Intermittent ADVOS vs. Hemodialysis in Non-intensive Care Patients With Liver Dysfunction

Study Overview
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Brief Summary
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In the planned randomized controlled prospective pilot study, we aim to evaluate ADVOS compared with conventional hemodialysis regarding the elimination of protein-bound toxins in patients with therapy-refractory hepatorenal syndrome. The study will be performed in a regular non-ICU ward with a large experience in the use of the ADVOS therapy.

Detailed Description
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Acute on chronic liver failure (ACLF) is a syndrome in patients with liver cirrhosis characterized by acute hepatic decompensation (i.e., jaundice, ascites, hepatic encephalopathy, bacterial infection, or gastrointestinal bleeding) and single or multi-organ failure, resulting in increased mortality. The European Association for the Study of the Liver (EASL) has established the Chronic Liver Failure (CLIF) consortium, which has developed a score for risk stratification and prognosis estimation, the CLIF-C ACLF score. Based on the CANONIC study, the CLIF consortium has developed a simplified CLIF Consortium Organ Failure Score (CLIF-C OFs), which includes liver, kidney, and lung function, hepatic encephalopathy, coagulation, and hemodynamics. Considering two other mortality factors (age and leukocyte count), the CLIF-C ACLF score was defined. The score has a higher predictive value for 28- and 90-day mortality than the Model of End Stage Liver Disease (MELD), MELD-Na, or Child-Turcotte-Pugh score. Therapeutic options are limited and aim to address specific organ complications. In most cases, due to progressive renal insufficiency as part of hepatorenal syndrome, renal replacement therapy is if indicated. The only potential cure is liver transplantation. There is some evidence that extracorporeal liver support can help a patient until liver transplantation or restoration of organ function. The Advanced Organ Support (ADVOS) system (ADVITOS GmbH, Munich, Germany) is an albumin-based advanced hemodialysis procedure, which can support the liver. The principles of conventional renal replacement therapy for the elimination of water-soluble substances are combined with the elimination of protein-bound substances by recirculating a dialysate containing 200 ml of human albumin. This procedure is typically used as continuous treatment in an intensive care setting. However, the investigators have already investigated the possibility of ADVOS as an intermittent procedure in patients with ACLF on a regular ward in a retrospective study. To the best of knowledge of the investigators, there are currently no randomized studies comparing the elimination of protein-bound toxins between ADVOS and hemodialysis. Nevertheless, based on the investigators clinical experience, the investigators hypothesize that treatment with ADVOS may confer advantages over hemodialysis. Therefore, the objective of this study is to assess the effectiveness of ADVOS in comparison to hemodialysis for the treatment of patients with therapy-refractory hepatorenal syndrome.

Official Title
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Prospective Randomized Controlled Trial for Protein-bound Toxins Removal With Intermittent ADVOS vs. Hemodialysis Treatment in Non-intensive Care Patients With Pre-existing Liver Dysfunction and Indication for Extracorporeal Renal Support. The ADVOMITTENT Study

Conditions
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Liver Cirrhosis, Kidney Failure, Acute, Kidney Replacement, Multi Organ Failure

Intervention / Treatment
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* Device: Hemodialysis
* Device: ADVOS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capacity of the patient to give consent Pre-existing liver disease in the sense of an ACLF with HRS Age >18 years Patient of the University Medical Center Mainz Bilirubin level ≥ 4 mg/dl Indication for renal replacement procedure is based on STARRT-AKI criteria (serum potassium ≥ 6 mmol/l in two independent blood samples; serum pH of 7.2 or less or serum bicarbonate of 12 mmol/l or less; respiratory failure secondary to volume excess) Exclusion Criteria: Age < 18 years Pregnancy Contraindications for ADVOS therapy Already started renal replacement therapy Contraindication for citrate anticoagulation Use of vasopressors and MAD ≤ 50 mmHg. Terminal cancer

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Hemodialysis<br>Patients receiving hemodialysis therapy mit Fresenius 5008 | Device: Hemodialysis<br>* 5 treatments with hemodialysis on day 1, 2, 3, 5 and 7<br>|
| Experimental: ADVOS<br>Patients receiving ADVOS therapy with ADVOS multi | Device: ADVOS<br>* 5 treatments with ADVOS on day 1, 2, 3, 5 and 7<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| course of total bilirubin in patients blood | measurement of concentration of total bilirubin in serum of patients in mg/dl | Within 6 hours before first treatment and within 2 hours after every treatment session | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| course of uremia toxins in patients blood | measurement of blood urea nitrogen in serum of patients in mg/dl | Within 6 hours before first treatment and within 2 hours after every treatment session | 
| course of bile acids | measurement of bile acids in serum of patients in mg/dl | Within 6 hours before first treatment and within 2 hours after every treatment session | 
| evaluation of safety of ADVOS versus hemodialysis | Rate of complications during procedure (for example hypotension, electrolyte disorders etc.) | during the five interventions | 
| Quality of life raised in a standardized questionnaire | We will use the WHOQOL-BREF-questionnaire with 26 questions and values from 1 to 5; 1 being the lowes value and 5 the highest value | baseline before intervention and on days 28, 90, 180 | 
| number of days in hospital during the intervention | we will measure the number of days in the hospital during the intervention from admission to our department until discharge from our department | admission in our department till discharge from our deparment | 
| course of pO2 | we will measure the pO2 (in mmHg) in a blood sample with blood gas system (ABL800 FLEX Plus) | Within 6 hours before first treatment and within 2 hours after every treatment session | 
| course of pCO2 | we will measure the pCO2 (in mmHg) in a blood sample with blood gas system (ABL800 FLEX Plus) | Within 6 hours before first treatment and within 2 hours after every treatment session | 
| course of base excess | we will measure the base excess (mmol/l) in a blood sample with blood gas system (ABL800 FLEX Plus) | Within 6 hours before first treatment and within 2 hours after every treatment session | 
| course of pH | we will measure the pH in a blood sample with blood gas system (ABL800 FLEX Plus) | Within 6 hours before first treatment and within 2 hours after every treatment session | 
| course of standard bicarbonat concentration | we will measure the standard bicarbonat concentration (mmol/l) in a blood sample with blood gas system (ABL800 FLEX Plus) | Within 6 hours before first treatment and within 2 hours after every treatment session | 
| course of potassium | we will measure the potassium (mmol/l) in a blood sample with blood gas system (ABL800 FLEX Plus) | Within 6 hours before first treatment and within 2 hours after every treatment session | 
| course of sodium | we will measure the sodium (mmol/l) in a blood sample with blood gas system (ABL800 FLEX Plus) | Within 6 hours before first treatment and within 2 hours after every treatment session | 
| course of ionised calcium | we will measure the ionised calcium (mmol/l) in a blood sample with blood gas system (ABL800 FLEX Plus) | Within 6 hours before first treatment and within 2 hours after every treatment session | 
| course of bilirubin | we will measure the bilirubin (in mg/dl) in a blood sample | Within 6 hours before first treatment and within 2 hours after every treatment session | 
| course of INR | we will measure the INR in a blood sample | Within 6 hours before first treatment and within 2 hours after every treatment session | 
| course of albumin | we will measure the albumin (in g/l) in a blood sample | Within 6 hours before first treatment and within 2 hours after every treatment session | 
| course of kidney function | we will measure the kreatinine (in mg/dl) in a blood sample | Within 6 hours before first treatment and within 2 hours after every treatment session | 
| course of MELD | MELD = Model for End-stage Liver Disease (6-40, Higher numbers indicate increased mortality) | Within 6 hours before first treatment and within 2 hours after 5 treatments | 
| course of CLIF-C ACLF score | CLIF-C ACLF Score = Chronich Liver failure Consortium acute on chronic liver failure score (6-15, higher numbers indicate increased mortality) | Within 6 hours before first treatment and within 2 hours after 5 treatments | 
| course of hepatic encephalopathy | an experienced clinician will determine the grade of the hepatic encephalopathy using the west haven criteria (grade 1 till grade 4, grade 1 beeing the lowest value und grade 4 beeing the highest value) | Within 6 hours before first treatment and within 2 hours after every treatment session | 
| mortality |  | 28, 90 and 180 days. | 
| elimination of blood urea nitrogen | We will measure the Blood urea nitrogen (mg/dl) in a blood sample | Within 6 hours before first treatment and within 2 hours after every treatment session |