Global Research Initiative for Patients Screening on NASH

Study Overview
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Brief Summary
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GRIP on NASH will assist primary care physicians and clinicians to implement the latest patient care pathway, as described by the European Association for the Study of the Liver (EASL), to identify patients at risk of severe fatty liver disease and to raise awareness on fatty liver disease. The primary objective is to implement a transmural patient care pathway, in order to identify patients with non-alcoholic fatty liver diseases (NAFLD) and its progressive form non-alcoholic steatohepatitis (NASH) in primary care centres and clinics in 10 European countries.

Detailed Description
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GRIP on NASH is an observational study in which 10.000 high risk patients (type 2 diabetes mellitus, metabolic syndrome, obesity or arterial hypertension) in 10 different European countries will be screened for the presence of non-alcoholic fatty liver disease and liver fibrosis using two non-invasive tests (FIB-4 and FibroScan). Blood samples and liver biopsy material will be collected. Genomic, proteomic, metabolomic and lipidomic studies will be applied to gain a better understanding of the pathophysiology of non-alcoholic fatty liver disease and to identify (bio)markers that will help to detect patients at risk. The predictive value of FIB-4 in relation to FibroScan results and liver biopsy will be analysed. Long-term follow-up of 5 years in all participants will provide insight into the natural history of the disease.

Official Title
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Global Research Initiative for Patients Screening on NASH - Implementation of an International Transmural Patient Care Pathway

Conditions
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NASH, NAFLD, NASH With Fibrosis, Fibrosis, Liver, Steatosis of Liver, Type 2 Diabetes, Obesity, Metabolic Syndrome, Arterial Hypertension

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed subjects should fulfil criteria for diagnosis of type 2 diabetes mellitus or metabolic syndrome or obesity or arterial hypertension, following the study definitions. Subjects that are currently being treated for type 2 diabetes mellitus or metabolic syndrome or obesity or arterial hypertension, should have had a prior diagnosis based on study definitions. Study definitions: Type 2 diabetes mellitus At least 2 times a fasting glucose > 7,0 mmol/L Or elevated non-fasting glucose >11,1 mmol/L 2 hrs after OGTT Obesity Body mass index (BMI) > 30 Or waist circumferences (Europids): male ≥ 94 cm, female ≥ 80 cm Arterial hypertension - Systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg Metabolic syndrome - Central obesity defined as waist circumference (Europids): male ≥ 94 cm and female ≥ 80 cm (if BMI is >30 kg/m2, central obesity can be assumed and waist circumference does not need to be measured) AND any two of the following: Raised triglycerides: ≥ 150 mg/dL (1.7 mmol/L), or specific treatment for this lipid abnormality Reduced HDL cholesterol: < 40 mg/dL (1.03 mmol/L) in males, < 50 mg/dL (1.29 mmol/L) in females, or specific treatment for this lipid abnormality Raised blood pressure (BP): systolic BP ≥ 130 or diastolic BP ≥ 85 mm Hg, or treatment of previously diagnosed hypertension Raised fasting plasma glucose (FPG): FGP ≥ 100 mg/dL (5.6 mmol/L), or previously diagnosed type 2 diabetes (if above >5.6 mmol/L or 100 mg/dL, an oral glucose tolerance test is strongly recommended, but is not necessary to define presence of the syndrome) Exclusion Criteria: The patient is known with hepatitis B, C or HIV or any other liver condition (like hemochromatosis, sarcoidosis, etc); The patient is known with any other condition that may lead to liver fibrosis or cirrhosis; (Excessive) alcohol use: > 3 units/day in males and > 2 units/day in females; The patient has a history or evidence of any other clinically significant condition or planned or expected procedure that in the opinion of the Investigator, may compromise the patient's safety or ability to be included in this study; The patient is an employee or contractor of the facility that is conducting the study or is a family member of the Investigator, sub-Investigator, or any Sponsor personnel; The patient is not able to understand the details of the protocol and/or is not able to provide written informed consent; The patient is pregnant or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of liver steatosis estimated by FibroScan in patients at risk coming from primary care | Steatosis grade deduced from controlled attenuation parameter (CAP) measurement with Fibroscan | Baseline | 
| Prevalence of liver fibrosis estimated by FibroScan in patients at risk coming from primary care | Fibrosis stage deduced from vibration controlled transient elastography (TE) measurement with Fibroscan | Baseline | 
| *Subset of patients: prevalence of NASH in patients at risk coming from primary care | NASH diagnosis confirmed by histology (NAS criteria) upon liver biopsy; only in patients with persistent F2-F3 on FibroScan re-test at visit 3 | 15 weeks | 
| Comparison of the prevalence of liver steatosis, liver fibrosis and NASH between the participating countries | Prevalence (see outcome 1, 2 and 3) stratified per country | Baseline (1,2) to 15 weeks for biopsy-confirmed NASH (3) | 
| Predictive power of non-invasive tests for detection of high-risk patients | FIB-4 scores in comparison to FibroScan measurements and FAST score, to identify patients at risk of liver steatosis and fibrosis | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Build clinical prediction model to identify NASH patients in a high-risk population | Possible model parameters are all baseline clinical characteristics reported in the eCRF | Baseline | 
| Prevalence of relevant genotypes related to NASH in different European countries | Genomic and proteomic analysis on collected blood samples, including pre-identified genes of interest: PNPLA3, TM6SF2, HSD17B13, MBOAT7, GCKR | Baseline | 
| Non-invasive metabolite biomarkers identifying NASH in patients at risk: Exploratory | Mass-spectrometry (MS) based metabolomic and lipidomic analyses on collected blood and samples, both targeted and untargeted approaches. | Baseline | 
| Prevalence of co-morbidities and associated therapies (especially for CVD) in patients with NASH compared to those without, in high-risk patient populations | Prevalence of comorbidities, medication use, medical history | Baseline | 
| Identify prognostic factors for complications in patients with NAFLD and NASH by 5 years follow up | Disease progression and liver-related and non-liver related complications | Throughout follow-up (at 3 and 5 years) | 
| *Subset of patients: evaluate if a 12-week (unstandardized) lifestyle intervention, following routine practice, lowers liver fibrosis (from F2/F3 to F0/F1) | Revisited FibroScan measurements (CAP and TE) after 12 weeks of lifestyle intervention (intervention starts in week 2); intervention only offered to patients classified as F2/F3 in first FibroScan | Week 14 | 
| Patient Reported Outcomes: Dietary habits | 14 item Mediterranean Diet Score; maximum score is 14, score >10 reflects adherence to Mediterranean diet | Baseline + throughout follow-up (at 3 and 5 years) | 
| Patient Reported Outcomes: Disease-specific health-related Quality of Life (HR-QoL) | Chronic Liver Disease Questionnaire - NAFLD NASH (CLDQ NAFLD-NASH); scores will be averaged for the 6 domains, higher scores reflect better HR-QoL | Baseline + throughout follow-up (at 3 and 5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NAFLD, NASH, Screening, Patient care pathway