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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Liver Cirrhosis; Kidney Failure, Acute; Multi Organ Failure; Kidney Replacement
• Intervention / Treatment: Device: Hemodialysis; Device: ADVOS

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 14
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Julia Weinmann-Menke, Prof.; Phone Number: 0049 06131 17 2213; Email: julia.weinmann-menke@unimedizin-mainz.de
• Study Contact Backup: Name: Pascal Klimpke, M.D.; Phone Number: 0049 06131 17 2213; Email: pascal.klimpke@unimedizin-mainz.de

Study Locations

• Germany
  • Rheinland-Pfalz
    • Mainz, Rheinland-Pfalz, Germany, 55130
      • Recruiting
      • UNIVERSITÄTSMEDIZIN der Johannes Gutenberg-Universität Mainz I. Medizinische Klinik und Poliklinik
      • Contact: Julia Weinmann-Menke, Prof. Dr.; Phone Number: 00496131/172462; Email: julia.weinmann-menke@unimedizin-mainz.de
      • Contact: Simone Cosima Boedecker, Dr.; Phone Number: 00496131/172213; Email: SimoneCosima.Boedecker@unimedizin-mainz.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Medical Center Mainz
• Collaborators: ADVITOS GmbH München
• Investigators: Principal Investigator: Julia Weinmann-Menke, Prof., Principal Investigator

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2023
• Primary Completion (Estimated): June 1, 2025
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: June 21, 2023
• First Submitted That Met QC Criteria: November 8, 2023
• First Posted (Estimated): November 13, 2023

Study Record Updates

• Last Update Posted (Estimated): November 13, 2023
• Last Update Submitted That Met QC Criteria: November 8, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Kidney Diseases; Urologic Diseases; Shock; Fibrosis; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Liver Diseases; Liver Cirrhosis; Renal Insufficiency; Acute Kidney Injury; Multiple Organ Failure
• Other Study ID Numbers: ADVOMITTENT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No