Clinical trial NCT05019352: Cytokine Adsorption in Acute-on-chronic Liver Failure
Official title: Cytokine Adsorption in Patients With Acute-on-chronic Liver Failure (CYTOHEP) - a Single Center, Open-label, Randomized, Controlled Intervention Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Acute-On-Chronic Liver Failure
Renal Failure
Keywords: cytokine adsorption
renal replacement therapy
interleukins
cytokines
Lead sponsor: University Hospital Freiburg
Sponsor class: OTHER
First posted: 2021-08-24
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: In a prallel design participants will be randomly assigned to three different trial groups
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Serum bilirubin
timeFrame: 72 hours
Secondary outcomes:
measure: Survival time
timeFrame: 30 days
measure: Interleukin-6
timeFrame: 72 hours
measure: Liver function parameters
timeFrame: 72 hours
measure: Blood lactate
timeFrame: 72 hours
measure: CLIF-SOFA-score
timeFrame: 72 hours
measure: MELD score
timeFrame: 72 hours
measure: SOFA score
timeFrame: 72 hours
measure: SAPS II
timeFrame: 72 hours
measure: FIPS score
timeFrame: 72 hours
measure: Ventilator free days
timeFrame: 30 days
measure: vasopressor dosage
timeFrame: 72 hours
measure: Vasopressor free days
timeFrame: 30 days
measure: Dialysis free days
timeFrame: 30 days
measure: Inflammatory biomarkers
timeFrame: 72 hours
Other outcomes:
Locations:
city: Freiburg
country: Germany
facility: University Clinic Freiburg
Study officials:
affiliation: University Hospital Freiburg
name: Alexander Supady, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.