A Novel COMBinATorial Therapy with Albumin and Enoxaparin in Patients with Decompensated Cirrhosis At High-risk of Poor Outcome (COMBAT Trial). (COMBAT)

The goal of this clinical trial is to determine primarily whether a combinatorial therapy based on the administration of human albumin and enoxaparin is safe and effective in patients with decompensated cirrhosis discharged from the hospital. The main questions it aims to answer are:

• Is this combinatorial therapy safe and tolerable?
• Is this combinatorial therapy effective?
• does this combinatorial therapy cost more or less than standard medical therapy? Participants will attend to study visits in which several test will be performed to asses disease evolution while they are taking study medication.

Researchers will compare experimental group treated with combinatorial therapy plus standard treatment with control group treated with standard treatment to see if there are differences in the responses to the questions raised above.

Study Overview

• Status: Recruiting
• Conditions: Liver Cirrhosis; Decompensated Cirrhosis of Liver; Acute on Chronic Liver Failure (ACLF)
• Intervention / Treatment: Drug: Human albumin; Drug: Enoxaparin; Drug: Standard medical treatment

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Anna Bosch; Phone Number: +34 93 227 14 03; Email: anna.bosch@efclif.com

Study Locations

• France
  • Clichy, France, 92110
    • Recruiting
    • Hopital Beaujon
    • Contact: Pierre Emmanuel Rautou, PI; Email: perautou@yahoo.fr
• Germany
  • Aachen, Germany, 52074
    • Recruiting
    • Universitätsklinikum Aachen AöR
    • Contact: Tony Bruns, PI
  • Münster, Germany, 48149
    • Recruiting
    • Universität Münster
    • Contact: Jonel Trebicka, PI
• Italy
  • Emilia Romagna
    • Bologna, Emilia Romagna, Italy, 40138
      • Recruiting
      • IRCSS Azienda Ospedaliero Universitaria di Bologna Policlinico di Sant'Orsola
      • Contact: Paolo Caraceni, PI; Email: paolo.caraceni@unibo.it
  • Piemonte
    • Torino, Piemonte, Italy, 10126
      • Recruiting
      • Azienda Ospedaliero-Universitaria "Città della Salute e della Scienza di Torino"
      • Contact: Carlo Alessandria, PI; Email: carloalessandria@libero.it
• Spain
  • Barcelona, Spain, 08035
    • Recruiting
    • Hospital Universitari Vall d'Hebron-VHIR
    • Contact: Joan Genescà, PI; Email: jgenesca@vhebron.net
  • Barcelona, Spain, 08036
    • Recruiting
    • Hospital Clínic de Barcelona-FCRB
    • Contact: Javier Fernández, PI; Email: Jfdez@clinic.cat
  • Madrid, Spain, 28034
    • Recruiting
    • Hospital Universitario Ramon y Cajal
    • Contact: Agustín Albillos, PI
• United Kingdom
  • London, United Kingdom, NW3 2QG
    • Not yet recruiting
    • Royal Free Hospital
    • Contact: Rajeshwar Mookerjee; Phone Number: 07887752300; Email: r.mookerjee@ucl.ac.uk
    • Contact: Rajeshwar Mookerjee

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age between 18 and 80 years.
2. Patients with decompensated cirrhosis admitted to hospital due to AD according to the EASL-CLIF criteria (rapid onset of ascites, hepatic encephalopathy, portal hypertensive-related gastrointestinal bleeding, bacterial infection, or any combination of these).
3. CLIF-C AD score ≥ 45 at admission or at any time during hospital stay.
4. Recovery from AD and expected to be discharged within the next 72 hours.

Exclusion Criteria:

1. Diagnosis of acute-on-chronic liver failure (ACLF) grade 3 or higher according to the EASL-CLIF criteria at admission or at any time during the index hospitalization
2. Admission for planned diagnostic or therapeutic procedures
3. Recent acute bleeding (unless the cause has been effectively treated and there is no evidence of ongoing bleeding for at least 5 days)
4. Chronic bleeding requiring periodic blood transfusions
5. Presence of an ongoing acute complication of the disease (i.e. hepatic encephalopathy [grade III or IV])
6. Conditions with a high risk of haemorrhage, including haemorrhagic diathesis not related to liver disease
7. Patients with INR > 3.0
8. Severe thrombocytopenia (<30x10 9 /L)
9. Ongoing chronic anticoagulation therapy or indication for starting anticoagulation due to hepatic and non-hepatic conditions
10. Ongoing anti-platelets therapy.
11. Active malignancy (except for hepatocellular carcinoma within the Milan criteria or non-melanocytic skin cancer)
12. Antiviral treatment for hepatitis C, B and delta initiated in the last 6 months or planned to be initiated in the following 6 months
13. Ongoing alcohol use disorder with an expected low adherence to protocol as judged by physician
14. Previous liver transplantation
15. Patients with TIPS or other surgical porto-caval shunts
16. Chronic organic renal failure stage IV and V or estimated Glomerular Filtration Rate <30 ml/min according to the MDRD equations
17. Chronic heart failure NYHA class III or IV
18. Pulmonary disease GOLD III or IV
19. Patients with extrahepatic diseases with life expectancy <6 months
20. Severe psychiatric disorders
21. Hypersensitivity to albumin preparations or to any of the excipients.
22. Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular weight heparins (LMWH) or to any of the excipients
23. History of immune mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in the presence of circulating antibodies
24. Pregnancy and breast-feeding
25. Expected low adherence to study protocol as judged by physician
26. Patients who can't provide written informed consent or refusal to participate
27. Participation in other concurrent clinical trials and within the prior 3 months from informed consent signature.

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
Experimental: Enoxaparin plus human albumin; Cohort 1 will receive standard medical treatment plus a combinatorial therapy of enoxaparin and human Albumin.	Drug: Human albumin; Human albumin solution is made from pooled human plasma. It is widely used as a plasma-expander in several disease conditions, such as liver cirrhosis and critically ill patients. ATC-Code: B05AA01; Drug: Enoxaparin; Enoxaparin is a drug that belongs to the group of anticoagulants. It exerts its antithrombotic activity by binding to antithrombin III (AT III). ATC-Code: B01AB05; Drug: Standard medical treatment; SMT will be considered non-study medication and is not specified in the protocol.
Active Comparator: Standard medical treatment; Cohort 2 (control) will receive only standard medical treatment.	Drug: Standard medical treatment; SMT will be considered non-study medication and is not specified in the protocol.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess the safety and tolerability of the combinatorial therapy in terms of TEAE (pulmonary edema, major bleeding and/or thrombocytopenia	The safety and tolerability of the combinatorial therapy of human albumin and enoxaparin on top of SMT compared to SMT alone, from baseline to Day 90, will be evaluated as the percentage of subjects who discontinued the study drug due to at least 1 of the following treatment-emergent adverse events (TEAE): pulmonary edema, severe thrombocytopenia and/or major bleeding. These variables will be described (counts and percentage).	from baseline to Day 90

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
90 and 180-days changes in prognostic scores of CLIF-Consortium Acute Decompensation score (CLIF-C AD) from baseline.	Lower scores of CLIF-C AD (<45) indicate a better prognostic than greater values (>50). In the statistical analysis Chi-Square test or Fisher exact test will be performed. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in prognostic scores of Mayo End stage Liver Disease (MELD) from baseline.	The MELD score ranges from six to 40 and is based on results from several lab tests. The higher the number, the more likely you are to receive a liver from a deceased donor when an organ becomes available. Chi-Square test or Fisher exact test will be performed. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in prognostic scores of Mayo End stage Liver Disease - sodio (MELDNa) from baseline	The MELDNa score ranges from six to 40 and is based on results from several lab tests. The higher the number, the more likely you are to receive a liver from a deceased donor when an organ becomes available. Chi-Square test or Fisher exact test will be performed. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
30 days, 90 and 180-days incidence of hospital readmission and ICU admission (causes and length of stay)	Chi-Square test or Fisher exact test will be performed. Pairwise Log-rank tests will be used for statistical comparisons.	30, 90 and 180-days
90 and 180-days incidence of ACLF according to the EASL-CLIF criteria	Chi-Square test or Fisher exact test will be performed. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days overall and transplant-free survival	Overall and transplant-free survival will be analyzed by estimating Kaplan-Meier survival curves for each treatment arm. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days incidence and cumulative number of therapeutic paracenteses	Chi-Square test or Fisher exact test will be performed. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days incidence of major complication of cirrhosis (grade 2-4 HE, portalhypertensive gastrointestinal bleedings, AKI, HRS-AKI, new-onset portal vein thrombosis)	Chi-Square test or Fisher exact test will be performed. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days incidence of proven bacterial infection	Chi-Square test or Fisher exact test will be performed. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in organ function from baseline: liver function variables: grade of ascites	Grade of ascites according to the criteria of the International Club of Ascites. Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in organ function from baseline: liver function variables: grade of hepatic encephalopathy (West Haven)	Grade of hepatic encephalopathy using the West Haven (score range 0, normal to 4, coma). Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in organ function from baseline: liver function variables: grade of hepatic encephalopathy (ANT)	Animal Naming Test (ANT): range from >15, normal to <10 Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in organ function from baseline: liver function variables: bilirrubin	Bilirubin in mg/dL. Ranges according reference ranges of each study site. Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in organ function from baseline: liver function variables: albumin serum levels	Albumin serum levels in g/dL. Ranges according reference ranges of each study site. Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in organ function from baseline: renal function variables: BUN	BUN in mg/dL. Ranges according reference ranges of each study site. Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in organ function from baseline: renal function variables: serum creatinine	Serum creatinine in mg/dL. Ranges according reference ranges of each study site. Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in organ function from baseline: renal function variables: electrolites	Electrolytes: Na, K, Ca (mmol/L). Ranges according reference ranges of each study site. Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in organ function from baseline: renal function variables: GFR	Glomerula Filtration Ratio (GFR) will be estimated by the Modification of Diet in Renal Disease (MDRD) equations. Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in organ function from baseline: lung function variables: respiratory rate	Respiratory rate in breaths per minute. Ranges according reference ranges of each study site. Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in organ function from baseline: lung function variables: FIO2	Fraction of inspired oxygen (FIO2) in percentage (%). Ranges according reference ranges of each study site. Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in organ function from baseline: lung function variables: pulse oxymetric saturation	Pulse oxymetric saturation in percentage (%). Ranges according reference ranges of each study site. Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in organ function from baseline: coagulative variables: INR	International Normalized Ratio (INR). Ranges according reference ranges of each study site. Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in organ function from baseline: coagulative variables: aPTT	Activated partial thromboplastin time (aPTT) in seconds. Ranges according reference ranges of each study site. Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in organ function from baseline: coagulative variables: fibrinogen	Fibrinogen in mg/dL. Ranges according reference ranges of each study site. Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in organ function from baseline: coagulative variables: Platelet count	Platelet count in platelets per microliter. Ranges according reference ranges of each study site. Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in organ function from baseline: hemodynamic variables: arterial pressure	Systolic, diastolic and mean arterial pressure in mmHg. Ranges according reference ranges of each study site. Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in organ function from baseline: hemodynamic variables: heart rate.	Heart rate in beats per minute. Ranges according reference ranges of each study site. Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in frailty (Liver Frailty Index, LFI)	LFI score of ≤ 3.2 indicates a patient is robust, 3.3-4.4 pre frail and ≥ 4.5 frail. Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in quality of life measure through European Quality of Life Five Dimension Five Levels (EQ-5D-5L)	EQ-5D-5L has a score from 5 (no problems) to 25 (extreme problems on all dimensions evaluated). Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
90 and 180-days changes in quality of life measure through Visual Analog Scale (VAS)	VAS has a score from 0 (worst health patient can imagine) to 100 (best health patient can imagine) Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	90 and 180-days from baseline
Total hospital costs during the 6-month period	To estimate the 90-days costs of an acute decompensation of cirrhosis for both arms in the trial In-hospital resource utilization will be described based on diagnosis and procedural codes and length of stay. Hospital costs will be assigned based on the primary indication for hospitalization and procedures performed during the hospitalization and the Severity-Diagnosis Related Groups. Costs will be then assigned based on the latest mean cost available. Costs will be calculated in euros by treatment arm. Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	180-days from baseline
Total hospital costs predictors during the 6-month period	To identify cost predictors (patients characteristics that are present before the treatment is initiated) and In-hospital resource utilization will be described based on diagnosis and procedural codes and length of stay. Hospital costs will be assigned based on the primary indication for hospitalization and procedures performed during the hospitalization and the Severity-Diagnosis Related Groups. Costs will be then assigned based on the latest mean cost available. Costs will be calculated in euros by treatment arm. Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	180-days from baseline
Total hospital costs drivers during the 6-month period cost drivers	Cost drivers (response to treatment, randomization arm, other treatments). In-hospital resource utilization will be described based on diagnosis and procedural codes and length of stay. Hospital costs will be assigned based on the primary indication for hospitalization and procedures performed during the hospitalization and the Severity-Diagnosis Related Groups. Costs will be then assigned based on the latest mean cost available. Costs will be calculated in euros by treatment arm. Student t-test or analysis of variance will be used to compare normally distributed variable or non-parametric methods if the assumptions of normality are not met. Pairwise Log-rank tests will be used for statistical comparisons.	180-days from baseline

Collaborators and Investigators

• Sponsor: European Foundation for Study of Chronic Liver Failure
• Collaborators: Horizon 2020 - European Commission

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2024
• Primary Completion (Estimated): September 1, 2025
• Study Completion (Estimated): September 1, 2025

Study Registration Dates

• First Submitted: May 11, 2023
• First Submitted That Met QC Criteria: June 6, 2023
• First Posted (Actual): June 8, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 14, 2025
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Enoxaparin; liver cirrhosis; Liver diseases; Human Albumin; decompensated cirrhosis; Acute on Chronic Liver Failure (ACLF)
• Additional Relevant MeSH Terms: Pathologic Processes; Digestive System Diseases; Liver Diseases; Liver Failure, Acute; Fibrosis; Liver Cirrhosis; End Stage Liver Disease; Liver Failure; Hepatic Insufficiency; Acute-On-Chronic Liver Failure; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Fibrinolytic Agents; Anticoagulants; Enoxaparin
• Other Study ID Numbers: COMBAT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Only aggregated data will be shared among sites.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No