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

Overview

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.

Interventions

• 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.

Primary outcome measures

• 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]

Secondary outcome measures (12)

• 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]
• 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]
• 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]
• 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]
• 90 and 180-days incidence of ACLF according to the EASL-CLIF criteria [Time frame: 90 and 180-days from baseline]
• 90 and 180-days overall and transplant-free survival [Time frame: 90 and 180-days from baseline]
• 90 and 180-days incidence and cumulative number of therapeutic paracenteses [Time frame: 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) [Time frame: 90 and 180-days from baseline]
• 90 and 180-days incidence of proven bacterial infection [Time frame: 90 and 180-days from baseline]
• 90 and 180-days changes in organ function from baseline: liver function variables: grade of ascites [Time frame: 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) [Time frame: 90 and 180-days from baseline]
• 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]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Spain · 3 centers

• Hospital Universitari Vall d'Hebron-VHIR — Barcelona
• Hospital Universitario Ramón y Cajal — Madrid
• Hospital Clínic de Barcelona-FCRB — Barcelona

Germany · 2 centers

• Universitätsklinikum Aachen AöR — Aachen
• Universität Münster — Münster

Italy · 2 centers

• IRCSS Azienda Ospedaliero Universitaria di Bologna Policlinico di Sant'Orsola — Bologna
• Azienda Ospedaliero-Universitaria "Città della Salute e della Scienza di Torino" — Turin

France · 1 center

• Hôpital Beaujon — Clichy

United Kingdom · 1 center

• Royal Free Hospital — London

Identifiers

NCT: NCT05895136 · COMBAT

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗