Safety and Performance Trial of DIALIVE Liver Dialysis Device in Acute On Chronic Liver Failure Patients

Study Overview
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Brief Summary
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The First-In-Man study is a multi-centre, randomised, controlled, study to generate data for the evaluation of safety and performance of DIALIVE Liver Dialysis Device in 24 evaluable patients with Acute on Chronic Liver Failure (ACLF) versus standard of care (SOC).

Detailed Description
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The First-In-Man study will evaluate the safety and performance of DIALIVE Liver Dialysis Device in Acute on Chronic Liver Failure (ACLF) patients and will compare the outcome with patients treated under standard of care (SOC). The hypothesis is that DIALIVE will significantly improve the prognosis of ACLF patients by modulating systemic inflammation. The target patient population are men and women ≥18 years, ≤81yr. Patients with ACLF grade 1 and ACLF grade 2 on the background of alcoholic cirrhosis. During the study, inclusion criteria were expanded to include also AKI-1 and ACLF 3a patients. Treatment will be undertaken in an intensive care (ICU) or renal dialysis unit setting if the patients are randomised to the DIALIVE treatment arm. For patients randomised to the 'Standard of care' arm, the location of treatment (ICU or general ward) will be determined by their clinical need and will be decided by the site Principal Investigator. This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 733057.

Official Title
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A Multi-centre, Randomised Controlled Study, to Evaluate the Safety and Performance of The DIALIVE Liver Dialysis Device (LDD) in Patients With Acute on Chronic Liver Failure (ACLF) Versus Standard of Care (SOC)

Conditions
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Acute on Chronic Liver Failure

Intervention / Treatment
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* Device: DIALIVE Liver Dialysis Device


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects aged ≥18 years ≤81yr who have given informed consent to participate in the study and are able to understand and comply with the requirements of the study (otherwise written informed consent must be obtained on behalf of the subject in accordance with local ethical and legal requirements). History indicative of alcohol-related cirrhosis based on clinical, radiological and/or histological evidence. History of an acute decompensating event (including but not limited to ascites, gastrointestinal bleeding, hepatic encephalopathy and/or acute bacterial infections), occurring within ≤6 weeks of screening. • Subject with : ACLF Grade 1, 2 or 3a defined per the CLIF-C OF scoring system OR single hepatic organ failure for serum bilirubin > 20 mg/dL (342 µmol/L) at screening and randomization, OR AKI-stage 1b (sCr > 1.5 mg/dL or 134 µmol/L). Where a subject has received corticosteroids for alcohol-induced ACLF, is unresponsive to at least 7 days of treatment (where lack of response defined as Lille score > 0.45 or steroids stopped before 7 days due to any complication such as infection). This refers to the first course of corticosteroid therapy only. Exclusion Criteria: Co-infection with HIV and AIDS defining illness. Subjects with acute or sub-acute liver failure without underlying cirrhosis. Subjects with severe thrombocytopaenia, defined by the platelet count of < 40,000 / mm3 or rapid reduction in platelet count (> 50% reduction) 24 hrs prior to inclusion. Subjects with International Normalised Ratio (INR) > 3 ACLF 3b patients, i.e. ACLF with more than 3 organ failures. Subjects with cirrhosis who develop decompensation at any time in the post-operative period following partial partial liver resection or major non-liver surgery. Subjects with uncontrolled infection. Patients may be entered into the study provided antimicrobials have been administered for at least 48 hours with an appropriate response observed prior to randomization. Subjects with respiratory organ failure (as per CLIF-C OF scoring: PaO2/FiO2< 200 mmHg or 27 kPa or SaO2/FiO2 < 214). Subjects with haemodynamic instability: i) persistent hypotension (mean arterial pressure < 65 mmHg) with evidence of tissue hypoperfusion, not responsive to volume resuscitation and/or low dose vasopressor support; ii) a norepinephrine dose of > 0.2 µg/kg/min, or a second pressor (terlipressin for variceal haemorrhage and/or hepato-renal syndrome does not count as pressor, unless it is specifically used to treat systemic hypotension) at screening or randomization. Patients can be reconsidered for study inclusion after at least a 24 hour period of norepinephrine requirement < 0.2 µg/kg/min. Subjects not considered appropriate for full active treatment including organ support or those with a Do Not Attempt Cardio-Pulmonary Resuscitation order (DNACPR). Subjects with active, or with a history of non hepatic malignancy unless adequately treated or in complete remission for five or more years. Patients with HCC outside Milan criteria. Significant systemic or major illness other than liver disease, including coronary artery disease, cerebrovascular disease, pulmonary disease, renal failure, serious psychiatric disease, that, in the opinion of the Investigator would preclude the subject from participating in and completing the study. Subject who has received any investigational drug or device within 30 days of dosing or who is scheduled to receive another investigational drug or device in the course of the study; concomitant observational studies are allowed. Evidence of uncontrolled seizures. Subjects diagnosed with Creutzfeldt-Jakob disease. In females: known pregnancy or lactating. Subjects weighing less than 30 kg (as per contra-indications of oXiris and septeX) Where subjectspresent with a known allergy to heparine of have type II thrombocytopaenia caused by heparin (HIT syndrome type II) In the opinion of the investigator, it is unsafe for the patient to be considered for the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 81 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Device Feasibility
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The design is a multi-centre, randomised, controlled, study to generate data for the evaluation of safety (as measured by the percentage of subjects who experience at least one serious adverse event (SAE)) and performance (as measured by lowering of the plasma endotoxin concentrations, and improved albumin function) of DIALIVE in 24 evaluable patients with Acute on Chronic Liver Failure (ACLF) versus standard of care (SOC). During the study the sample size was increased to include a total 30 evaluable patients.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard of Care<br>For patients with ACLF grade 1 or 2 and randomised to the 'Standard of care' arm, the location of treatment (ICU or general ward) will be determined by their clinical need and will be decided by the site Principal Investigator. They will receive standard of care. | |
| Active Comparator: DIALIVE Liver Dialysis Device treatment arm<br>Patients with ACLF grade 1 and ACLF grade 2 on the background of alcoholic cirrhosis randomized to the DIALIVE arm will receive treatment in an intensive care (ICU) or renal dialysis unit setting. They will receive DIALIVE treatment according to a fixed treatment schedule over a period of 10 days post-randomization. | Device: DIALIVE Liver Dialysis Device<br>* ACLF patients will receive dialysis treatment for 8-12 hrs/day and on three to five consecutive days over a 10-day time period. Dialysis treatment is performed by using the DIALIVE device provided by YAQRIT Ltd.<br>* Other names: YAQ 002;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of DIALIVE in terms of percentage of ACLF patients experiencing serious adverse events during DIALIVE treatment period. | To evaluate the safety of the DIALIVE device in patients with Acute on Chronic Liver Failure Grades 1 and 2 (ACLF). Outcome measure is: The percentage of subjects who experience at least one (1) serious adverse event (SAE) between Day 1 and Day 10.(DIALIVE arm only). Outcome is measured on day 10 and compared between treatment arms. | Treatment period is from 1 to 10 days post-randomization. | 
| Safety of DIALIVE in terms of percentage of ACLF patients who discontinued treatment due to severe adverse event. | The outcome measure is the percentage of subjects who discontinued DIALIVE treatment due to a serious adverse device event (SADE) between Day 1 (first day of treatment) and Day 10.(DIALIVE arm only) | Treatment period is from 1 to 10 days post-randomization. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Performance of DIALIVE by assessing removal of endotoxins. | To evaluate the performance of the DIALIVE device in patients with ACLF (DIALIVE arm only). Outcome measure is : - Change in Plasma endotoxin concentrations between end of treatment with DIALIVE and the beginning of treatment with DIALIVE (Day 1). TV: 40% reduction; AV: 20% reduction | End of DIALIVE treatment (max 10 days after randomization) | 
| Performance of DIALIVE by assessing removal of albumin. | To evaluate the performance of the DIALIVE device in patients with ACLF (DIALIVE arm only). Outcome measure is : - Change in Albumin function (Human non-mercapt albumin -2 (HNA-2) / Human mercapt albumin (HMA ratio) between end of treatment with DIALIVE and the beginning of treatment with DIALIVE (Day 1) | End of DIALIVE treatment (max 10 days after randomization) | 
| Change in Clinical Parameters by DIALIVE treatment (ACLF grade and score) between treatment arms. | Evaluate the improvement in clinical parameters between Acute on Chronic Liver Failure (ACLF) patients receiving DIALIVE treatment vs Standard of Care. Outcome measure is: - Change in CLIF-C score (Chronic LIver Failure Consortium) | Treatment period is from 1 to 10 days post-randomization | 
| Change in Clinical Parameters by DIALIVE treatment (ACLF grade) between treatment arms. | Evaluate the improvement in clinical parameters between Acute on Chronic Liver Failure (ACLF) patients receiving DIALIVE treatment vs Standard of Care. Outcome measure is: - Change in ACLF Grade | Treatment period is from 1 to 10 days post-randomization | 
| Change in mortality between treatment arms. | The outcome measure is the difference in mortality between the DIALIVE treatment arm and the Standard of Care arm at day 28 post-randomization. During the study, the follow up period was prolonged to 90 days (3 months). | At day 28 post-randomization (for all patients). At day 90 for those patients enrolled under protocol version 6.0. | 
| Change in Clinical Parameters by DIALIVE treatment (CLIF-C score) between treatment arms. | Evaluate the improvement in clinical parameters between Acute on Chronic Liver Failure (ACLF) patients receiving DIALIVE treatment vs Standard of Care. Outcome measure is: - Change in CLIF-C score (Chronic LIver Failure Consortium) | Treatment period is from 1 to 10 days post-randomization | 
| Status of ICU and hospital discharge. | Location of patient at day 28 and 90 post randomization, and timing of discharge from hospital. | Treatment period is from 1 to 90 days post-randomization. | 
| Length of stay in ICU and in hospital | Evaluation of length of stay of patient in the hospital and on the ICU. | Assessment is done on day 28 and day 90. | 
| ICU and hospital re-adminssions with another episode of ACLF | Assessment of re-admissions of patients for another episode of ACLF after hospital discharge post-randomization. | Assessment is done on day 28 and day 90. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Medical device, Liver dialysis, Haemofilter, ACLF