Clinical trial NCT02034279: The INFECIR-2 Albumin Prevention Study
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Advanced Chronic Liver Disease
Urinary Infection
Pneumonia
Cholangitis
Other Bacterial Diseases
Keywords: cirrhosis
Lead sponsor: EASL - CLIF Consortium
Sponsor class: OTHER
First posted: 2014-01-13
Enrollment: 136
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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).

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.

Eligibility criteria: 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.

Primary outcomes:
measure: survival
timeFrame: hospitalization
Secondary outcomes:
measure: survival
timeFrame: 28-d and 90-day survival
measure: Renal dysfunction
timeFrame: hospitalization (expected average 2 weeks)
measure: circulatory dysfunction
timeFrame: day 3 and day of infection resolution
measure: Inflammation and endothelial function
timeFrame: day of infection resolution
measure: subsequent organ failure
timeFrame: hospitalization (expected average 2 weeks)
Other outcomes:
Locations:
city: Barcelona
country: Spain
facility: Hospital Clinic
Study officials:
affiliation: Erasme University Hospital, Brussels, Belgium
name: Thierry Gustot
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospitals KU, Leuven, Belgium
name: Frederick Nevens
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Paul Brousse, Villejuif, France
name: Faouzi Saliba
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Beaujon, Clichy, France
name: François Durand
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Ulm, Heidelberg and Tübingen, Germany
name: Matthias Dollinger
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital of Frankfurt, Germany
name: Stefan Zeuzem
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital of Munich, Germany
name: Alexander Gerbes
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital of Bonn, Germany
name: Jonel Trebicka
role: PRINCIPAL_INVESTIGATOR
affiliation: Aarhus University Hospital
name: Henning Gronbaeck
role: PRINCIPAL_INVESTIGATOR
affiliation: Rigshospitalet, University of Copenhagen
name: Fin Stolze Larsen
role: PRINCIPAL_INVESTIGATOR
affiliation: Oslo University Hospital
name: John Willy Haukeland
role: PRINCIPAL_INVESTIGATOR
affiliation: Bern University Hospital, Switzerland
name: Andrea de Gottardi
role: PRINCIPAL_INVESTIGATOR
affiliation: University College of Dublin, Ireland
name: Aide McCormick
role: PRINCIPAL_INVESTIGATOR
affiliation: University College, London
name: Rajiv Jalan
role: PRINCIPAL_INVESTIGATOR
affiliation: Santa Orsola-Malpighi Hospital, Bologna, Italy
name: Marco Domenicali
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Padova, Italy
name: Paolo Angeli
role: PRINCIPAL_INVESTIGATOR
affiliation: San Giovanni Battista Hospital, University of Turin, Italy
name: Carlo Alessandria
role: PRINCIPAL_INVESTIGATOR
affiliation: Policlinico IRCCS San Donato, University of Milan, Italy
name: Francesco Salerno
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Ramon y Cajal, Madrid, Spain
name: Agustin Albillos
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Vall d'Hebron, Barcelona, Spain
name: Victor Vargas
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Clinic, Barcelona, Spain
name: Javier Fernandez
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Santa Creu i Sant Pau, Barcelona, Spain
name: German Soriano
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Gregorio Marañon, Madrid, Spain
name: Rafael Bañares
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Reina Sofia, Cordoba, Spain
name: Jose Luis Montero
role: PRINCIPAL_INVESTIGATOR
affiliation: Sapienza University of Rome, Italy
name: Manuela Merli
role: PRINCIPAL_INVESTIGATOR
affiliation: Leiden University Medical Center
name: Minneke Coenraad
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical University of Graz
name: Rudolf Stauber
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical Hospital Innsbrück
name: Wolfgang Vogel
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.