- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03634098
Identification and Validation of Noninvasive Biomarkers of the Diagnosis and Severity of NASH in Type 2 Diabetics (Quid-Nash)
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
Status
Conditions
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
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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-
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Clichy, France
- Hopital Beaujon
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
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
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:
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magnetic resonance +/- Primovist and ultrafast ultrasound UFUS +Sonovue
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Experimental: T2D liver test abnormalities's participants
Exams performed on type 2 diabetic patients with liver test abnormalities :
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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
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No Intervention: T2D participants without liver test abnormality
type 2 diabetic participants without liver test abnormality and not undergoing liver biopsy
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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
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Histological diagnosis of NASH (as established by centralized re-reading of liver biopsy slides), blinded to omic results and imaging.
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1 month
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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
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diagnosis of clinically significant liver metabolic disease (SAF-Score ≥A2 or ≥F2) adjudicated by an independent committee
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1 month
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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
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histological diagnosis of elementary lesions of NASH (lobular inflammation, ballooning, steatosis)
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1 month
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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
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By MRI: steatosis, biomechanical properties, T1, diffusivity
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1 month
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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
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By AixPlorer ultrasound: steatosis, biomechanical properties, vascular properties
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1 month
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To study in type 2 diabetic participants the performance of second-generation tests for the diagnosis of metabolic liver diseases
Time Frame: 1 day
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metabolic liver disease (adjudicated by an independent committee)
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1 day
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Constitution of a bio-collection
Time Frame: 1 month
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stool
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1 month
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Constitution of a bio-collection
Time Frame: 1 month
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urine
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1 month
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Constitution of a bio-collection
Time Frame: 1 month
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plasma
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1 month
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Constitution of a bio-collection
Time Frame: 1 month
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serum
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1 month
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Constitution of a bio-collection
Time Frame: 1 month
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mononuclear cells of peripheral blood
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1 month
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Constitution of a bio-collection
Time Frame: 1 month
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Liver tissue
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1 month
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Collaborators and Investigators
Investigators
- Principal Investigator: Laurent Castera, APHP
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
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)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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