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NCT Number: NCT05895136

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

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.

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Key information

Conditions

Liver Cirrhosis Acute on Chronic Liver Failure (ACLF) Acute-On-Chronic Liver Failure Decompensated Cirrhosis of Liver Digestive System Diseases Fibrosis Hepatic Insufficiency Liver Diseases Liver Failure Liver Failure, Acute Pathologic Processes Pathological Conditions, Signs and Symptoms

Age range

18 year–80 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Hôpital Beaujon, Clichy, France

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Age between 18 and 80 years.
  • 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).
  • CLIF-C AD score ≥ 45 at admission or at any time during hospital stay.
  • Recovery from AD and expected to be discharged within the next 72 hours.

Exclusion criteria

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

Treatment and study plan

Human albumin

Drug

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

Enoxaparin

Drug

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

Standard Medical Treatment

Drug

SMT will be considered non-study medication and is not specified in the protocol.

Primary outcomes

  1. To assess the safety and tolerability of the combinatorial therapy in terms of TEAE (pulmonary edema, major bleeding and/or thrombocytopenia

    Time frame: 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 outcomes

  1. 90 and 180-days changes in prognostic scores of CLIF-Consortium Acute Decompensation score (CLIF-C AD) from baseline.

    Time frame: 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.

  2. 90 and 180-days changes in prognostic scores of Mayo End stage Liver Disease (MELD) from baseline.

    Time frame: 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.

  3. 90 and 180-days changes in prognostic scores of Mayo End stage Liver Disease - sodio (MELDNa) from baseline

    Time frame: 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.

  4. 30 days, 90 and 180-days incidence of hospital readmission and ICU admission (causes and length of stay)

    Time frame: 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.

  5. 90 and 180-days incidence of ACLF according to the EASL-CLIF criteria

    Time frame: 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.

  6. 90 and 180-days overall and transplant-free survival

    Time frame: 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.

  7. 90 and 180-days incidence and cumulative number of therapeutic paracenteses

    Time frame: 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.

  8. 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)

    Time frame: 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.

  9. 90 and 180-days incidence of proven bacterial infection

    Time frame: 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.

  10. 90 and 180-days changes in organ function from baseline: liver function variables: grade of ascites

    Time frame: 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.

  11. 90 and 180-days changes in organ function from baseline: liver function variables: grade of hepatic encephalopathy (West Haven)

    Time frame: 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.

  12. 90 and 180-days changes in organ function from baseline: liver function variables: grade of hepatic encephalopathy (ANT)

    Time frame: 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.

  13. 90 and 180-days changes in organ function from baseline: liver function variables: bilirrubin

    Time frame: 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.

  14. 90 and 180-days changes in organ function from baseline: liver function variables: albumin serum levels

    Time frame: 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.

  15. 90 and 180-days changes in organ function from baseline: renal function variables: BUN

    Time frame: 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.

  16. 90 and 180-days changes in organ function from baseline: renal function variables: serum creatinine

    Time frame: 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.

  17. 90 and 180-days changes in organ function from baseline: renal function variables: electrolites

    Time frame: 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.

  18. 90 and 180-days changes in organ function from baseline: renal function variables: GFR

    Time frame: 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.

  19. 90 and 180-days changes in organ function from baseline: lung function variables: respiratory rate

    Time frame: 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.

  20. 90 and 180-days changes in organ function from baseline: lung function variables: FIO2

    Time frame: 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.

  21. 90 and 180-days changes in organ function from baseline: lung function variables: pulse oxymetric saturation

    Time frame: 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.

  22. 90 and 180-days changes in organ function from baseline: coagulative variables: INR

    Time frame: 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.

  23. 90 and 180-days changes in organ function from baseline: coagulative variables: aPTT

    Time frame: 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.

  24. 90 and 180-days changes in organ function from baseline: coagulative variables: fibrinogen

    Time frame: 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.

  25. 90 and 180-days changes in organ function from baseline: coagulative variables: Platelet count

    Time frame: 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.

  26. 90 and 180-days changes in organ function from baseline: hemodynamic variables: arterial pressure

    Time frame: 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.

  27. 90 and 180-days changes in organ function from baseline: hemodynamic variables: heart rate.

    Time frame: 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.

  28. 90 and 180-days changes in frailty (Liver Frailty Index, LFI)

    Time frame: 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.

  29. 90 and 180-days changes in quality of life measure through European Quality of Life Five Dimension Five Levels (EQ-5D-5L)

    Time frame: 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.

  30. 90 and 180-days changes in quality of life measure through Visual Analog Scale (VAS)

    Time frame: 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.

  31. Total hospital costs during the 6-month period

    Time frame: 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.

  32. Total hospital costs predictors during the 6-month period

    Time frame: 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.

  33. Total hospital costs drivers during the 6-month period cost drivers

    Time frame: 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.

Study contacts

Contact information is provided by the study sponsor or research team.

Anna Bosch

CONTACT

[email protected]

+34 93 227 14 03

Sponsors and collaborators

Lead sponsor

European Foundation for Study of Chronic Liver Failure

Other

Collaborators

  • Horizon 2020 - European Commission

Registry information

Acronym: COMBAT

Important dates

Study start
2024
Primary completion
2025
Study completion
2025
First posted
Jun 8, 2023
Registry last updated
Mar 19, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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