NCT05895136 - A Novel COMBinATorial Therapy With Albumin and Enoxaparin in Patients With Decompensated Cirrhosis at High-risk of Poor Outcome (COMBAT Trial). | Crick | Crick

NCT05895136 - A Novel COMBinATorial Therapy With Albumin and Enoxaparin in Patients With Decompensated Cirrhosis at High-risk of Poor Outcome (COMBAT Trial). | Crick | Crick

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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).

Time frame: from baseline to Day 90

Secondary Outcomes

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.

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.

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.

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

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.

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)

Chi-Square test or Fisher exact test will be performed. Pairwise Log-rank tests will be used for statistical comparisons.

Time frame: 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.

Time frame: 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.

Time frame: 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.

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)

Chi-Square test or Fisher exact test will be performed. Pairwise Log-rank tests will be used for statistical comparisons.

Time frame: 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.

Time frame: 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.

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)

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.

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)

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 180-days from baseline