A novel COMBinATorial therapy with albumin and enoxaparin in patients with decompensated cirrhosis at high-risk of poor outcome (COMBAT trial).

Overview

Sponsor-declared trial summary

Key facts

Sponsor

European Foundation For The Study Of Chronic Liver Failure

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

24 Apr 2024 → ongoing

Decision date (initial)

2024-01-09

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

EU-funded Grant Agreement No: 847949

External identifiers

EU CT number

2023-507073-18-00

ClinicalTrials.gov

NCT05895136

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety

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

Secondary objectives 4

1. To evaluate signals of efficacy of the combinatorial therapy.
2. To explore the impact of the combinatorial therapy on pathophysiological mechanisms of cirrhosis in blood samples extracted at several time points.
3. To explore the role of selected biomarkers in predicting the response to the combinatorial therapy in blood samples extracted at several time points.
4. To estimate the healthcare costs associated with the combinatorial therapy

Conditions and MedDRA coding

Cirrhosis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

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 27

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 (<30x109/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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. The percentage of subjects who experience at least 1 treatment-emergent adverse events (TEAE) or serious adverse events (SAE)
2. The percentage of subjects who discontinue the study drug due to pulmonary edema, severe thrombocytopenia and/or major bleeding according to the definition by Shulman et al (56)

Secondary endpoints 23

1. 90 and 180-days changes in prognostic scores from baseline (CLIF- C AD, MELD, MELD-Na)
2. 30 days, 90 and 180-days incidence of hospital readmission and ICU admission (causes and length of stay)
3. 90 and 180-days incidence of ACLF according to the EASL-CLIF criteria
4. 90 and 180-days overall and transplant-free survival
5. 90 and 180-days incidence and cumulative number of therapeutic paracenteses
6. 90 and 180-days incidence of major complication of cirrhosis (grade 2-4 HE, portal-hypertensive gastrointestinal bleedings, AKI, HRS-AKI, new-onset portal vein thrombosis)
7. 90 and 180-days incidence of proven bacterial infection
8. 90 and 180-days changes in organ function from baseline: liver function variables: grade of ascites according to the criteria of the International Club of Ascites, grade of hepatic encephalopathy using the West Haven and Animal Naming Test (ANT), bilirubin and albumin serum levels
9. 90 and 180-days changes in organ function from baseline: renal function variables: BUN, serum creatinine and electrolytes. GFR will be estimated by the MDRD equations
10. 90 and 180-days changes in organ function from baseline: lung function variables: respiratory rate, fraction of inspired oxygen (FIO2) and pulse oximetric saturation
11. 90 and 180-days changes in organ function from baseline: coagulative variables: INR, aPTT, fibrinogen, platelet count
12. 90 and 180-days changes in organ function from baseline: hemodynamic variables: systolic, diastolic and mean arterial pressure and heart rate
13. 90 and 180-days incidence of liver- and non-liver related Serious Adverse Event (SAE)
14. 90 and 180-days changes in frailty (Liver Frailty Index)
15. 90 and 180-days changes in quality of life (EQ-5D, VAS)
16. Total hospital costs during the 6-month period, cost predictors and cost drivers
17. 30, 90 and 180-days changes in systemic inflammation
18. 30, 90 and 180-days changes in blood and microRNA transcriptome
19. 30, 90 and 180-days changes in the metabolomic landscape
20. 30, 90 and 180-days changes in albumin structure and function
21. 30, 90 and 180-days changes in coagulation assays
22. 30, 90 and 180-days changes in extracellular vesicles
23. 30, 90 and 180-days changes in endothelial function

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

European Foundation For The Study Of Chronic Liver Failure

Sponsor organisation

European Foundation For The Study Of Chronic Liver Failure

Address

Travessera De Gracia 11 7th Floor

City

Barcelona

Postcode

08021

Country

Spain

Scientific contact point

Organisation

European Foundation For The Study Of Chronic Liver Failure

Contact name

Chief investigator

Public contact point

Organisation

European Foundation For The Study Of Chronic Liver Failure

Contact name

General Manager

Third parties 1

Locations

4 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 28 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications