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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01288794
Recruitment Status : Completed
First Posted : February 2, 2011
Last Update Posted : January 20, 2017
Agenzia Italiana del Farmaco
Information provided by (Responsible Party):
Mauro Bernardi, University of Bologna

Brief 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.

Condition or disease Intervention/treatment Phase
Liver Cirrhosis Ascites Drug: Diuretics plus human albumin Drug: Diuretics (standard medical treatment) Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 431 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The Use of Human Albumin for the Treatment of Ascites in Patients With Hepatic Cirrhosis: a Multicenter, Open-label Randomized Clinical Trial
Study Start Date : March 2011
Actual Primary Completion Date : November 2014
Actual Study Completion Date : May 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cirrhosis

Arm Intervention/treatment
Active Comparator: Standard medical treatment plus albumin
The patients will receive standard medical treatment (diuretics) plus weekly albumin infusion
Drug: Diuretics plus human albumin
The patients will receive standard medical treatment plus albumin infusion at the dose of 40 g twice weekly for 2 weeks, and then 40 g weekly for the rest of the study (up to 24 months).
Other Names:
  • Furosemide and antialdosteronic drugs
  • Human albumin vials 50 cc 20% solution

Standard medical treatment
The patients will receive the standard medical treatment (diuretics), but non albumin for the therapy of ascites
Drug: Diuretics (standard medical treatment)
The patients will receive standard medical treatment (diuretics)
Other Name: Furosemide and antialdosteronic drugs

Primary Outcome Measures :
  1. Mortality [ Time Frame: 18 months ]

Secondary Outcome Measures :
  1. Incidence of cirrhosis-related clinical complications [ Time Frame: 18 months ]
  2. Number of total paracentesis [ Time Frame: 18 months ]
  3. Number of patients potentially needing TIPS (3 paracentesis/month) [ Time Frame: 18 months ]
  4. Quality of life [ Time Frame: 18 months ]
    QoL will be assessed by the SF-36 and EQ-5D questionnaires

  5. Analysis of the cost/effectiveness ratio [ Time Frame: 18 months ]
  6. Incidence of refractory ascites according to the IAC criteria [ Time Frame: 18 months ]

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

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To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01288794

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Sponsors and Collaborators
University of Bologna
Agenzia Italiana del Farmaco
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Principal Investigator: Mauro Bernardi, MD University of Bologna
Study Director: Paolo Caraceni, MD University of Bologna
Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Mauro Bernardi, Full Professor of Medicine, University of Bologna Identifier: NCT01288794    
Other Study ID Numbers: FARM6P824B
2008-000625-19 ( EudraCT Number )
First Posted: February 2, 2011    Key Record Dates
Last Update Posted: January 20, 2017
Last Verified: January 2017
Keywords provided by Mauro Bernardi, University of Bologna:
Uncomplicated ascites
Refractory ascites
Chronic albumin treatment
Additional relevant MeSH terms:
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Liver Cirrhosis
Pathologic Processes
Liver Diseases
Digestive System Diseases
Natriuretic Agents
Physiological Effects of Drugs
Sodium Potassium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action