Decompensated Cirrhosis and Ascites
Conditions
Brief summary
The goal of this clinical biomarker validation trial is to test the effect of a predictive biomarker panel to human albumin infusions in patients with liver cirrhosis and ascites. The main questions it aims to answer are: * If the predictive biomarker panel can identify patients who are likely to benefit from regular human albumin infusions * If the predictive biomarker panel can lower the number-needed-to-treat of regular human albumin infusions in patients with liver cirrhosis and ascites The predictive biomarker panel will stratify patients into either a high- or low-expected effect of human albumin infusions. Hereafter are participants randomized into treatment arms. Participants in the active treatment arm will receive regular human albumin infusions during a course of 6 months. Infusions will occur every 10th day for the duration of the study. Researchers will compare 20% human albumin infusions with regular 0.9% sodium chloride to identify the effects on the number of liver-related events.
Interventions
DRUGHuman albumin
20% Human Albumin infusions (every 10th day +/- 4 days) with dosing according to the participants bodyweight (1.5 grams of albumin per kg bodyweight with a maximum of 100 grams)
DRUGsodium chloride
0.9% NaCl infusions (every 10th day +/- 4 days) with dosing according to the corresponding volume used of 20% Human Albumin (1.5 grams of albumin per kg bodyweight with a maximum of 100 grams)
Sponsors
Aleksander Krag
EASL - CLIF Consortium
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
There will exist two levels of masking in the current trial. Masking of biostratification outcome (high expected effect of human albumin or low expected effect of human albumin): Participant, Investigator and Outcome Assessor Masking of treatment assignment (human albumin 20% or saline 0.9%): Participant and Outcome Assessor
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Decompensated liver cirrhosis defined as Child-Pugh score 7-12 * Clinical and/or ultrasound evidenced ascites * Age ≥ 18 years * At least five days since resolution of a decompensation event or any condition requiring hospitalisation
Exclusion criteria
* Patients with acute or subacute liver failure without underlying cirrhosis * Patients with cirrhosis who develop decompensation in the postoperative period following partial hepatectomy * Refractory ascites as defined by the International Ascites Club * Existing TIPS inserted \<6 months ago * Portal vein thrombosis without signs of cavernous transformation or recanalization * Severe alcoholic hepatitis (Glasgow Alcoholic Hepatitis Score \> 11) * Hepatic encephalopathy grade III-IV * Current, planned or previous treatment with direct antiviral agents for hepatitis C virus (HCV) in the last six months Contraindications for human albumin infusion (pulmonary oedema, hypersensitivity etc.) * Evidence of current malignancy except for non-melanocytic skin cancer and hepatocellular carcinoma within Barcelona Clinic Liver Cancer (BCLC)-0 or BCLC-A * Presence or history of severe extra-hepatic diseases (e.g.,chronic renal failure requiring hemodialysis, severe heart disease (NYHA \> II); severe chronic pulmonary disease (GOLD Score ≥ C), severe neurological and psychiatric disorders, pulmonary arterial hypertension) * HIV positive or other condition associated with and/or requiring immunosuppression * Previous liver or other transplantation * Pregnancy * Breastfeeding * Patients who decline to participate, patients who cannot provide prior written informed consent due to other causes than hepatic encephalopathy or patients with hepatic encephalopathy who cannot provide prior written informed consent and when there is documented evidence that the patient has no legal surrogate decision maker or sufficient ability to provide delayed informed consent * Physician's denial (investigator considers that the patient will not adhere to the study protocol scheduled, e.g. in case of heavy drinking) * Participation in another study within 3 months prior to screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative number of liver-related clinical outcomes | 6 months | Cumulative number of liver-related clinical outcomes (variceal bleeding, ascites, spontaneous bacterial peritonitis, infection requiring hospitalization, acute kidney injury and overt hepatic encephalopathy) and TIPS (insertion or revision) with death and liver transplantation as counting and censoring events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 6-months survival | 6 months | — |
| The number of episodes of acute-on-chronic liver failures | 6 months | Acute-on-chronic liver failure (ACLF) is defined according to the CLIF-C ACLF definition. |
| Number of organ failures | 6 months | Where an organ failure is defined according to the CLIF-C ACLF definition. |
| Time-to-first liver-related clinical outcome | 6 months | A liver-related clinical outcome is defined as variceal bleeding, ascites, spontaneous bacterial peritonitis, infection requiring hospitalization, acute kidney injury (\>=1B), overt hepatic encephalopathy, TIPS insertion, liver transplantation or death. Time to any of these outcomes are defined as the time from trial inclusion until 1) the date of diagnosis of any of the complications, 2) the date of the procedure (TIPS or liver transplantation) or date of death. |
| Change in SF-36 | 6 months | Quality of life for participants, as measured by Short Form 36 (SF-36), ranging from 0 to 100 with a score of 0 equal to maximum disability and score of 100 no disability. |
| Change in CLDQ | 6 months | Quality of life for participants, as measured by the Chronic Liver Disease Questionnaire (CLDQ), consisting of 29 items within 7 domains. Response on a Likert scale ranging from 1 (most impairment) to 7 (least impairment). Total score by adding score for each item and divide by number of items (29). |
| Change in EQ-5D-5L | 6 months | Quality of life for participants, as measured by the EuroQoL-5 Domain, 5 levels (EQ-5D-5L). Consist of 5 domains with 5 levels where the lowest level (1) is the worst imaginable health and highest level (5) is the best imaginable health. |
| Time to first hospital admission (in days) | 180 days | — |
| Number of hospital admissions | 180 days | — |
| Days spent on hospitalization (in days) | 180 days | — |
| Number of intensive care unit admissions | 180 days | — |
| Length of intensive care unit admissions (in days) | 180 days | — |
| Number of large volume paracentesis | 6 months | — |
| Analysis of the cost/effectiveness ratio | 6 months | Analyzed by an incremental cost-effectiveness ratio (ICER) calculation |
| Health economic evaluation | 6 months | Analyzed by the change in quality-adjusted life years (QALYs) relative to the ICER. |
| Changes in serum albumin levels | 6 months | Measured from baseline and throughout the trial in grams per litre (g/L) |
| Number of treatment-related adverse events | 6 months | Adverse events which are deemed related to the trial intervention |
| Number of treatment-related serious adverse events | 6 months | Adverse events which are deemed related to the trial intervention |
| Signatures associated with a poor prognosis as defined by the Microb-Predict biomarker | 6 months | Change in concentration of the panel of predictive circulating metabolites compared to metabolite levels in other body fluid compartments (blood, urin, stool and saliva) |
| Incidence of refractory ascites | 6 months | — |
| Incidence of variceal bleeding | 6 months | — |
| Incidence of spontaneous bacterial peritonitis | 6 months | — |
| Incidence of infection requiring hospitalization | 6 months | — |
| Incidence of acute kidney injury >= 1B | 6 months | According to the Kidney Disease: Improving Global Outcomes (KDIGO) definition ranging from stage 1A to 3 where a higher stage is worse. |
| Incidence of hepatorenal syndrome acute kidney injury | 6 months | — |
| Incidence of overt hepatic encephalopathy | 6 months | — |
| Incidence of liver transplantation | 6 months | — |
| Incidence of TIPS insertion or revision | 6 months | — |
Countries
Belgium, Denmark, Germany, Hungary, Netherlands, Spain, United Kingdom
Contacts
CONTACTAleksander Krag, Professor
CONTACTJonel Trebicka, Professor
PRINCIPAL_INVESTIGATORAleksander Krag, Professor
Odense University Hospital
Outcome results
None listed