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Secondary Sclerosis Cholangitis Prospective (SSCpro)

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ClinicalTrials.gov Identifier: NCT03566797
Recruitment Status : Recruiting
First Posted : June 25, 2018
Last Update Posted : August 8, 2019
Sponsor:
Information provided by (Responsible Party):
Medical University of Graz

Tracking Information
First Submitted Date May 7, 2018
First Posted Date June 25, 2018
Last Update Posted Date August 8, 2019
Actual Study Start Date July 20, 2018
Estimated Primary Completion Date June 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: June 21, 2018)
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
Original Primary Outcome Measures Same as current
Change History Complete list of historical versions of study NCT03566797 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures
 (submitted: June 21, 2018)
  • Gut microbiome composition [ Time Frame: at inclusion ]
    16S rRNA sequencing
  • Stool zonulin [ Time Frame: at inclusion ]
    gut permeability marker, ELISA
  • Stool calprotectin [ Time Frame: at inclusion ]
    gut inflammation marker, ELISA
  • Serum endotoxin [ Time Frame: at inclusion ]
    bacterial translocation marker, cell-based assay
  • Serum lipopolysaccharide binding protein [ Time Frame: at inclusion ]
    bacterial translocation marker, ELISA
  • soluble cluster of differentiation 14 (sCD14) [ Time Frame: at inclusion ]
    bacterial translocation marker, ELISA
  • bile acid transporter polymorphisms [ Time Frame: at inclusion ]
    sequencing of bile acid transporter genes
  • NOD2 polymorphisms [ Time Frame: at inclusion ]
    sequencing of the NOD2 gene
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Secondary Sclerosis Cholangitis Prospective
Official Title Secondary Sclerosing Cholangitis in Critically Ill Patients (SC-CIP): A Prospective Cohort Study
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.
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.

Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
DNA, serum, plasma, stool urine
Sampling Method Probability Sample
Study Population Patients admitted to Intensive Care Units at the University Hospital Graz
Condition Secondary Sclerosis Cholangitis in Critically Ill Patients
Intervention Not Provided
Study Groups/Cohorts
  • SC-CIP
    Patients developing SC-CIP
  • noSC-CIP
    Patients with similar severity of critical illness not developing SC-CIP
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: June 21, 2018)
380
Original Estimated Enrollment Same as current
Estimated Study Completion Date June 1, 2022
Estimated Primary Completion Date June 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria

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
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts
Listed Location Countries Austria
Removed Location Countries  
 
Administrative Information
NCT Number NCT03566797
Other Study ID Numbers SC_prospective
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement Not Provided
Responsible Party Medical University of Graz
Study Sponsor Medical University of Graz
Collaborators Not Provided
Investigators Not Provided
PRS Account Medical University of Graz
Verification Date August 2019