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Secondary Sclerosis Cholangitis Prospective (SSCpro)

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03566797
Recruitment Status : Recruiting
First Posted : June 25, 2018
Last Update Posted : August 8, 2019
Information provided by (Responsible Party):
Medical University of Graz

Brief Summary:
SC-CIP is increasing in patients after critical illness. Pathogenesis is still largely unclear. Gut microbiome composition, gut permeability, bacterial translocation, inflammation and/or genetic variants contribute to the pathogenesis The aim of this project is to study gut microbiome composition, gut permeability, bacterial translocation, inflammation, bile acid composition and genetic polymorphisms by conducting a prospective cohort study in patients with a high risk to develop SC-CIP.

Condition or disease
Secondary Sclerosis Cholangitis in Critically Ill Patients

Detailed Description:

Secondary sclerosing cholangitis in critically ill patients (SC-CIP) is a rare, quickly progressive, cholestatic liver disease which is observed in patients suffering from a severe illness with the need for long term treatment on an intensive care unit (ICU). Invasive ventilation, polytrauma, hypotension, systemic inflammatory response syndrome, burns, complex operations and severe (co-) morbidities such as obesity have been discussed as risk factors. Patients suffering from SC-CIP do not have any underlying liver disease. Usually, long- term ICU treatment is described as the trigger mechanism for the development of this disease, although also rapid development of SC-CIP after an ICU stay as short as nine days is described in a single case.

The pathogenesis of SC-CIP is not fully understood yet: Ischemic injury of the intrahepatic biliary system, bile cast formation and recurrent biliary infections are discussed as major factors. The disease leads to a progressive destruction of the intra- and extrahepatic biliary tree with the development of strictures resulting in liver fibrosis with in some cases rapid progression to cirrhosis with the need for liver transplantation within months. The gold standard for diagnosis is endoscopic retrograde cholangiopancreaticography (ERCP), although magnetic resonance cholangiopancreatography (MRCP) as non-invasive alternative can lead to the diagnosis in most cases. Prognosis is poor and transplant-free survival has been found to be 40 months in average. Liver transplantation is the only curative treatment, which shows excellent outcome and quality of life comparable to other indication for liver transplantation.

Microbiological analysis of bile from patients with SC-CIP and primary sclerosing cholangitis (PSC) show a significant different microbiological profile in these two cohorts with dominance of drug resistant organisms in the bile of SC-CIP. No data on the gut microbiome in SC-CIP are available so far. Other chronic liver diseases show distinct changes in microbiome composition with potential influence on the inflammation process in these liver diseases (non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, PSC and liver cirrhosis). In general a decrease in diversity, a higher abundance of potentially pathogenic species and a lower abundance of beneficial species has been observed.

Dysbiosis is thought to increase intestinal permeability. Increased gut permeability is most frequently observed in liver cirrhosis but was also found in alcohol-induced injury, NAFLD and hepatitis C-mediated liver injury. With an impaired gut permeability bacteria from the intestinal lumen can be translocated into extraintestinal parts of the body (lymph nodes, blood) and prompt inflammatory responses. Genetic polymorphisms in the Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene, a known risk factor for bacterial translocation, increases the odds of developing SC-CIP.

It is hypothesized that the gut microbiome composition is altered in SC-CIP and that this is associated with increased gut permeability and markers of inflammation. Reasons for this might lie in gene polymorphisms influencing bacterial translocation or bile acid composition.

The aim of this study is to prospectively assess the incidence of SC-CIP in a cohort of patients at risk for developing SC-CIP (ICU treatment with the need for mechanical ventilation or extracorporeal membrane oxygenation >/= 5 days) and study differences in gut microbiome composition, gut permeability, bacterial translocation, inflammation as well as genetic polymorphisms in patients developing SC-CIP and patients with comparable disease severity who did not develop SC-CIP.

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Study Type : Observational
Estimated Enrollment : 380 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Secondary Sclerosing Cholangitis in Critically Ill Patients (SC-CIP): A Prospective Cohort Study
Actual Study Start Date : July 20, 2018
Estimated Primary Completion Date : June 1, 2021
Estimated Study Completion Date : June 1, 2022

Patients developing SC-CIP
Patients with similar severity of critical illness not developing SC-CIP

Primary Outcome Measures :
  1. Incidence of SC-CIP in patients at risk [ Time Frame: during hospital stay, on average 4 weeks ]
    risk is defined as need for mechanical ventilation or extracorporeal membrane oxygenation >/= 5 days

Secondary Outcome Measures :
  1. Gut microbiome composition [ Time Frame: at inclusion ]
    16S rRNA sequencing

  2. Stool zonulin [ Time Frame: at inclusion ]
    gut permeability marker, ELISA

  3. Stool calprotectin [ Time Frame: at inclusion ]
    gut inflammation marker, ELISA

  4. Serum endotoxin [ Time Frame: at inclusion ]
    bacterial translocation marker, cell-based assay

  5. Serum lipopolysaccharide binding protein [ Time Frame: at inclusion ]
    bacterial translocation marker, ELISA

  6. soluble cluster of differentiation 14 (sCD14) [ Time Frame: at inclusion ]
    bacterial translocation marker, ELISA

  7. bile acid transporter polymorphisms [ Time Frame: at inclusion ]
    sequencing of bile acid transporter genes

  8. NOD2 polymorphisms [ Time Frame: at inclusion ]
    sequencing of the NOD2 gene

Biospecimen Retention:   Samples With DNA
DNA, serum, plasma, stool urine

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Patients admitted to Intensive Care Units at the University Hospital Graz

Inclusion Criteria:

  • Participant is willing and able to give informed consent for participation in the study OR "surrogate consent" by the institutional review board.
  • Age above 18 years
  • Mechanical ventilation or extracorporeal membrane oxygenation >/= 5 days

Exclusion Criteria:

  • Primary or secondary sclerosing cholangitis diagnosed before current ICU admission

Information from the National Library of Medicine

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): NCT03566797

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Medical University Graz Recruiting
Graz, Austria
Contact: Vanessa Stadlbauer-Köllner, MD    0043 316 385 ext 82282   
Sponsors and Collaborators
Medical University of Graz

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Responsible Party: Medical University of Graz Identifier: NCT03566797    
Other Study ID Numbers: SC_prospective
First Posted: June 25, 2018    Key Record Dates
Last Update Posted: August 8, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasm Metastasis
Critical Illness
Pathologic Processes
Neoplastic Processes
Disease Attributes
Bile Duct Diseases
Biliary Tract Diseases
Digestive System Diseases