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Integrated Approaches for Identifying Molecular Targets in Liver Disease (InLi)

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ClinicalTrials.gov Identifier: NCT03915002
Recruitment Status : Recruiting
First Posted : April 16, 2019
Last Update Posted : May 5, 2020
Sponsor:
Information provided by (Responsible Party):
Ramon Bataller, University of Pittsburgh

Tracking Information
First Submitted Date April 5, 2019
First Posted Date April 16, 2019
Last Update Posted Date May 5, 2020
Actual Study Start Date June 13, 2019
Estimated Primary Completion Date April 15, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: April 12, 2019)
  • Molecular Subtypes for Targeted Therapies in Liver disease [ Time Frame: 5 years ]
    • Generation of consistent non-invasive molecular footprints of disease severity and prognosis: plasma and peripheral blood cells from groups of patients with different disease prognosis will be analyzed by means of high throughput proteomics (Mass Spectrometry and aptamer mediated identification) and single cell RNA sequencing, respectively. Data will be integrated with liver RNA-sequencing to detect relevant liver fingerprints in plasma.
    • Mechanisms of ductular reaction and hepatocyte de-differentiation will be studied by micro-dissection and region-specific RNA-sequencing.
    • Mechanisms of hepatocyte dedifferentiation will be evaluated using methylation bead chip and chromatin immunoprecipitation coupled to DNA sequencing (ChIP-seq) of histone marks related with activation, enhancement, poisoning and repression of gene expression.
  • Determination of key drivers of the disease progression [ Time Frame: 5-10 years ]
    • To describe and identified the histological patters in each phase of the disease (using imaging technics, including second harmonic generation imaging microscopy and electronic microscopy as well as classical IHC technics)
    • To quantified and compare the degree of hepatic steatosis and fibrosis assessed by non-invasive techniques such as FibroScan® (CAP controlled attenuation parameter) across different cohorts of patients and across the different stages of the disease within the same patient's phenotype.
    • To identify the main genetic. psychosocial, and environmental factors influencing the development of advanced liver fibrosis among patients with known or suspected excessive alcohol intake. Through DNA
  • repository capable of providing a framework fro the other outcomes [ Time Frame: 2-10 years ]
    To develop a bio-specimen bank comprised of plasma, DNA, and other biological specimens obtained from patients with alcoholic hepatitis, control disease and healthy controls
Original Primary Outcome Measures Same as current
Change History
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Integrated Approaches for Identifying Molecular Targets in Liver Disease
Official Title Integrated Approaches for Identifying Molecular Targets in Liver Disease
Brief Summary

To provide a framework for successful clinical trials testing novel targets for therapy in liver disease.

To identify molecular and cellular drivers of liver disease to provide a molecular classification and study the determinants or key drivers of disease progression.

Consecutive patients admitted with steatohepatitis (alcoholic or non-alcoholic) will be enrolled in this study where liver tissue, blood and stool will be collected to discover and validate factors associated with diagnosis, severity, histological characteristics, development of decompensations, progression of disease and survival.

Detailed Description Not Provided
Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
-Serum, plasma, whole blood, urine, stool, liver tissue, visceral fat and saliva
Sampling Method Non-Probability Sample
Study Population
  1. Alcoholic Steatohepatitis and Alcoholic liver disease
  2. Nonalcoholic fatty liver disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH)
Condition
  • Alcoholic Liver Disease
  • Non-Alcoholic Fatty Liver Disease
  • Steatohepatitis, Nonalcoholic
  • Steatohepatitis
Intervention Not Provided
Study Groups/Cohorts
  • Patients

    Steatohepatitis:

    1. Alcoholic Steatohepatitis and Alcoholic liver disease
    2. Nonalcoholic fatty liver disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH)
  • Disease control
    Patients 18 years or older with a diagnosis of cholestatic liver diseases (primary biliary cholangitis or primary sclerosing cholangitis) or hepatotropic virus (hepatitis C or B virus), according to the current international guidelines.
  • Control subjects

    Patients over 18 years old without a diagnosis of liver disease that for any other reason (i.e candidate to liver donor, patients with liver metastasis that require surgery, patients with any type of benign liver tumor or HCC in a healthy liver).

    Patient over 18 years old with a documented alcoholic used disorder in their clinical records and without any evidence of liver disease.

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: April 12, 2019)
1000
Original Estimated Enrollment Same as current
Estimated Study Completion Date April 15, 2030
Estimated Primary Completion Date April 15, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria

Patients with Alcoholic hepatitis:

Inclusion:

• Patients with a previous probable or possible AH episode will be defined following the guidelines proposed by the NIAAA.

Exclusion

  • Terminal illness with less than 6 months live expectancy (e.g. advanced hepatocellular
  • carcinoma).
  • Patients who are pregnant or breastfeeding.
  • Complete portal vein thrombosis (PVT).
  • Previous liver transplant recipient

Patients with cirrhosis due to alcohol related liver disease without AH with or without a prior episode of decompensation.

Inclusion:

• Patients with a diagnosis of cirrhosis due to alcohol related liver disease according to clinical and/or analytic and/or radiological criteria.

Exclusion

  • Terminal illness with less than 6 months live expectancy (e.g. advanced hepatocellular carcinoma).
  • Patients who are pregnant or breastfeeding.
  • Complete portal vein thrombosis
  • Previous liver transplant recipient
  • Current alcoholic hepatitis episode

Alcoholic liver disease with compensated never decompensated liver disease.

Inclusion:

  • Patients diagnosed with an alcohol use disorder identification test (AUDIT) total scores of 8 or more OR Patients with a score lower than 8 in the AUDIT test but for whom there is a high suspicion of current or recent (within one year) AUD based on medical history, self reported history of excessive alcohol use, stigmata of alcohol use on physical exam, liver chemistry abnormalities, or alcohol induced organ involvement other than decompensated liver disease.
  • Patients who admit having a persistent alcohol intake of more than 40 g/daily for women and 60 g/daily for men.
  • Any stage of liver disease: from simple elevation of transaminases to any METAVIR or Ishack score assess by liver biopsy or by any validated noninvasive fibrosis score.
  • Patients without a preexistent liver fibrosis assessment for whom there is a high suspicion of liver disease according to clinical and/or analytic and/or radiological criteria will also be included.

Exclusion

  • Patients with a past history of decompensated advanced liver disease (i.e. jaundice episodes, ascites, hepatic encephalopathy, variceal bleeding, hepatorenal syndrome) or known hepatocellular carcinoma.
  • Terminal illness with less than 6 months live expectancy (e.g. advanced hepatocellular carcinoma).
  • Patients who are pregnant or breastfeeding.

NonAlcoholic Fatty Liver (NAFL)

Inclusion:

• Patients with a biopsy proven steatosis or steatosis and mild lobular inflammation OR Patients without a biopsy but with a high suspicious of NAFL and with at least three of the next 5 components of metabolic syndrome. (Waist circumference≥102/≥88 cm (40/35 inches) for men/women, Arterial pressure≥130/85mmHg or treated for hypertension, Fasting glucose 100mg/dl (5.6mmol/L) or treated for Type 2 diabetes, Serum triglyceride (triacylglycerols)>150mg/dL (>1.7mmol/L) if available, HDL cholesterol <40/50mg/dl for men/women (<1/<1.3 mmol/L) if available)

Exclusion

  • Terminal illness with less than 6 months live expectancy (e.g. advanced hepatocellular carcinoma).
  • Patients who are pregnant or breastfeeding.
  • Complete portal vein thrombosis
  • Alcohol intake of more than 20g/daily.
  • Absence of other possible diagnoses (HCV and HBV negative, ANA's < 1:160, ASMA <1:80)

Patients with compensated early NASH.

Inclusion:

• Patients with a biopsy proven NASH and Metavir fibrosis score (or equivalent score) of F0-F2 OR Patients without a biopsy but with a high suspicious of NASH, with at least three of the next 5 components of metabolic syndrome and with a validated noninvasive score of F0-F2. (Waistcircumference≥102/≥88 cm (40/35 inches) for men/women, Arterial pressure≥130/85mmHg or treated for hypertension, Fasting glucose 100mg/dl (5.6mmol/L) or treated for Type 2 diabetes, Serum triglyceride (triacylglycerols) >150mg/dL (>1.7mmol/L) if available, HDL cholesterol <40/50mg/dl for men/women (<1/<1.3 mmol/L) if available)

Exclusion

  • Terminal illness with less than 6 months live expectancy (e.g. advanced hepatocellular carcinoma).
  • Patients who are pregnant or breastfeeding.
  • Complete portal vein thrombosis.
  • Alcohol intake of more than 20g/daily.
  • Absence of other possible diagnoses (HCV and HBV negative, ANA's < 1:160, ASMA <1:80).
  • Decompensated liver diseases.

Patients with NASH advance fibrosis or cirrhosis compensated or decompensated.

Inclusion:

• Patients with a biopsyproven NASH and a METAVIR fibrosis score (or equivalent score) of F3-F4 OR Patients without a biopsy proven but with a high suspicious of NASH, with at least three of the next 5 components of metabolic syndrome and with a validated noninvasive fibrosis test score of F2-F3. (Waist circumference≥102/≥88 cm (40/35 inches) for men/women, Arterial pressure≥130/85mmHg or treated for hypertension, Fasting glucose 100mg/dl (5.6mmol/L) or treated for Type 2 diabetes, Serum triglyceride (triacylglycerols)>150mg/dL (>1.7mmol/L) if available, HDL cholesterol <40/50mg/dl for men/women (<1/<1.3 mmol/L) if available)

Exclusion

  • Terminal illness with less than 6 months live expectancy (e.g. advanced hepatocellular carcinoma).
  • Patients who are pregnant or breastfeeding.
  • Complete portal vein thrombosis.
  • Alcohol intake of more than 20g/daily.
  • Absence of other possible diagnoses (HCV and HBV negative, ANA's < 1:160, ASMA < 1:80).

Dual NonAlcoholic Fatty Liver Disease and Alcoholic fatty liver disease (DAFLD) compensated or decompensated.

Inclusion:

  • Patients diagnosed with an alcohol use disorder identification test (AUDIT) total scores of 8 or more or Patients with a score lower than 8 in the AUDIT test but for whom there is a high suspicion of current or recent (within one year) AUD based on medical history, self reported history of excessive alcohol use, stigmata of alcohol use on physical exam, liver chemistry abnormalities, or alcohol induced organ involvement other than decompensated liver disease.
  • Patients who admit having a persistent alcohol intake of more than 40 g/daily for women and 60 g/daily for men.
  • At least three of the next 5 components of metabolic syndrome (Waist circumference≥102/≥88 cm (40/35 inches) for men/women, Arterial pressure≥130/85mmHg or treated for hypertension, Fasting glucose 100mg/dl (5.6mmol/L) or treated Type 2 diabetes, Serum triglyceride (triacylglycerols)>150mg/dL (>1.7mmol/L), HDL <40/50mg/dl for men/women (<1/<1.3 mmol/L).)
  • BMI≥30
  • Any stage of liver disease: from simple elevation of transaminases to any METAVIR orIshack score assess by liver biopsy or by any validated noninvasive methods.
  • Patients without a preexistent liver fibrosis assessment for whom there is a high suspicion of liver disease according to clinical and/or analytic and/or radiological criteria will also be included.

Exclusion

  • Terminal illness with less than 6 months live expectancy (e.g. advanced hepatocellular carcinoma).
  • Patients who are pregnant or breastfeeding.
  • Complete portal vein thrombosis.
  • Absence of other possible diagnoses (HCV and HBV negative, ANA's < 1:160, ASMA < 1:80).
  • A probable or possible episode of Alcoholic Hepatitis as defined by the NIAAA guidelines.
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers Yes
Contacts
Listed Location Countries United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT03915002
Other Study ID Numbers PRO18110273
Has Data Monitoring Committee Not Provided
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 Ramon Bataller, University of Pittsburgh
Study Sponsor University of Pittsburgh
Collaborators Not Provided
Investigators Not Provided
PRS Account University of Pittsburgh
Verification Date May 2020