title: The INCA trial (Impact of NOD2 genotype-guided antibiotic prevention on survival in patients with liver Cirrhosis and Ascites): study protocol for a randomized controlled trial.
abstract: BACKGROUND
  Patients with liver cirrhosis have a highly elevated risk of developing bacterial infections that significantly decrease survival rates. One of the most relevant infections is spontaneous bacterial peritonitis (SBP). Recently, NOD2 germline variants were found to be potential predictors of the development of infectious complications and mortality in patients with cirrhosis. The aim of the INCA (Impact of NOD2 genotype-guided antibiotic prevention on survival in patients with liver Cirrhosis and Ascites) trial is to investigate whether survival of this genetically defined high-risk group of patients with cirrhosis defined by the presence of NOD2 variants is improved by primary antibiotic prophylaxis of SBP.
  
  
  METHODS
  The INCA trial is a double-blind, placebo-controlled clinical trial with two parallel treatment arms (arm 1: norfloxacin 400 mg once daily; arm 2: placebo once daily; 12-month treatment and observational period). Balanced randomization of 186 eligible patients with stratification for the protein content of the ascites (<15 versus ≥ 15 g/L) and the study site is planned. In this multicenter national study, patients are recruited in at least 13 centers throughout Germany. The key inclusion criterion is the presence of a NOD2 risk variant in patients with decompensated liver cirrhosis. The most important exclusion criteria are current SBP or previous history of SBP and any long-term antibiotic prophylaxis. The primary endpoint is overall survival after 12 months of treatment. Secondary objectives are to evaluate whether the frequencies of SBP and other clinically relevant infections necessitating antibiotic treatment, as well as the total duration of unplanned hospitalization due to cirrhosis, differ in both study arms. Recruitment started in February 2014.
  
  
  CONCLUSIONS
  Preventive strategies are required to avoid life-threatening infections in patients with liver cirrhosis, but unselected use of antibiotics can trigger resistant bacteria and worsen outcome. Thus, individualized approaches that direct intervention only to patients with the highest risk are urgently needed. This trial meets this need by suggesting stratified prevention based on genetic risk assessment. To our knowledge, the INCA trial is first in the field of hepatology aimed at rapidly transferring and validating information on individual genetic risk into clinical decision algorithms.
  
  
  BACKGROUND
  German Clinical Trials Register DRKS00005616 . Registered 22 January 2014. EU Clinical Trials Register EudraCT 2013-001626-26 . Registered 26 January 2015.
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Kirrberger Straße 100, 66421, Homburg, Germany. markus.casper@uks.eu.
authors.forename: Markus
authors.initials: M
authors.lastname: Casper
authors.affiliation: Study Center Bonn, Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Sigmund-Freud-Straße 25, 53125, Bonn, Germany. martinmengel@web.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Mengel
authors.affiliation: Study Center Bonn, Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Sigmund-Freud-Straße 25, 53125, Bonn, Germany. christine.fuhrmann@ukb.uni-bonn.de.
authors.forename: Christine
authors.initials: C
authors.lastname: Fuhrmann
authors.affiliation: Institute for Biostatistics and Mathematical Modelling, Goethe University Hospital, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany. herrmann@med.uni-frankfurt.de.
authors.forename: Eva
authors.initials: E
authors.lastname: Herrmann
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Kirrberger Straße 100, 66421, Homburg, Germany. beate.appenrodt@uks.eu.
authors.forename: Beate
authors.initials: B
authors.lastname: Appenrodt
authors.affiliation: Department of Medicine, Nardini Hospital, Kaiserstraße 14, 66482, Zweibrücken, Germany. schiedermaier@nardiniklinikum.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Schiedermaier
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Kirrberger Straße 100, 66421, Homburg, Germany. matthias.reichert@uks.eu.
authors.forename: Matthias
authors.initials: M
authors.lastname: Reichert
authors.affiliation: Department of Medicine IV, University Hospital Jena, Bachstraße 18, 07743, Jena, Germany. tony.bruns@med.uni-jena.de.
authors.forename: Tony
authors.initials: T
authors.lastname: Bruns
authors.affiliation: Department of Medicine II, University Hospital Leipzig, Liebigstraße 18, 04103, Leipzig, Germany. cornelius.engelmann@medizin.uni-leipzig.de.
authors.forename: Cornelius
authors.initials: C
authors.lastname: Engelmann
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Kirrberger Straße 100, 66421, Homburg, Germany. frank.gruenhage@uks.eu.
authors.forename: Frank
authors.initials: F
authors.lastname: Grünhage
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Kirrberger Straße 100, 66421, Homburg, Germany. frank.lammert@uks.eu.
authors.forename: Frank
authors.initials: F
authors.lastname: Lammert
mesh_terms: D019072:Antibiotic Prophylaxis; D001201:Ascites / Q000401:mortality*; D002985:Clinical Protocols; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D005838:Genotype; D006801:Humans; D008103:Liver Cirrhosis / Q000401:mortality*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D018401:Sample Size
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein