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

Phase 2

Recruiting

• Conditions: Liver Cirrhosis; Decompensated Cirrhosis of Liver; Acute on Chronic Liver Failure (ACLF)
• Interventions: Drug: Human albumin; Drug: Enoxaparin; Drug: Standard medical treatment

• Registration Number: NCT05895136
• Lead Sponsor: European Foundation for Study of Chronic Liver Failure

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2023-05-11
• Study First Submitted QC: 2023-06-06
• Study First Posted: 2023-06-08
• Study Start: 2024-07-01
• Status Verified: 2024-08
• Last Update Submitted: 2025-03-14
• Last Update Posted: 2025-03-19
• Primary Completion: 2025-09
• Study Completion: 2025-09

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 90

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Enoxaparin plus human albumin	Human albumin	Cohort 1 will receive standard medical treatment plus a combinatorial therapy of enoxaparin and human Albumin.
Enoxaparin plus human albumin	Enoxaparin	Cohort 1 will receive standard medical treatment plus a combinatorial therapy of enoxaparin and human Albumin.
Enoxaparin plus human albumin	Standard medical treatment	Cohort 1 will receive standard medical treatment plus a combinatorial therapy of enoxaparin and human Albumin.
Standard medical treatment	Standard medical treatment	Cohort 2 (control) will receive only standard medical treatment.

Primary Outcome Measures

Name	Time	Method
To assess the safety and tolerability of the combinatorial therapy in terms of TEAE (pulmonary edema, major bleeding and/or thrombocytopenia	from baseline to Day 90	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).

Secondary Outcome Measures

Name	Time	Method
90 and 180-days changes in organ function from baseline: coagulative variables: INR	90 and 180-days from baseline	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 changes in organ function from baseline: coagulative variables: Platelet count	90 and 180-days from baseline	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 changes in organ function from baseline: hemodynamic variables: arterial pressure	90 and 180-days from baseline	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 changes in prognostic scores of CLIF-Consortium Acute Decompensation score (CLIF-C AD) from baseline.	90 and 180-days 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 incidence of ACLF according to the EASL-CLIF criteria	90 and 180-days from baseline	Chi-Square test or Fisher exact test will be performed. Pairwise Log-rank tests will be used for statistical comparisons.
90 and 180-days incidence of proven bacterial infection	90 and 180-days from baseline	Chi-Square test or Fisher exact test will be performed. Pairwise Log-rank tests will be used for statistical comparisons.
90 and 180-days changes in organ function from baseline: liver function variables: grade of hepatic encephalopathy (ANT)	90 and 180-days from baseline	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 changes in organ function from baseline: liver function variables: albumin serum levels	90 and 180-days from baseline	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 changes in organ function from baseline: coagulative variables: aPTT	90 and 180-days from baseline	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 changes in organ function from baseline: coagulative variables: fibrinogen	90 and 180-days from baseline	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 changes in organ function from baseline: liver function variables: grade of hepatic encephalopathy (West Haven)	90 and 180-days from baseline	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 changes in organ function from baseline: renal function variables: BUN	90 and 180-days from baseline	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 changes in organ function from baseline: renal function variables: electrolites	90 and 180-days from baseline	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 changes in organ function from baseline: lung function variables: respiratory rate	90 and 180-days from baseline	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 changes in organ function from baseline: liver function variables: bilirrubin	90 and 180-days from baseline	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 changes in organ function from baseline: renal function variables: serum creatinine	90 and 180-days from baseline	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 changes in organ function from baseline: renal function variables: GFR	90 and 180-days from baseline	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 changes in prognostic scores of Mayo End stage Liver Disease - sodio (MELDNa) from baseline	90 and 180-days 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 incidence of major complication of cirrhosis (grade 2-4 HE, portalhypertensive gastrointestinal bleedings, AKI, HRS-AKI, new-onset portal vein thrombosis)	90 and 180-days from baseline	Chi-Square test or Fisher exact test will be performed. Pairwise Log-rank tests will be used for statistical comparisons.
90 and 180-days changes in organ function from baseline: lung function variables: FIO2	90 and 180-days from baseline	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 changes in organ function from baseline: lung function variables: pulse oxymetric saturation	90 and 180-days from baseline	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 changes in prognostic scores of Mayo End stage Liver Disease (MELD) from baseline.	90 and 180-days 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.
30 days, 90 and 180-days incidence of hospital readmission and ICU admission (causes and length of stay)	30, 90 and 180-days	Chi-Square test or Fisher exact test will be performed. Pairwise Log-rank tests will be used for statistical comparisons.
90 and 180-days overall and transplant-free survival	90 and 180-days from baseline	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 incidence and cumulative number of therapeutic paracenteses	90 and 180-days from baseline	Chi-Square test or Fisher exact test will be performed. Pairwise Log-rank tests will be used for statistical comparisons.
90 and 180-days changes in organ function from baseline: liver function variables: grade of ascites	90 and 180-days from baseline	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 changes in organ function from baseline: hemodynamic variables: heart rate.	90 and 180-days from baseline	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.
Total hospital costs during the 6-month period	180-days from baseline	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.
Total hospital costs drivers during the 6-month period cost drivers	180-days from baseline	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.
90 and 180-days changes in frailty (Liver Frailty Index, LFI)	90 and 180-days from baseline	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 changes in quality of life measure through European Quality of Life Five Dimension Five Levels (EQ-5D-5L)	90 and 180-days from baseline	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 changes in quality of life measure through Visual Analog Scale (VAS)	90 and 180-days from baseline	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.
Total hospital costs predictors during the 6-month period	180-days from baseline	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.

Trial Locations

Locations (9)

Royal Free Hospital; 🇬🇧 London, United Kingdom

Hôpital Beaujon; 🇫🇷 Clichy, France

Universitätsklinikum Aachen AöR; 🇩🇪 Aachen, Germany

Universität Münster; 🇩🇪 Münster, Germany

IRCSS Azienda Ospedaliero Universitaria di Bologna Policlinico di Sant'Orsola; 🇮🇹 Bologna, Emilia Romagna, Italy

Azienda Ospedaliero-Universitaria "Città della Salute e della Scienza di Torino"; 🇮🇹 Torino, Piemonte, Italy

Hospital Universitari Vall d'Hebron-VHIR; 🇪🇸 Barcelona, Spain

Hospital Clínic de Barcelona-FCRB; 🇪🇸 Barcelona, Spain

Hospital Universitario Ramón y Cajal; 🇪🇸 Madrid, Spain