COOLEY- Study: aCute On chrOnic Liver failurE Using the cYtosorb Device

Study Overview
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Brief Summary
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A Prospective, Single-Center trial, in Patients With Acute on Chronic Liver Failure. Study of Standard Medical Care Plus CytoSorb® Compared to Standard Medical Care Alone in a historical group.

Detailed Description
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The study team wants to investigate the effect of Cytosorb hemoadsorption on the bilirubin level as well as on the ammonia level changes induced by the therapy in patients with Acute on Chronic Liver Failure (ACLF) . In this group of patients with ACLF grade 2 and 3 the investigators want to determine the prevalence and development of sarcopenia by sequential quadriceps and thenar ultrasound images and by handgrip strength measurement. The investigators will objectify muscle mass by skeletal muscle ultrasound of quadriceps and thenar muscles in this sickest subgroup of cirrhotic patients. Ultrasound forms a part of the daily clinical routine in ICU. The study team wants to compare both measurements and objectify the evolution to study the reliability and validity of ultrasound to quantify muscles in chronic liver disease and its clinical values. Most of ultrasonographic studies are based on quadriceps exploration, which is more inconvenient and takes more time than exploring the hands because patients need to remove clothes and lie down. The study team also hypothesizes that thenar muscles are less subject to fluid overload than the quadriceps muscles are. When available, lumbar skeletal muscle indices will be compared by computed tomography or magnetic resonance imaging. In this group of patients with ACLF, receiving Continuous Renal Replacement Therapy (CRRT) the appropriate choice of anticoagulant remains controversial. The objective of this study is to compare the efficacy and safety of regional citrate anticoagulation (RCA) and Low Molecular Weight Heparin (LMWH) in critically ill ACLF patients requiring CRRT. These two commercially available anticoagulation methods are used in daily practice in the ICU. The first 10 patients will receive anticoagulation with LMWH with monitoring of anti-Xa. The second cohort of patients will receive RCA.

Official Title
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COOLEY- Study: aCute On chrOnic Liver failurE Using the cYtosorb Device

Conditions
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Acute-On-Chronic Liver Failure, Anticoagulant Adverse Reaction, Sarcopenia, Ultrasonography

Intervention / Treatment
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* Device: CytoSorb


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients (≥ 18 years) admitted to the University Hospital of Antwerp (UZA), Belgium. Written informed consent from patient or if not possible due to encephalopathy (> grade 2): legal representative acute-on-chronic liver failure (ACLF) grade ≥ 2: Acute decompensation event (identifiable trigger) Hepatic encephalopathy grade ≥ 2 Acute kidney injury (AKI) 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) Serum bilirubin ≥ 10 mg/dl Hemodynamic instability with vasopressor support (norepinephrine > 0.05 mcg/kg/min) 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 ongoing intermittent or CRRT before study inclusion

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: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Application of CytoSorb treatment to ACLF patients
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CytoSorb hemoadsorption<br>Patients with acute on chronic liver failure will receive CytoSorb treatment for 72 hours. The aim is to remove the molecules that drive systemic inflammation. | Device: CytoSorb<br>* Application of CytoSorb treatment for 72 hours in patients with ACLF<br>|
| No Intervention: Control group<br>Historical group that received only standard medical care | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The impact of CytoSorb on serum bilirubin removal | 20 participants with a serum bilirubin of ≥ 10 mg/dl will undergo CytoSorb for 72 hours | 24 and 72 hours | 
| Changes in ammonia and severity of hepatic encephalopathy during treatment period | The West Haven criteria are used for grading the severity of hepatic encephalopathy, which include 5 grades ranging from minimal (slightly impaired) to grade IV (comatose) | 24 and 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| changes in hemodynamic profile | Change in hemodynamic profile (i.e. mean arterial pressure normalized to norepinephrine equivalents) during the 72-h study intervention. | 24 and 72 hours | 
| Vasopressors | Duration of vasopressor support in days | 24 and 72 hours | 
| ACLF (Acute on Chronic Liver Failure) Grading | Assessment of ACLF grading (minimum 0 - maximum 3; higher score means a worse outcome) during the 72h intervention up to 1 week after diagnosis of ACLF | first week | 
| SOFA Score | Changes in Sequential Organ Failure Assessment (SOFA) (minimum 0-maximum 24; higher score means a worse outcome) score during the 72h study period and up to 1 week after. | 0, 72 and 168 hours | 
| scores | Changes in CLIF-C (Chronic Liver Failure Consortium)(minimu 0 - maximum 100; higher score means a worse outcome) score during the 72-h intervention, up to 15 days after diagnosis of ACLF | 15 days | 
| Ventilation | Duration of mechanical ventilation, | 0, 24 and 72 hours | 
| Cytokines | Changes in cytokines (IL-6, IL-8, IL-16, TNF (tumor necrosis factor)-alpha) value (pg/ml) | 0, 24 and 72 hours | 
| Mortality | Mortality at 28, 60 and 90 days after enrolment | 28, 60 and 90 days after enrolment | 
| Improvement of Renal function after application of CytoSorb | Acute kidney injury (AKI) 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) will receive CytoSorb treatmetn. Serum creatinine will be measured at day 7, 14, 21 and 90 days | 7, 14, 21 and 90 days after enrolment | 
| Cytosorb filter | Adverse events attributable to CytoSorb up to 28 days after enrolment | up to 28 days after enrolment | 
| Change in Bile acids | Bile acids after 72 hours | 72 hours after enrolment | 
| Sarcopenia | Prevalence and development of sarcopenia | 0, 24 and 72 hours | 
| Anticoagulation | Adverse events attributable to anticoagulation | 0, 24 and 72 hours | 
| SAPS II score | Simplified Acute Physiology Score II (SAPS II) (minimum 0 - maximum 163; higher score means a worse outcome) during the 72-h study intervention and up to 1 week after | Day 0, Day 3, Day 7 | 
| Change in inflammatory values: lactate | measurement of lactate (reference < 2 mmol/L) | Day 0, Day 1 and Day 3 | 
| Change in inflammatory values: procalcitonin | measurement of procalcitonin (reference < 0.5 ng/mL) | Day 0, Day 1 and Day 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute on chronic liver failure, sarcopenia, citrate anticoagulation, low molecular weight heparins, hand grip strength, skeletal muscle ultrasound, hemoadsorption, CRRT