Cytokine Adsorption in Acute-on-chronic Liver Failure

Not Applicable

• Conditions: Acute-On-Chronic Liver Failure; Renal Failure
• Interventions: Device: CytoSorb cytokine adsorber; Device: CRRT

• Registration Number: NCT05019352
• Lead Sponsor: Dr. Alexander Supady

Brief Summary

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.

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 Timeline

• Study First Submitted: 2021-08-17
• Study First Submitted QC: 2021-08-18
• Study First Posted: 2021-08-24
• Status Verified: 2021-10
• Study Start: 2021-10-25
• Last Update Submitted: 2021-10-30
• Last Update Posted: 2021-11-02
• Primary Completion: 2022-12-31
• Study Completion: 2023-01-30

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 51

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CRRT with cytokine adsorption	CRRT	Patients will be treated with CRRT and extracorporeal hemoadsorption for 72 hours
CRRT without cytokine adsorption	CRRT	Patients will be treated with CRRT without extracorporeal hemoadsorption for 72 hours
CRRT with cytokine adsorption	CytoSorb cytokine adsorber	Patients will be treated with CRRT and extracorporeal hemoadsorption for 72 hours

Primary Outcome Measures

Name	Time	Method
Serum bilirubin	72 hours	Serum bilirubin after 72 hours

Secondary Outcome Measures

Name	Time	Method
CLIF-SOFA-score	72 hours	CLIF-SOFA-score
Liver function parameters	72 hours	Quick/INR, AST, ALT, AP, g-GT
MELD score	72 hours	MELD score
Inflammatory biomarkers	72 hours	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)
Survival time	30 days	Survival time from baseline
Interleukin-6	72 hours	Interleukin-6 after 72 hours
vasopressor dosage	72 hours	dosage of epinephrine, norepinephrine, dobutamine, argipressin and terlipressin
Vasopressor free days	30 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
Blood lactate	72 hours	Lactate concentration after 72 hours
SOFA score	72 hours	SOFA score
SAPS II	72 hours	SAPS II
Dialysis free days	30 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
FIPS score	72 hours	FIPS score
Ventilator free days	30 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

Trial Locations

Locations (1)

University Clinic Freiburg; 🇩🇪 Freiburg, Germany