Global Research Initiative for Patients Screening on MASH (GRIPonMASH)

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

GRIPonMASH will assist (primary) health care providers 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 metabolic dysfunction-associated steatotic liver disease (MASLD) and to raise awareness. The primary objective is to implement a transmural patient care pathway, in order to identify patients with MASLD and its progressive form metabolic dysfunction-associated steatohepatitis (MASH) in primary care centres and clinics in 10 European countries.

Study Overview

• Status: Recruiting
• Conditions: Obesity; Metabolic Syndrome; Type 2 Diabetes; Fibrosis, Liver; Arterial Hypertension; Steatosis of Liver; MASLD; MASH With Fibrosis; MASH

Detailed Description

GRIPonMASH 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 MASLD, liver fibrosis and (at-rsik) MASH using at least two non-invasive tests (FIB-4 and FibroScan). Additional published and exploratory non-invasive test will also be investigated. Blood samples and liver biopsy material will be collected. Genomic, proteomic, metabolomic, lipidomic and fluxomic studies will be applied to gain a better understanding of the pathophysiology of MASLD 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.

• Study Type: Observational
• Enrollment (Estimated): 10000

Contacts and Locations

• Study Contact: Name: de Jong; Phone Number: +31628259968; Email: griponmash@juliusclinical.com
• Study Contact Backup: Name: Wijkhuis; Email: griponmash@juliusclinical.com

Study Locations

• Belgium
  • Antwerp, Belgium, B-2650
    • Active, not recruiting
    • Antwerp University Hospital
  • Vlaams-brabant
    • Brussels, Vlaams-brabant, Belgium, B-1070
      • Recruiting
      • Hôpital Erasme, Cliniques Universitaires De Bruxelles
• Czechia
  • Bohemia
    • Prague, Bohemia, Czechia, 128 08
      • Not yet recruiting
      • 4th internal clinic General University Hospital
• France
  • Il-de-France
    • Paris, Il-de-France, France, 75013
      • Not yet recruiting
      • Hôpital de la Pitié Salpêtrière
• Germany
  • Rhineland-Palatinate
    • Mainz, Rhineland-Palatinate, Germany, 55131
      • Recruiting
      • Universitätsmedizin Mainz
  • Saarland
    • Homburg, Saarland, Germany, 66421
      • Not yet recruiting
      • Universitätsklinikum des Saarlandes
• Greece
  • Athens, Greece, 17676
    • Not yet recruiting
    • Harokopio University of Athens
• Italy
  • Lazio
    • Rome, Lazio, Italy, 00168
      • Not yet recruiting
      • Fondazione Policlinico Universitario Agostino Gemelli IRCCS (FPG), Università Cattolica del Sacro Cuore (UCSC)
• Netherlands
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3045 PM
      • Recruiting
      • Franciscus Gasthuis & Vlietland
  • Zuid-holland
    • Amsterdam, Zuid-holland, Netherlands, 1105 AZ
      • Recruiting
      • Amsterdam UMC
• Portugal
  • Lisbon, Portugal, 1649-028
    • Recruiting
    • ULSSM - Unidade Local de Saúde Santa Maria, E.P.E
• Romania
  • Brasov
    • Sacele, Brasov, Romania, 505600
      • Not yet recruiting
      • Sacele Municipal Hospital
• Spain
  • Seville, Spain, 41013
    • Recruiting
    • Hospital Universitario Virgen del Rocio

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Male and female patients aged 18-75 years with a current or prior diagnosis of at least one of the following four conditions: type 2 diabetes mellitus or metabolic syndrome or obesity or arterial hypertension. Subjects who meet the inclusion and exclusion criteria will be enrolled at primary care centers in one of the 10 countries.

Description

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
• Or HbA1c ≥48 mmol/mol (≥6.5%)
• Or being actively treated for previously diagnosed type 2 diabetes by a health care provider

Obesity

• Body mass index (BMI) > 30
• Or waist circumferences Caucasian: male ≥ 94 cm, female ≥ 80 cm South-Asian/Chinese: male ≥90 cm, female ≥80 cm Japanese: male ≥85 cm, female ≥90 cm

Arterial hypertension

• Systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg
• Or being actively treated for previously diagnosed arterial hypertension by a health care provider

Metabolic syndrome

- Central obesity defined as waist circumference (see above), 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, Wilson's disease etc);
• The patient is known with any other condition that may lead to liver fibrosis or cirrhosis;
• The patient engages in (excessive) alcohol use: > 3 units/day in males [30 grams/day] and > 2 units/day in females [20 grams/day];
• 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.
• The patient underwent bariatric surgery in the last 12 months.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence of liver steatosis and MASLD estimated by FibroScan CAP in patients at risk	Steatosis grade deduced from controlled attenuation parameter (CAP) measurement with Fibroscan	Baseline
Prevalence of liver fibrosis estimated by FibroScan LSM in patients at risk	Fibrosis stage deduced from liver stiffness measurement (LSM) by vibration controlled transient elastography (VCTE) measurement with Fibroscan	Baseline
Prevalence of at-risk MASH estimated by FAST score in patients at risk	At-risk MASH deduced from FAST score	Baseline
*Subset of patients: prevalence of MASH in patients at risk	MASH diagnosis confirmed by histology (NAS/SAF criteria) upon liver biopsy; only in patients with >12 kPa at 1st FibroScan or >=8 kPa at 2nd FibroScan	16 or 30 weeks
Comparison of the prevalence of MASLD, liver fibrosis and (at-risk) MASH between the participating countries	Prevalence (see outcome 1-4) stratified per country	Baseline (1-3) to 16/30 weeks for biopsy-confirmed MASH (4)
Evaluate added value of a 2-step pathway as compared to FibroScan only for detection of high-risk patients	Number of patients at risk identified by FIB-4 compared to numbers found using LSM by VCTE with FibroScan measurements, and numbers found in combination	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Build diagnostic model to identify MASH patients in a high-risk population	Possible model parameters are all baseline clinical characteristics reported in the eCRF	Baseline
Genotypes related to MASH in different European countries: Exploratory	Genomic (GWAS) and proteomic analysis on collected blood samples	Baseline
(Non-invasive) metabolite biomarkers identifying MASH 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 MASH compared to those without, in high-risk patient populations	Prevalence of comorbidities, medication use, medical history	Baseline
Identify prognostic factors/biomarkers for complications in patients with MASLD and MASH by 5 years follow up	Disease progression and liver-related and non-liver related complications	Throughout follow-up (at 3 and 5 years)
Patient Reported Outcomes: Dietary habits and lifestyle	14 item Mediterranean Diet Score; lifestyle surveys	Baseline + throughout follow-up (at 3 and 5 years)
*Subset of patients: Second FibroScan examination	CAP and LSM by VCTE at 2nd FibroScan examination	14 weeks
Longitudinal changes in liver assessments	Repeated CAP, LSM by VCTE and FAST measurements over time	Baseline, 14 weeks + throughout follow-up (at 3 and 5 years)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Estimation of the additional costs of implementing a patient care pathway as proposed in this study in clinical practice: Pilot	Estimation of the actual costs of implementing the patient care pathway	Baseline + throughout follow-up (at 3 and 5 years)
Assess if implementation of the patient care pathway as proposed in this study increases awareness and knowledge of NAFLD and NASH management among participating physicians and clinicians	Questionnaire send out to participating physicians and clinicians to assess awareness and knowledge of NAFLD and NASH management (questionairre to be developed within this study)	Baseline + throughout follow-up (at 3 and 5 years)

Collaborators and Investigators

• Sponsor: Julius Clinical
• Collaborators: Novo Nordisk A/S; Roche Pharma AG; UMC Utrecht; Catholic University of the Sacred Heart; Leiden University; University Hospital, Antwerp; Andaluz Health Service; Leiden University Medical Center; Inventiva Pharma; University Hospital, Saarland; Maastricht University; Harokopio University; General University Hospital, Prague; Université Libre de Bruxelles; Echosens; Nordic Bioscience A/S; National Research Council, Institute of Clinical Physiology, Italy; Institute of Cardiometabolism and Nutrition, France; Amsterdam University Medical Center; Franciscus Gasthuis & Vlietland (Hospital); European Atherosclerosis Society; MIMETAS BV; Elevate BV; Medical Education Research And Innovation Center S.R.L.; EUROPEAN LIVER PATIENTS ASSOCIATION; Mercodia Aktiebolag; EXIT071 BV; MetaDeq Limited; Associação para Investigação e Desenvolvimento da Faculdade de Medicina; Biocellvia
• Investigators: Principal Investigator: Manuel Castro Cabezas, MD/PhD, Sint Franciscus Gasthuis; Principal Investigator: Diederick E. Grobbee, MD/PhD/FESC, UMC Utrecht; Study Chair: Oscar H. Franco, MD/PhD/FESC/FFPH, UMC Utrecht

Publications and helpful links

Helpful Links

• GRIPonMASH consortium website

Study record dates

Study Major Dates

• Study Start (Actual): June 30, 2023
• Primary Completion (Estimated): March 31, 2031
• Study Completion (Estimated): March 31, 2031

Study Registration Dates

• First Submitted: October 18, 2022
• First Submitted That Met QC Criteria: December 13, 2022
• First Posted (Actual): December 15, 2022

Study Record Updates

• Last Update Posted (Actual): August 1, 2024
• Last Update Submitted That Met QC Criteria: July 30, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: Screening; Patient care pathway; MASLD; MASH
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Liver Diseases; Insulin Resistance; Hyperinsulinism; Fibrosis; Fatty Liver; Metabolic Syndrome; Liver Cirrhosis
• Other Study ID Numbers: GOM

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