Cytokine Adsorption in Acute-on-chronic Liver Failure (CYTOHEP)

Cytokine Adsorption in Patients With Acute-on-chronic Liver Failure (CYTOHEP) - a Single Center, Open-label, Randomized, Controlled Intervention Trial

The CYTOHEP study is a prospective, randomized, single center, open-label, controlled intervention trial to assess the benefit of extracorporeal hemoadsorption using the CytoSorb device in patients with acute-on-chronic liver failure. The primary goal for this trial is to assess whether the CytoSorb device used in addition to continuous renal replacement therapy (CRRT) will be able to significantly reduce bilirubin in the patient blood as compared to the control group treated with CRRT alone (i.e., without extracorporeal hemoadsorption).

The rationale for this study is based on considerations about the role of systemic inflammation in acute decompensation of liver cirrhosis and ACLF, in-vitro data of the effectiveness CytoSorb for the removal of molecules with a pathophysiological role in acute-on-chronic liver failure, and recent reports on the successful use of extracorporeal hemoadsorption in combination with CRRT in critically ill patients with acute liver dysfunction.

Study Overview

• Status: Recruiting
• Conditions: Acute-On-Chronic Liver Failure; Renal Failure
• Intervention / Treatment: Device: CytoSorb cytokine adsorber; Device: CRRT

Detailed Description

Liver cirrhosis is a major healthcare problem. The clinical course of cirrhosis can be separated in compensated and decompensated cirrhosis. Patients with compensated cirrhosis are largely asymptomatic and the development of decompensating events is a major hallmark in the course of the disease as median survival decreases from 12 years to less than 2 years. The development of extrahepatic organ complications in decompensated cirrhosis has been identified as a major prognostic milestone and has been described as acute-on-chronic liver failure (ACLF). ACLF is understood as a dynamic process and may evolve within days leading to multi-organ failure with renal failure being the most common organ involvement (56%), followed by liver and coagulation failure (44% and 28%, respectively). ACLF is associated with a high 28-day mortality.

During recent years, systemic inflammation has been recognized as a major driver of hepatic decompensation and progression of liver cirrhosis to ACLF. Importantly, systemic inflammation was described as an important trigger for development of extrahepatic organ failures, such as renal failure, development of hepatopulmonary syndrome, cirrhotic cardiomyopathy and hepatic encephalopathy. Systemic inflammation is particularly relevant in the pathogenesis of acute hepatic decompensation and is also associated with reduced survival. Therefore, elimination of drivers of inflammatory response and inflammatory cytokines in addition to established therapeutic approaches aiming at a reduction of bacterial translocation and mitigation of portal hypertension may help control excessive inflammatory activity and thus support hepatic recompensation. Previous in-vitro examinations and studies in non-cirrhotic inflammatory disorders have shown that proinflammatory cytokines and other factors can effectively be removed by extracorporeal hemoadsorption in the CytoSorb adsorber.

The CYTOHEP study is designed as a prospective, randomized, single center, open-label, controlled intervention trial to assess the benefit of extracorporeal hemoadsorption using the CytoSorb device in patients with acute-on-chronic liver failure. The primary goal for this pilot trial is to assess whether the CytoSorb device used in addition to CRRT will be able to significantly reduce bilirubin in the patient blood as compared to the control group treated with CRRT alone (i.e., without extracorporeal hemoadsorption).

Within this trial, CRRT will be initiated early, i.e., in patients with acute kidney injury (AKI) Kidney Disease: Improving Global Outcome (KDIGO) stage 3. For safety assessment, a third group will be assessed without early initiation of CRRT and extracorporeal hemoadsorption. After trial inclusion, all patients will be randomized in a 1:1:1 fashion in one of the study groups.

• Study Type: Interventional
• Enrollment (Anticipated): 51
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Alexander Supady, MD, MPH; Phone Number: 34010 +49761270; Email: alexander.supady@uniklinik-freiburg.de
• Study Contact Backup: Name: Dominik Bettinger, MD; Phone Number: 34010 +49761270; Email: dominik.bettinger@uniklinik-freiburg.de

Study Locations

• Germany
  • Freiburg, Germany, 79108
    • Recruiting
    • University Clinic Freiburg
    • Contact: Alexander Supady, Dr., MPH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• adult patients (≥ 18 years) admitted to the University Medical Center Freiburg, Germany
• acute-on-chronic liver failure (ACLF) WITH acute kidney injury according to Kidney Disease: Improving Global Outcome (KDIGO) criteria stage 3 (≥ 3-fold increase of serum creatinine OR increase of serum creatinine to ≥ 4 mg/dl OR urine output ≤ 0.3 ml/kg/h for ≥ 24 hours OR anuria for ≥ 12 hours) AND serum bilirubin ≥ 5 mg/dl

Exclusion Criteria:

• known patient will against participation in the study or against the measures applied in the study
• a decision made prior to inclusion to stop further treatment of the patient within the next 24 hours
• no complete remission of malignancy including hepatocellular carcinoma within the past 12 months
• patients on the waiting list for liver transplant or the potential option for being listed for liver transplant within the next 6 months
• liver cirrhosis in patients after liver transplantation
• ongoing intermittent or continuous renal replacement therapy before study inclusion

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CRRT with cytokine adsorption; Patients will be treated with CRRT and extracorporeal hemoadsorption for 72 hours	Device: CytoSorb cytokine adsorber; device for extracorporeal hemoadsorption; Device: CRRT; continuous renal replacement therapy
Experimental: CRRT without cytokine adsorption; Patients will be treated with CRRT without extracorporeal hemoadsorption for 72 hours	Device: CRRT; continuous renal replacement therapy
No Intervention: no CRRT, no cytokine adsorption; Patients will not receive CRRT, nor extracorporeal hemoadsorption. CRRT will only be initiated in case of severe electrolyte disorders or unmanageable fluid overload

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum bilirubin	Serum bilirubin after 72 hours	72 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival time	Survival time from baseline	30 days
Interleukin-6	Interleukin-6 after 72 hours	72 hours
Liver function parameters	Quick/INR, AST, ALT, AP, g-GT	72 hours
Blood lactate	Lactate concentration after 72 hours	72 hours
CLIF-SOFA-score	CLIF-SOFA-score	72 hours
MELD score	MELD score	72 hours
SOFA score	SOFA score	72 hours
SAPS II	SAPS II	72 hours
FIPS score	FIPS score	72 hours
Ventilator free days	Ventilator free days (VeFD) in the first 30 days after randomization, where each day on invasive mechanical ventilation (IMV), non-invasive ventilation (NIV), or ECMO is defined as ventilator day. VeFD=0, if the patient dies in the first 30 days after randomization	30 days
vasopressor dosage	dosage of epinephrine, norepinephrine, dobutamine, argipressin and terlipressin	72 hours
Vasopressor free days	Vasopressor free days (VaFD) in the first 30 days after randomization, where each day with any dose of epinephrine, norepinephrine, dobutamine, argipressin or terlipressin is defined as vasopressor day. VaFD=0, if the patient dies in the first 30 days after randomization	30 days
Dialysis free days	Dialysis free days (DFD) in the first 30 days after randomization, where each day on renal replacement therapy (RRT) is defined as dialysis day. DFD=0, if the patient dies in the first 30 days after randomization	30 days
Inflammatory biomarkers	A biomarker panel of pro- and anti-inflammatory cytokines (blood samples will be frozen and stored for later analyses, panel will be determined at the time of analysis)	72 hours

Collaborators and Investigators

• Sponsor: Dr. Alexander Supady
• Investigators: Principal Investigator: Alexander Supady, MD, MPH, University Hospital Freiburg

Publications and helpful links

General Publications

• Sekandarzad A, Weber E, Prager EP, Graf E, Bettinger D, Wengenmayer T, Supady A. Cytokine adsorption in patients with acute-on-chronic liver failure (CYTOHEP)-a single center, open-label, three-arm, randomized, controlled intervention trial. Trials. 2022 Mar 18;23(1):222. doi: 10.1186/s13063-022-06139-6. Erratum In: Trials. 2022 Apr 15;23(1):319.

Study record dates

Study Major Dates

• Study Start (Actual): October 25, 2021
• Primary Completion (Anticipated): December 31, 2022
• Study Completion (Anticipated): January 30, 2023

Study Registration Dates

• First Submitted: August 17, 2021
• First Submitted That Met QC Criteria: August 18, 2021
• First Posted (Actual): August 24, 2021

Study Record Updates

• Last Update Posted (Actual): November 2, 2021
• Last Update Submitted That Met QC Criteria: October 30, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: cytokines; renal replacement therapy; interleukins; cytokine adsorption
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Liver Failure, Acute; End Stage Liver Disease; Liver Failure; Hepatic Insufficiency; Acute-On-Chronic Liver Failure
• Other Study ID Numbers: CYTOHEP

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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