Does caffeine supplementation, compared to placebo, improve hepatic steatosis and fibrosis in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD)?

The study will be conducted at the Department of Medicine, Faculty of Medicine, University of Kelaniya, in collaboration with the affiliated teaching hospital. Participants will be randomly assigned to either the intervention or control group using block randomization to ensure balanced allocation. Randomization will be performed using a computer-generated random number sequence. Allocation concealment will be maintained by sequentially numbering identical white high-density polyethylene (HDPE) bottles from 1 to 110, prepared by a pharmacist or an independent third party according to the randomization list. Each bottle will contain either caffeine or placebo tablets based on the allocation sequence. The randomization list will be securely sealed in an envelope and kept inaccessible to investigators, participants, and study personnel until trial completion, ensuring effective blinding. Participants in the intervention group will receive caffeine supplementation in the form of oral capsules at a dose of 400 mg per day, administered once daily for six months. The caffeine tablets will be sourced locally. Participants in the control group will receive placebo capsules identical in size, shape, color, and weight to the caffeine capsules, also administered once daily for six months. The placebo will consist of inert substances such as microcrystalline cellulose and will be manufactured to closely mimic the caffeine capsules in appearance and taste. This study will be conducted as a quadruple-blinded trial, with participants, investigators, outcome assessors, and data analysts all blinded to group allocation to minimize bias and ensure the integrity of the results.

• Both male and non-pregnant, non-lactating female patients aged 18 - 65 years who provide written informed consent before starting the study
• Patients meeting the diagnostic criteria for Metabolic dysfunction-associated steatotic liver disease (MASLD) (defined as hepatic steatosis on ultrasound [>=2 of the following: increased echogenicity vs. renal cortex, blurring of intrahepatic vessels, posterior beam attenuation] plus >=1 cardiometabolic risk factor [type 2 diabetes mellitus: Fasting Plasma Glucose (FPG) >=5.6 mmol/L, 2-hr post-load glucose >=7.8 mmol/L, Hemoglobin A1c(HbA1c) >=5.7%, or on antidiabetic treatment; Body Mass Index (BMI) >=23 kg/m²; hypertension >=130/85 mmHg or on antihypertensive medication; dyslipidemia: Triglycerides (TG) >=1.70 mmol/L or on lipid-lowering therapy, High-Density Lipoprotein Cholesterol (HDL-C) <=1.0 mmol/L (men) or <=1.3 mmol/L (women); waist circumference >=94 cm (men) or >=80 cm (women)]))

• Controlled Attenuation Parameter (CAP) score >263

• Fulfilling 2/3 USS criteria for fatty liver

• History of unsafe alcohol consumption ( Alcohol Use Disorders Identification Test -AUDIT score ?8)
• Other liver disease (chronic viral/autoimmune/hereditary) • Use of steatogenic medications • History of drug dependence • Body mass index (BMI) >=35 kg/m2