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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.

Casper M, Mengel M, Fuhrmann C, Herrmann E, Appenrodt B, Schiedermaier P, Reichert M, Bruns T, Engelmann C, Grünhage F, Lammert F, INCA trial gro - Trials (2015)

Bottom Line: Recently, NOD2 germline variants were found to be potential predictors of the development of infectious complications and mortality in patients with cirrhosis.Recruitment started in February 2014.Thus, individualized approaches that direct intervention only to patients with the highest risk are urgently needed.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine II, Saarland University Medical Center, Kirrberger Straße 100, 66421, Homburg, Germany. markus.casper@uks.eu.

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/design: 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.

Discussion: 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.

Trial registrations: German Clinical Trials Register DRKS00005616 . Registered 22 January 2014. EU Clinical Trials Register EudraCT 2013-001626-26 . Registered 26 January 2015.

No MeSH data available.


Related in: MedlinePlus

Study flowchart. Overall, 186 patients meeting the inclusion criteria and no exclusion criteria are randomly assigned to two treatment arms. Especially, present SBP has to be ruled out, and patients have to be verified to carry at least one of the three common NOD2 variants. It is expected that about 1,400 patients need to be evaluated to finally randomize the calculated 186 patients. SBP, Spontaneous bacterial peritonitis.
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Fig1: Study flowchart. Overall, 186 patients meeting the inclusion criteria and no exclusion criteria are randomly assigned to two treatment arms. Especially, present SBP has to be ruled out, and patients have to be verified to carry at least one of the three common NOD2 variants. It is expected that about 1,400 patients need to be evaluated to finally randomize the calculated 186 patients. SBP, Spontaneous bacterial peritonitis.

Mentions: The trial has been designed to assess the effect of antibiotic primary prophylaxis on survival in carriers of NOD2 risk variants without SBP. Figure 1 summarizes the design of the study. The INCA trial is a double-blind, placebo-controlled clinical trial with two parallel treatment arms. It is planned to randomly allocate 186 eligible patients to one of these arms (1:1 ratio). Balanced randomization, stratified for the protein content of the ascites (<15 g/L or ≥15 g/L, given that a low protein content is an established risk factor for SBP) and the study center, will be performed as centralized, computer-based block randomization using separate randomization lists for each stratum. Only the central and independent pharmacy (Heidelberg University Hospital) performing the randomization procedure, and neither the investigators nor the patients, will be aware of the allocation sequence or the block size used. Blinding of participants and study personnel responsible for treatment and outcome assessment is ensured by identical encapsulation of placebo and active substance that makes both indistinguishable, as well as by the use of identical blisters and folding boxes. The unique patient randomization number labeled on the boxes makes the medication patient-specific. The confidential block size ensures randomization concealment after emergency un-blinding because of safety reasons or after unblinding due to SBP. Access to emergency envelopes is regulated at all sites.Figure 1


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.

Casper M, Mengel M, Fuhrmann C, Herrmann E, Appenrodt B, Schiedermaier P, Reichert M, Bruns T, Engelmann C, Grünhage F, Lammert F, INCA trial gro - Trials (2015)

Study flowchart. Overall, 186 patients meeting the inclusion criteria and no exclusion criteria are randomly assigned to two treatment arms. Especially, present SBP has to be ruled out, and patients have to be verified to carry at least one of the three common NOD2 variants. It is expected that about 1,400 patients need to be evaluated to finally randomize the calculated 186 patients. SBP, Spontaneous bacterial peritonitis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4359533&req=5

Fig1: Study flowchart. Overall, 186 patients meeting the inclusion criteria and no exclusion criteria are randomly assigned to two treatment arms. Especially, present SBP has to be ruled out, and patients have to be verified to carry at least one of the three common NOD2 variants. It is expected that about 1,400 patients need to be evaluated to finally randomize the calculated 186 patients. SBP, Spontaneous bacterial peritonitis.
Mentions: The trial has been designed to assess the effect of antibiotic primary prophylaxis on survival in carriers of NOD2 risk variants without SBP. Figure 1 summarizes the design of the study. The INCA trial is a double-blind, placebo-controlled clinical trial with two parallel treatment arms. It is planned to randomly allocate 186 eligible patients to one of these arms (1:1 ratio). Balanced randomization, stratified for the protein content of the ascites (<15 g/L or ≥15 g/L, given that a low protein content is an established risk factor for SBP) and the study center, will be performed as centralized, computer-based block randomization using separate randomization lists for each stratum. Only the central and independent pharmacy (Heidelberg University Hospital) performing the randomization procedure, and neither the investigators nor the patients, will be aware of the allocation sequence or the block size used. Blinding of participants and study personnel responsible for treatment and outcome assessment is ensured by identical encapsulation of placebo and active substance that makes both indistinguishable, as well as by the use of identical blisters and folding boxes. The unique patient randomization number labeled on the boxes makes the medication patient-specific. The confidential block size ensures randomization concealment after emergency un-blinding because of safety reasons or after unblinding due to SBP. Access to emergency envelopes is regulated at all sites.Figure 1

Bottom Line: Recently, NOD2 germline variants were found to be potential predictors of the development of infectious complications and mortality in patients with cirrhosis.Recruitment started in February 2014.Thus, individualized approaches that direct intervention only to patients with the highest risk are urgently needed.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine II, Saarland University Medical Center, Kirrberger Straße 100, 66421, Homburg, Germany. markus.casper@uks.eu.

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/design: 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.

Discussion: 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.

Trial registrations: German Clinical Trials Register DRKS00005616 . Registered 22 January 2014. EU Clinical Trials Register EudraCT 2013-001626-26 . Registered 26 January 2015.

No MeSH data available.


Related in: MedlinePlus