Liver CirrhosisPhase 2COMBATNCT05895136
A Novel COMBinATorial Therapy With Albumin and Enoxaparin in Patients With Decompensated Cirrhosis at High-risk of Poor Outcome (COMBAT Trial).
A Phase 2 study testing Human albumin, Enoxaparin and Standard medical treatment in people with Liver Cirrhosis and Decompensated Cirrhosis of Liver, run by European Foundation for Study of Chronic Liver Failure at 9 sites in 5 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Liver Cirrhosis, Decompensated Cirrhosis of Liver, Acute on Chronic Liver Failure (ACLF)
- What is being tested?
- Human albumin, Enoxaparin and Standard medical treatment
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 90 participants
- Where
- 9 sitesin 5 countries
- Study dates
- 1 Jul 2024to 31 Oct 2026
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
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- 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.
Trial locations and contacts
9 sites in 5 countries. Contact the study team or a site near you to ask about taking part.
9 sites in 5 countries
Spain3 sites
- Completed
Hospital Universitari Vall d'Hebron-VHIR
Barcelona, 08035
- Completed
Hospital Clínic de Barcelona-FCRB
Barcelona, 08036
- Completed
Hospital Universitario Ramón y Cajal
Madrid, 28034
Germany2 sites
- Completed
Universitätsklinikum Aachen AöR
Aachen, 52074
- Completed
Universität Münster
Münster, 48149
Italy2 sites, 1 recruiting
- Recruiting
IRCSS Azienda Ospedaliero Universitaria di Bologna Policlinico di Sant'Orsola
Bologna, Emilia-Romagna, 40138
Paolo Caraceni, PI, paolo.caraceni@unibo.it
- Completed
Azienda Ospedaliero-Universitaria "Città della Salute e della Scienza di Torino"
Turin, Piedmont, 10126
About this study
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.
- Being tested
- Human albumin, Enoxaparin, Standard medical treatment
- Keywords
- decompensated cirrhosis, Acute on Chronic Liver Failure (ACLF), Liver diseases, liver cirrhosis, Human Albumin, Enoxaparin
- Medical subject headings
- Liver Cirrhosis, Acute-On-Chronic Liver Failure, Liver Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Human albuminDrug
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
EnoxaparinDrug
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 treatmentDrug
SMT will be considered non-study medication and is not specified in the protocol.
| Study group | Role | What they receive |
|---|---|---|
| Enoxaparin plus human albumin | Experimental | Cohort 1 will receive standard medical treatment plus a combinatorial therapy of enoxaparin and human Albumin. Receives: Drug: Human albumin; Drug: Enoxaparin; Drug: Standard medical treatment |
| Standard medical treatment | Active comparator | Cohort 2 (control) will receive only standard medical treatment. Receives: Drug: Standard medical treatment |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: from baseline to Day 90
Secondary outcomes (33)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 180-days from baseline
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Jun 2023
- Study start1 Jul 2024
- Primary completion31 Oct 2026 (estimated)
- Study completion31 Oct 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Liver CirrhosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- The patients enrolled in the study will be divided in two cohorts: Cohort 1 will receive standard medical treatment plus a combinatorial therapy of enoxaparin and human Albumin. Cohort 2 (control) will receive only standard medical treatment.
- Masking
- None (open label)
- Enrolment
- 90 participants (estimated)
Sponsor and investigators
- Lead sponsor
- European Foundation for Study of Chronic Liver Failure
- Sponsor type
- University, hospital or other
- Collaborators
- Horizon 2020 - European Commission
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05895136
- Sponsor's protocol ID
- COMBAT
- Acronym
- COMBAT
- Status last verified
- Sep 2026
- First submitted
- 11 May 2023
- Last updated
- 11 Sep 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: Only aggregated data will be shared among sites.