The INFECIR-2 Albumin Prevention Study (INFECIR2)

Albumin Administration in the Prevention of Hepatorenal Syndrome and Death in Patients With Cirrhosis, Bacterial Infections Other Than Spontaneous Bacterial Peritonitis and High Risk of Hospital Mortality

The aim of this study is to evaluate whether albumin administration improves short-term survival in patients with advanced cirrhosis and bacterial infections other than Spontaneous Bacterial Peritonitis (SBP).

Study Overview

• Status: Terminated
• Conditions: Pneumonia; Cholangitis; Advanced Chronic Liver Disease; Urinary Infection; Other Bacterial Diseases
• Intervention / Treatment: Drug: Albumin

Detailed Description

The aim of this study is to evaluate if IV albumin administration improves short-term survival in patients with advanced cirrhosis (serum creatinine ≥ 1.2 mg/dl, serum sodium ≤ 130 mEq/l -milliequivalents per liter- and/or serum bilirubin ≥4 mg/dl) and bacterial infections other than spontaneous bacterial peritonitis (urinary infection, pneumonia, spontaneous or secondary bacteremia, skin/soft tissue infection, acute cholangitis or suspected bacterial infection).

Primary goals of the study:

• Effect of albumin administration on hospital survival

Secondary goals of the study:

• Effect of albumin administration on 28-day and 90-day survival.
• Effect of albumin administration on the incidence of renal dysfunction, AKI, type-1 and 2 Hepatorenal Syndrome (HRS) during hospitalization.
• Effect of albumin on circulatory function estimated by changes in plasma levels of renin and noradrenaline and in serum levels of lactate among infection diagnosis, day 3 and infection resolution.
• Effect of albumin on serum levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha) and nitric oxide (NOX) and on plasma levels of von Willebrand factor (vWF:Ag) at diagnosis and resolution of infection.
• Effect of albumin on blood leukocyte count and serum C-reactive protein levels (CRP) during infection.
• Effect of albumin on the development of other individual organ failures (renal, liver, cerebral, circulatory, coagulation and respiratory), acute-on-chronic liver failure (ACLF type 1, 2 and 3 according to the Canonic Study), CLIF-SOFA score, CLIF-Consortium score, Child-Pugh score and MELD score during hospitalization.
• Evaluation of predictive factors of HRS and ACLF development in non-SBP infections.
• Samples (blood, plasma, serum and urine) will be obtained and stored for genomic, proteomic and standard biochemical investigations in future ancillary studies related to the aim of the study.

• Study Type: Interventional
• Enrollment (Actual): 136
• Phase: Phase 4

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08036
    • Hospital Clínic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Cirrhotic patients with age ≥18 years
• Diagnosis of urinary infection, pneumonia, spontaneous or secondary bacteremia, skin/soft tissue infection, acute cholangitis or suspected bacterial infection at hospital admission or during hospitalization
• Patients with uncomplicated urinary infections or suspected bacterial infection will require the presence of signs of systemic inflammation: at least 1 diagnostic criterion of systemic inflammatory response syndrome (SIRS) and serum CRP levels ≥1 mg/dl (10 mg/L). This criterion will not be required for the rest of infections
• Analytical data of renal and/or liver dysfunction (serum creatinine ≥ 1.2 mg/dl, serum sodium ≤ 130 mEq/l, serum bilirubin ≥4 mg/dl). Patients with pneumonia or documented bacteremia (positive blood cultures) will require the presence of at least 1 of these analytical criteria to be included in the study. Patients with urinary infection, skin/soft tissue infection, acute cholangitis or suspected bacterial infection will require 2 or more criteria for inclusion

Exclusion Criteria:

• > 72h after infection diagnosis
• Pregnancy
• Acute or subacute liver failure without underlying cirrhosis
• Septic shock
• Severe acute respiratory distress syndrome (Pa02/Fi02 ≤ 100)
• Active or recent variceal bleeding unless controlled for > 48h
• Ongoing type-1 HRS (past IAC criterion: serum creatinine ≥ 2.5 mg/dl)
• Type-3 ACLF (defined according to the Canonic Study criteria)
• Hemodialysis or other renal replacement therapy
• Evidence of current malignancy (except for hepatocellular carcinoma within Milan criteria or non-melanocytic skin cancer)
• Moderate or severe chronic heart (NYHA class II, III or IV) or pulmonary disease (GOLD IV)
• Severe psychiatric disorders
• Previous liver transplantation
• HIV infection (except for patients under antiretroviral therapy with undetectable viral load, CD4>200/mm3 and no history of opportunistic infections diagnostic of AIDS)
• Contraindications to albumin (allergy, signs of pulmonary edema)
• Albumin administration (≥ 80g) in the last 2 days
• Spontaneous bacterial peritonitis coinfection
• Use of any investigational drug within 90 days prior to randomization
• Refusal to participate
• Patients who cannot provide prior informed consent and when there is documented evidence that the patient has no legal surrogate decision maker and it appears unlikely that the patient will regain consciousness or sufficient ability to provide delayed informed consent
• Physician and team not committed to intensive care if needed.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intravenous infusion of albumin; Treatment arm will receive intravenous albumin on days 1 and 3 plus antibiotics	Drug: Albumin; Intravenous infusion of 20% albumin; Other Names: Albutein 20 by Grifols
No Intervention: No albumin; Only antibiotics

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
survival	Hospital survival will be the primary outcome	hospitalization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
survival	Percentage of subjects within each arm that survived at these time points	28-d and 90-day survival
Renal dysfunction	number of participants	hospitalization (expected average 2 weeks)
circulatory dysfunction	plasma concentration of hormones	day 3 and day of infection resolution
Inflammation and endothelial function	Plasma concentration of cytokines	day of infection resolution
subsequent organ failure	number of organ failures	hospitalization (expected average 2 weeks)

Collaborators and Investigators

• Sponsor: EASL - CLIF Consortium
• Investigators: Principal Investigator: Thierry Gustot, Erasme University Hospital, Brussels, Belgium; Principal Investigator: Frederick Nevens, University Hospitals KU, Leuven, Belgium; Principal Investigator: Faouzi Saliba, Hôpital Paul Brousse, Villejuif, France; Principal Investigator: François Durand, Hôpital Beaujon, Clichy, France; Principal Investigator: Matthias Dollinger, University of Ulm, Heidelberg and Tübingen, Germany; Principal Investigator: Stefan Zeuzem, University Hospital of Frankfurt, Germany; Principal Investigator: Alexander Gerbes, University Hospital of Munich, Germany; Principal Investigator: Jonel Trebicka, University Hospital of Bonn, Germany; Principal Investigator: Henning Gronbaeck, Aarhus University Hospital, Aarhus, Denmark; Principal Investigator: Fin Stolze Larsen, Rigshospitalet, University of Copenhagen; Principal Investigator: John Willy Haukeland, Oslo University Hospital; Principal Investigator: Andrea de Gottardi, Bern University Hospital, Switzerland; Principal Investigator: Aide McCormick, University College of Dublin, Ireland; Principal Investigator: Rajiv Jalan, University College, London; Principal Investigator: Marco Domenicali, Santa Orsola-Malpighi Hospital, Bologna, Italy; Principal Investigator: Paolo Angeli, University of Padova, Italy; Principal Investigator: Carlo Alessandria, San Giovanni Battista Hospital, University of Turin, Italy; Principal Investigator: Francesco Salerno, Policlinico IRCCS San Donato, University of Milan, Italy; Principal Investigator: Agustin Albillos, Hospital Ramon y Cajal, Madrid, Spain; Principal Investigator: Victor Vargas, Hospital Vall d'Hebron, Barcelona, Spain; Principal Investigator: Javier Fernandez, Hospital CLinic, Barcelona, Spain; Principal Investigator: German Soriano, Hospital Santa Creu i Sant Pau, Barcelona, Spain; Principal Investigator: Rafael Bañares, Hospital Gregorio Marañón, Madrid, Spain; Principal Investigator: Jose Luis Montero, Hospital Reina Sofia, Cordoba, Spain; Principal Investigator: Manuela Merli, Sapienza University of Rome, Italy; Principal Investigator: Minneke Coenraad, Leiden University Medical Center; Principal Investigator: Rudolf Stauber, Medical University of Graz; Principal Investigator: Wolfgang Vogel, Medical Hospital Innsbrück

Publications and helpful links

General Publications

• Guevara M, Terra C, Nazar A, Sola E, Fernandez J, Pavesi M, Arroyo V, Gines P. Albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis. A randomized, controlled study. J Hepatol. 2012 Oct;57(4):759-65. doi: 10.1016/j.jhep.2012.06.013. Epub 2012 Jun 23.
• Thevenot T, Bureau C, Oberti F, Anty R, Louvet A, Plessier A, Rudler M, Heurgue-Berlot A, Rosa I, Talbodec N, Dao T, Ozenne V, Carbonell N, Causse X, Goria O, Minello A, De Ledinghen V, Amathieu R, Barraud H, Nguyen-Khac E, Becker C, Paupard T, Botta-Fridlung D, Abdelli N, Guillemot F, Monnet E, Di Martino V. Effect of albumin in cirrhotic patients with infection other than spontaneous bacterial peritonitis. A randomized trial. J Hepatol. 2015 Apr;62(4):822-30. doi: 10.1016/j.jhep.2014.11.017. Epub 2014 Nov 21.
• Fernandez J, Angeli P, Trebicka J, Merli M, Gustot T, Alessandria C, Aagaard NK, de Gottardi A, Welzel TM, Gerbes A, Soriano G, Vargas V, Albillos A, Salerno F, Durand F, Banares R, Stauber R, Prado V, Arteaga M, Hernandez-Tejero M, Aziz F, Morando F, Jansen C, Lattanzi B, Moreno C, Campion D, Gronbaek H, Garcia R, Sanchez C, Garcia E, Amoros A, Pavesi M, Claria J, Moreau R, Arroyo V. Efficacy of Albumin Treatment for Patients with Cirrhosis and Infections Unrelated to Spontaneous Bacterial Peritonitis. Clin Gastroenterol Hepatol. 2020 Apr;18(4):963-973.e14. doi: 10.1016/j.cgh.2019.07.055. Epub 2019 Aug 5.

Helpful Links

• Web page of the INFECIR-2 RCT

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2014
• Primary Completion (Actual): December 31, 2016
• Study Completion (Actual): February 10, 2017

Study Registration Dates

• First Submitted: January 7, 2014
• First Submitted That Met QC Criteria: January 10, 2014
• First Posted (Estimate): January 13, 2014

Study Record Updates

• Last Update Posted (Actual): May 18, 2017
• Last Update Submitted That Met QC Criteria: May 17, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: cirrhosis
• Additional Relevant MeSH Terms: Digestive System Diseases; Urologic Diseases; Bacterial Infections and Mycoses; Biliary Tract Diseases; Bile Duct Diseases; Liver Diseases; Infections; Urinary Tract Infections; Bacterial Infections; Cholangitis
• Other Study ID Numbers: INFECIR 2; 2013-002416-27 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: Undecided yet

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No