Human Albumin for the Treatment of Ascites in Patients With Hepatic Cirrhosis

• Status: Completed
• Trial end date: 2016-05-01
• Target enrollment: 0
• Participant gender: All

Summary

Ascites is the most frequent complication of liver cirrhosis and carries a significant worsening of the prognosis. Approximately 10% of patients per year develop refractory ascites because of either the lack of response to medical treatment or the onset of diuretic-induced complications that preclude the use of an effective dosage. Refractory ascites is associated with an increased incidence of severe complications of cirrhosis. Thus, the overall probability of survival of patients with refractory ascites is very poor, being approximately 30% at 2 years. Repeated large-volume paracentesis, transjugular intrahepatic portosystemic shunt (TIPS), and liver transplantation represent the therapeutic alternatives for refractory ascites. As renal sodium retention and ascites formation are the consequence of portal hypertension and effective hypovolemia, the preservation of the central blood volume represents a major purpose in the management of patients with advanced cirrhosis. Although albumin is responsible for about 70% of the plasma oncotic pressure, the absence of large multicenter randomized studies together with its high cost explains why albumin infusion is not usually included among the therapeutic options for difficult-to-treat ascites.

The objective of the present study is to define the effectiveness of the prolonged administration of human albumin in the treatment of liver cirrhosis with ascitic decompensation. This goal will be reached by performing a multicenter, prospective, randomized clinical trial comparing the efficacy of chronic albumin administration on top of standard medical treatment versus standard medical treatment alone in patients with cirrhosis and ascites.

The study will be conducted in 44 Italian clinical centers and will enrol 440 in- or out-patients affected by liver cirrhosis with uncomplicated ascites who will be randomized with a ratio of 1:1. The duration of the study for each patient is 18 months from randomization. The enrolment of patients will last 18 months and will be competitive between centers. Treatment will be interrupted if one of the following condition occur: orthotopic liver transplantation, TIPS, need of 3 paracentesis/month (indication to TIPS), patient refusal to continue, and medical judgement.

An ancillary optional study will be performed in a subset of patients to analyze the non-oncotic properties of albumin.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Bologna
• Collaborator: Agenzia Italiana del Farmaco
• Treatments: Diuretics; Furosemide

Criteria

Inclusion criteria

• Diagnosis of liver cirrhosis (based on clinical, laboratory, endoscopic and ultrasonographic features) and uncomplicated ascites according to the criteria of the International Ascites Club (1).

• Ongoing diuretic treatment with an anti-mineralocorticoid drug at a dose of 200 mg/day and furosemide of 25 mg/day, stable for at least 4 days prior enrollment, not inducing response (defined according to the criteria of the International Ascites Club as body weight reduction ≥ 800 grams in the 4 days prior enrollment). With this limitation, we aim to identify a fairly homogeneous population with a relatively advanced stage of the disease that will likely have more benefit from albumin administration, as also suggested by Gentilini at al. (17).

• Ongoing diuretic treatment with an anti-mineralocorticoid drug at a dose > 200 mg/day and furosemide > 25mg/day, independent of response to treatment.

• EGDS performed in the last 12 months, abdominal ultrasonography performed in the last 30 days, and laboratory tests required by the protocol in the last 7 days.

Exclusion criteria

• Age lower than 18 years

• No written informed consent

• Inability to follow written consent

• Established diagnosis of refractory ascites, as defined by the IAC (1)

• Need of 2 or more paracentesis during the last month

• Serum creatinine > 1.5 mg/dl

• Organic nephropathy, as defined by the IAC (1)

• Hepatorenal syndrome type 1 in the last 15 days

• Gastrointestinal bleeding in the last 15 days

• Ongoing endoscopic eradication after a recent gastro-esophageal variceal bleeding

• Bacterial or fungal infection, including spontaneous bacterial peritonitis, in the last 7 days

• Hepatic encephalopathy grade III/IV

• Budd-Chiari Syndrome

• Patients with TIPS or other surgical porto-caval shunts

• Known and suspected active hepatocellular carcinoma or other malignancies

• Previous liver transplantation

• Ongoing alcohol abuse (patients should be abstinent for at least three months)

• Antiviral therapy for hepatitis B started in the last 6 months

• Heart failure

• Respiratory failure as defined as PO2 <60 mmHg

• Known or suspected hypersensitivity to albumin

• Previous albumin administration given for the treatment of ascites in the last 30 days

• Patients enrolled in other clinical study for the treatment of ascites

• Use of experimental drugs for the last 2 months prior the inclusion in the present study

• Pregnancy and breast-feeding

• Females of child-bearing potential are excluded unless they meet one of the following criteria:

• Post-menopausal for 6 months or more, and if post-menopausal for less than 2 years, a negative pregnancy test

• Surgical sterilisation for more than one month duration and a negative pregnancy test

• Intrauterine device in combination with a secondary barrier (e.g. diaphragm, condom or spermicide) and a negative pregnancy test