DIALIVE 2.0 is delivered as a daily treatment lasting six to eight hours, with a plasma filtration dose equivalent to 5% of the participant's ideal body weight. Albumin is replaced at a dose of one gram per kilogram of body weight using a 20% human albumin solution to offset albumin losses and maintain oncotic pressure. To address coagulation factor depletion observed in preclinical studies (see Investigators Brochure), one unit of fresh frozen plasma is administered at the end of each session to restore haemostatic balance. The DIALIVE 2.0 system includes the following components: * Medica FRACTIOsmart Small 1.0 haemodialyser with a high cut-off membrane (150 to 200 kilodaltons), used for the removal of albumin-bound toxins and medium-sized inflammatory molecules. This component is commercially available under European certification MDR 00048-A. * Alteco® Medical LPS Adsorber, an extracorporeal filter designed for the selective removal of circulating endotoxin in conditions where endotoxemia is suspected or confirmed. This is a commercially available device certified under CE 0402, (awaiting MHRA registration). * Medica AFERsmart Plus™ System, a plasmapheresis platform that controls flow rates, treatment duration, and pressure regulation. This is commercially available, and CE marked under number 0476. * Medica AFERsmart Standard TPE Line, a sterile, CE-marked disposable tubing set compatible with the AFERsmart Plus device. * Male to male tubing set, and absorber connector, (pending commercial approval).

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

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 \<20,000/mm3 at screening) or evidence of rapid decline in 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) \<30 mL/min for 3 months or longer prior to screening * Severe frailty (Clinical Frailty Scale, CFS\>5) * Severe malnourishment (BMI\<18) * Participants not considered appropriate for full active treatment including organ support * Participants who have a "do not attempt cardio-pulmonary resuscitation" order in place * Any participant who has received an investigational drug or device within 30 days, or who is scheduled to receive another investigational drug or device during the course of the study (concomitant observational studies are allowed) * Uncontrolled seizures * Evidence of new intracranial pathology such as cerebral hemorrhage or infarction. * Participants diagnosed with Creutzfeldt-Jakob disease. * Participants unable to consent for themselves, unless a legal representative/consultee is appointed and approved as dictated by local and national legislation. * Known allergy to heparin, or type II thrombocytopaenia caused by heparin (HIT syndrome type II). * In the opinion of the investigator, recruitment to the the study would be unsafe for the participant.

Outcomes

Primary Outcomes

Change in the proportion of participants with resolution of ACLF following DIALIVE 2.0 treatmen

Assessment of the change in the proportion of participants achieving resolution of ACLF following treatment with DIALIVE 2.0 plus standard of care (SoC) within 10 days of treatment.

Time frame: From Baseline to within 10 Days

Secondary Outcomes

Transplant-free survival following DIALIVE 2.0 treatment plus standard of care compared with standard of care alone

Assessment of transplant-free survival in participants treated with DIALIVE 2.0 plus standard of care (SoC) compared with participants treated with SoC alone.

Time frame: From enrollment through Day 90 for each participant (assessed at Day 28 and Day 90)

Incidence of serious adverse events (SAEs) following DIALIVE 2.0 treatment

Assessment of the incidence of treatment-emergent serious adverse events in participants receiving DIALIVE 2.0 plus standard of care (SoC).

Time frame: From baseline through Day 90 for each participant (assessed at Day 28 and Day 90)

Predicted six-month and one-year survival following DIALIVE 2.0 treatment plus standard of care compared with standard of care alone

Assessment of predicted six-month and one-year survival rates in participants treated with DIALIVE 2.0 plus standard of care (SoC) compared with participants treated with SoC alone.

Time frame: Predicted at baseline using data collected through Day 28 for each participant

Time to discharge from ICU and/or hospital following DIALIVE 2.0 treatment plus standard of care compared with standard of care alone

Assessment of time to discharge from the intensive care unit (ICU) and/or hospital in participants treated with DIALIVE 2.0 plus standard of care (SoC) compared with participants treated with SoC alone.

Time frame: From baseline until discharge from ICU and/or hospital, assessed up to Day 28 for each participant

Resolution of individual organ failures following DIALIVE 2.0 treatment plus standard of care compared with standard of care alone

Assessment of the proportion of participants with resolution of individual organ failures in participants treated with DIALIVE 2.0 plus standard of care (SoC) compared with participants treated with SoC alone.

Time frame: From baseline through Day 28 for each participant

Resolution of A-TANGO ACLF grade 2-4 following DIALIVE 2.0 treatment plus standard of care compared with standard of care alone

Assessment of resolution from A-TANGO ACLF grade 2-4 to absence of ACLF in participants treated with DIALIVE 2.0 plus standard of care (SoC) compared with participants treated with SoC alone.

Time frame: From baseline through Day 10 for each participant

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

Overview

Conditions

Interventions

Eligibility

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts