UNMASK: Unveiling the Pathobiology of Metabolic Dysfunction-Associated Steatotic Liver Disease for the Discovery of Novel Therapeutics and Biomarkers

UNMASK: Unveiling the Pathobiology of Metabolic Dysfunction-Associated Steatotic Liver Disease for the Discovery of Novel Therapeutics and Biomarkers - Study Protocol Version 2.0

Overall design: The study will include one intervention based on Mediterranean diet plus structured lifestyle intervention (150 min/week of moderate-intensity or 75 min/week of high-intensity exercise) for a total of 16 weeks. Following a screening period of up to 12 months, eligible participants will be included in a single cohort.

Study details include:

• Study duration will be up to 36 months including the screening period.
• Intervention will be up to 16 weeks.
• Visit frequency will be every 4 weeks for the interventional period and every 12 weeks during follow-up.

The UNMASK trial is a multicenter (Spain, Italy and Turkey), prospective, open-label lifestyle intervention based on tailored caloric restriction and monitored exercise. UNMASK aims to prove that the amelioration of MASLD at systemic and hepatic levels will be parallel to the improvement in our selected biomarkers. Given the known challenges with diagnosis and staging of MASH when using histopathological assessments of liver biopsies, the study will evaluate various blood-based non-invasive biomarkers. Non-invasive tests will be performed to asses endpoints. UNMASK includes a single arm in which patients undergo lifestyle changes, chiefly through the prescription of Mediterranean diet and physical exercise.

Inclusion Criteria:

• Metabolic disarrangements following ATPIII criteria (i.e. comorbidities such as Type 2 diabetes, central obesity, BMI≥>25 kg/m2, hypertension, dyslipidaemia.
• Written informed consent
• No dietetical counsellor/weight loss higher than 10% within the prior 6 months
• Age over 18 years old
• Liver stiffness measurement by Fibroscan ≥ 8, CAP ≥ 248 db/m and MRI PDFF ≥ 5%. ,

Exclusion Criteria:

• Significant alcohol intake (≥30 g/day in men and ≥20 g/day in women)
• Other causes of liver disease (evidence of viral or autoimmune hepatitis, HIV, drug-induced fatty liver or other metabolic liver diseases)
• Use of recreational drugs
• Decompensated acute or chronic liver disease
• Cirrhosis or transplant waitlist
• Pregnancy or parenteral nutrition
• No nutritional interventions, medications for weight loss or weight loss higher than 5% within the last year
• Presence of other comorbidities that would impact lifestyle intervention (i. e. prosthesis)
• Absence of a personal smartphone with a compatible operating system capable of supporting the Amazfit Bip 6 accelerometer app's functionalities: Android 7.0 or iOS 14.0, or later.