Identification and Validation of Noninvasive Biomarkers of the Diagnosis and Severity of NASH in Type 2 Diabetics (Quid-Nash)

December 7, 2022 updated by: Assistance Publique - Hôpitaux de Paris

Identification and Validation of Noninvasive Biomarkers (Virtual Biopsy) of the Diagnosis and Severity of NASH in Type 2 Diabetics: a Cross-sectional Study

Metabolic diseases of the liver are silent affections whose morbidity is important. About 70% of patients with type 2 diabetes (T2D) are concerned. Of these, 50% develop clinically significant lesions (including non-alcoholic steatohepatitis or NASH) as they are associated with an increased risk of complications; and 15% progress to severe fibrosis or cirrhosis. These diseases are slowly progressive and asymptomatic. Their pathophysiology is poorly known. Management is hampered by the absence of a specific diagnostic marker, the need for invasive diagnostic procedures (liver biopsy), and the lack of established treatment.

QUID-NASH aims to develop a virtual liver biopsy in T2D participants, based on the identification of single or combined, multimodal, non-invasive biomarkers obtained by new quantitative imaging techniques (magnetic resonance and ultrafast ultrasound UFUS); and /or extensive clinical-biological phenotyping data; and/or data obtained by different omic approaches (metabolomics, targeted genetics, transcriptomics). Extracellular vesicle and immune cell profiling will complement these phenotyping data. This approach will also enable us to improve our understanding of pathophysiology (new signaling pathways, new therapeutic targets).

Study Overview

Detailed Description

Metabolic diseases of the liver are silent affections whose morbidity is important. About 70% of patients with type 2 diabetes (T2D) are concerned. Of these, 50% develop clinically significant lesions (including non-alcoholic steatohepatitis or NASH) as they are associated with an increased risk of complications; and 15% progress to severe fibrosis or cirrhosis. These diseases are slowly progressive and asymptomatic. Their pathophysiology is poorly known. Management is hampered by the absence of a specific diagnostic marker, the need for invasive diagnostic procedures (liver biopsy), and the lack of established treatment. Non-invasive methods ("first-generation" tests) have recently seen significant growth: commercialization of FibroTest as a marker of fibrosis; FibroTest, Fibrometer and FibroScan, for the initial assessment of adult chronic hepatitis C; FibroTest, Fibrometer, and Enhanced Liver Fibrosis test (ELF-test) for diagnosis of metabolic liver disease and diagnosis of fibrosis; SteatoTest (APHP patent) for the diagnosis of steatosis. The ActiTest (APHP patent) is widely used in evaluating the necrotic-inflammatory activity of chronic viral hepatitis C and B. For the diagnosis of NASH alone the ActiTest is validated. The NashTest (APHP patent) is little used. Several biomarkers of imaging (liver ultrasound, FibroScan Controller Attenuated Parameter (CAP), elastography and nuclear magnetic resonance) are widely used for the diagnosis of steatosis. Two new "second generation" blood tests (APHP patents) are under development, Non Invasive Test-NASHr (NIT-NASHr), and NIT-A2F2. NIT-NASHr is a new combination of the components of SteatoTest and NASH-Test to assess the severity of NASH. NIT-A2F2 is a combination of NIT-NASHr and FibroTest for the diagnosis of clinically significant liver metabolic disease. These tests will be the subject in the project of a validation of their performances in the context of use (T2D without other liver disease). At the same time, significant progress has been made in integrating omic data to characterize various pathologies and to identify their mechanisms. The transcriptomics and metabolomics of body fluids are particularly promising for the construction of "third generation" tests.

QUID-NASH aims to develop a virtual liver biopsy in T2D participants, based on the identification of single or combined, multimodal, non-invasive biomarkers obtained by new quantitative imaging techniques (magnetic resonance and ultrafast ultrasound UFUS); and / or extensive clinical-biological phenotyping data; and / or data obtained by different omic approaches (metabolomics, targeted genetics, transcriptomics). Extracellular vesicle and immune cell profiling will complement this data. This approach will also enable us to improve knowledge of the pathology (new signaling pathways, new therapeutic targets).

Study Type

Interventional

Enrollment (Actual)

970

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Clichy, France
        • Hopital Beaujon

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Pilot phase : Volunteers (for reproducibility study) Inclusion criteria

  • Voluntary
  • Person aged 18 or over

Criteria for non-inclusion

  • Refusal or inability to sign consent
  • Vulnerable person according to article L1121-6 of the CSP
  • Protected person of age

Clinical Study of Clinically Significant NASH or NASH Markers Performance with Standard NASH Criteria (patient with liver biopsy) Inclusion criteria

  • Participant aged 18 or over
  • Diabetic type 2 (ADA / WHO criteria mentioned in section 20.5)
  • Liver biopsy planned in day hospital (HDJ) as part of routine care (indication of biopsy: or ALT> 30 IU for men or> 20 IU for women less than 1 month old) and/or steatosis on ultrasound )
  • Hemoglobin> 7g / dL (or> 10 g / dL in case of cardiovascular or respiratory pathology)

Criteria for non-inclusion

  • Refusal or inability to sign consent
  • Vulnerable person: person deprived of liberty by a judicial or administrative decision, or subject to psychiatric care, and person admitted to a health or social institution for purposes other than that of research
  • Protected person of age
  • No affiliation or non-beneficiary of a social security scheme
  • Pregnant or lactating woman
  • Contraindication to MRI according to the French Society of Radiology (mentioned in section 20.4)
  • Corpulence incompatible with the realization of an MRI
  • Disease related to other etiologies

    • Alcoholic liver disease
    • Current infection of hepatitis B virus
    • Current infection of hepatitis C virus
    • Autoimmune hepatitis according to AASLD and EASL oTransferrin saturation>50%
    • Alpha-1 antitrypsin deficiency ZZ or SZ
    • Wilson's disease
    • Obstruction of the blood vessels or bile ducts on ultrasound (on routine ultrasound If nothing is mentioned on the report, it is considered that there is no obstruction of the vessels blood or bile ducts)
  • Liver transplant

Subgroup with Primovist:

-Contraindication to gadoxetic acid: Hypersensitivity to gadoxetic acid or to one of the excipients depending on the composition. Severe renal faillure (GFR <30 mL / min / 1.73 m²).

Subgroup with Sonovue:

-Any contraindication to Sonovue®, namely: hypersensitivity to sulfur hexafluoride or to one of the excipients of the specialty, right-left shunt, severe pulmonary arterial hypertension (> 90 mmHg), uncontrolled systemic hypertension, respiratory distress syndrome in adults, combination with dobutamine

Clinical study of the performance of second-generation tests for the diagnosis of metabolic liver disease: border population Inclusion criteria

  • Consecutive patients aged 18 years or over
  • Diabetic Type 2 (ADA / WHO criteria mentioned in section 20.5)

Criteria for non-inclusion

  • Refusal or inability to sign consent
  • Vulnerable person: person deprived of liberty by a judicial or administrative decision, person under psychiatric care and person admitted to a health or social institution for purposes other than research
  • Protected person of age

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Volunteers

Exams performed on volunteers with other purpose than liver disease or diabetes in two centers:

  • MRI
  • Ultrasound AixPlorer These examinations are carried out in 2 differents centers at 1month intervals
magnetic resonance +/- Primovist and ultrafast ultrasound UFUS +Sonovue
Experimental: T2D liver test abnormalities's participants

Exams performed on type 2 diabetic patients with liver test abnormalities :

  • sample for analysis and biocollection
  • MRI +/-Primovist
  • Ultrasound AixPlorer +Sonovue
magnetic resonance +/- Primovist and ultrafast ultrasound UFUS +Sonovue
extensive clinical-biological phenotyping data; and / or data obtained by different omic approaches (metabolomics, targeted genetics, transcriptomics). Extracellular vesicle and immune cell profiling will complement this data
second generation tests NIT-NASHr et NIT-A2F2
No Intervention: T2D participants without liver test abnormality
type 2 diabetic participants without liver test abnormality and not undergoing liver biopsy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To study in type 2 diabetic participants with liver biopsy, the performance of a composite biomarker (3rd generation test) for the diagnosis of NASH
Time Frame: 1 month
Histological diagnosis of NASH (as established by centralized re-reading of liver biopsy slides), blinded to omic results and imaging.
1 month

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To study in type 2 diabetic participants with or without liver biopsy, performance of a composite biomarker for the diagnosis of clinically significant metabolic liver diseases
Time Frame: 1 month
diagnosis of clinically significant liver metabolic disease (SAF-Score ≥A2 or ≥F2) adjudicated by an independent committee
1 month
To study in type 2 diabetic participants with liver biopsy, the performance of a single or composite biomarker for the diagnosis of NASH elemental lesions
Time Frame: 1 month
histological diagnosis of elementary lesions of NASH (lobular inflammation, ballooning, steatosis)
1 month
To study inter-center and intra-participants reproducibility of imaging measurements. a graphical evaluation will be conducted using a representation of Bland-Altman.
Time Frame: 1 month
By MRI: steatosis, biomechanical properties, T1, diffusivity
1 month
To study inter-center and intra-participants reproducibility of imaging measurements.a graphical evaluation will be conducted using a representation of Bland-Altman.
Time Frame: 1 month
By AixPlorer ultrasound: steatosis, biomechanical properties, vascular properties
1 month
To study in type 2 diabetic participants the performance of second-generation tests for the diagnosis of metabolic liver diseases
Time Frame: 1 day
metabolic liver disease (adjudicated by an independent committee)
1 day
Constitution of a bio-collection
Time Frame: 1 month
stool
1 month
Constitution of a bio-collection
Time Frame: 1 month
urine
1 month
Constitution of a bio-collection
Time Frame: 1 month
plasma
1 month
Constitution of a bio-collection
Time Frame: 1 month
serum
1 month
Constitution of a bio-collection
Time Frame: 1 month
mononuclear cells of peripheral blood
1 month
Constitution of a bio-collection
Time Frame: 1 month
Liver tissue
1 month

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Laurent Castera, APHP

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 25, 2018

Primary Completion (Actual)

July 31, 2022

Study Completion (Actual)

September 30, 2022

Study Registration Dates

First Submitted

July 16, 2018

First Submitted That Met QC Criteria

August 14, 2018

First Posted (Actual)

August 16, 2018

Study Record Updates

Last Update Posted (Estimate)

December 8, 2022

Last Update Submitted That Met QC Criteria

December 7, 2022

Last Verified

March 1, 2022

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • P171105j
  • 2018-A00311-54 (Other Identifier: IDRCB)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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