Nutrition Intervention Combined With Resmetirom for MASH (NOURISH-MASH)

Sperimentale: Resmetirom plus medically tailored meals and lifestyle education

Participants receive resmetirom once daily by weight-based dosing (80 mg if <100 kg; 100 mg if ≥100 kg) plus 10 medically tailored meals per week based on Mediterranean-diet principles, along with online nutrition and physical activity education at baseline and follow-up.

Droga: Resmetirom therapy

All participants involved in the study will receive treatment according to resemetirom protocol:

For patients weighing:

• <100 kg, the recommended dosage is 80 mg orally, once daily
• ≥100 kg, the recommended dosage is 100 mg orally, once daily

Comportamentale: Comprehensive nutritional intervention

The nutritional intervention will consist of two components:

1. Medically tailored meals (MTMs): Participants will receive 10 MTMs per week delivered by God's Love We Deliver in New York City. Meals will follow Mediterranean diet principles (40% carbohydrate, 35-45% fat, 15-25% protein), be delivered frozen with preparation and safety instructions, and meal preferences will be collected in advance. Participants will be encouraged to eat two meals per weekday and source any additional food independently.
2. Nutritional and physical activity educational support: Online educational materials will be provided at baseline and follow-up visits, covering healthy eating, Mediterranean-diet principles, and exercise recommendations.

Comparatore attivo: Resmetirom plus standard-of-care lifestyle education

Participants receive the same resmetirom protocol once daily by weight-based dosing (80 mg if <100 kg; 100 mg if ≥100 kg), plus healthy diet and physical activity handouts and the option of a telehealth consultation with a dietitian.

Droga: Resmetirom therapy

All participants involved in the study will receive treatment according to resemetirom protocol:

For patients weighing:

• <100 kg, the recommended dosage is 80 mg orally, once daily
• ≥100 kg, the recommended dosage is 100 mg orally, once daily

Comportamentale: Standard dietary support

Participants will receive standard-of-care lifestyle recommendations, including handouts on healthy diet and physical activity, and the option of a telehealth consultation with a dietitian.

MRI-PDFF change

Magnetic resonance imaging derived proton-density-fat-fraction (MRI-PDFF) will be used to evaluate liver steatosis. Absolute change in MRI-PDFF (%) between the two groups at month 12, as an indicator for steatosis change

MRE change

Magnetic resonance elastography (MRE) will be used to evaluate liver fibrosis. Absolute change in MRE (kPa) between the two groups at month 12

Controlled attenuation parameter (CAP) change

The CAP will be used to assess liver steatotis. Absolute change in CAP (dB/m) between the two groups at month 12

Vibration-controlled transient elastography (VCTE) responder

The VSTE will be used to assess liver fibrosis. The percentage of patients that achieve a ≥25% relative reduction at months 6 and 12, as compared with baseline VCTE (kPa)

Plasma LDL-C responder

The percentage of patients with plasma LDL-C >100 mg/dL at baseline who are able to reduce it to <100 mg/dL at months 6 and 12

Triglyceride responder

The percentage of patients with triglycerides >150 mg/dL at baseline who are able to reduce it to <150 mg/dL at months 6 and 12

Apolipoprotein B change

Change (%) from baseline in directly measured apolipoprotein B at months 6 and 12

Lp(α) change

Change (%) from baseline in directly measured Lp(α) in patients with baseline Lp(α) >10 nmol/L at months 6 and 12

ALT responder

The percentage of patients with ALT >30 IU/L at baseline with a >20% and/or 17 IU/L reduction at months 6 and 12

Weight reduction

The percentage of patients that achieve a ≥5% relative reduction in weight (Kg) at months 6 and 12, as compared with baseline weight (Kg)

Waist to hip ratio

The waist-to-hip ratio will be calculated by dividing the waist circumference (cm) by the hip circumference (cm). Waist circumference will be measured at the narrowest part of the waist (or midway between the lowest rib and the top of the hip bone), and hip circumference will be measured at the widest part of the buttocks. A higher waist-to-hip ratio indicates a greater proportion of abdominal fat relative to hip circumference.

BMI

Body mass index (BMI) will be calculated by dividing a person's weight in kilograms by the square of their height in meters (weight [kg] ÷ height [m²]). BMI is commonly used as a screening measure to classify body weight relative to height and to identify categories such as underweight, normal weight, overweight, and obesity.

Medication adherence

At each study visit, participants will bring any remaining resmetirom pills. Study staff will count the pills and compare this to the number dispensed. Adherence is defined as taking at least 80% of dispensed medication.

Medication adherence blood biomarker

Serum sex hormone-binding globulin (SHBG) concentrations will be measured using a standardized immunoassay and reported in nanomoles per liter (nmol/L). SHBG is a glycoprotein produced primarily by the liver and is regulated, in part, by thyroid hormone receptor beta (THR-β) signaling. As SHBG is a downstream target of THR-β agonism, increases in SHBG levels have been observed following treatment with the THR-β agonist resmetirom and may serve as a pharmacodynamic marker of hepatic drug exposure. Therefore, SHBG levels will be assessed as an indirect measure of treatment adherence and biological response to resmetirom therapy.

Dietary intake

Will be measured using a Food Frequency Questionnaire (FFQ)

Physical activity

Will be evaluated using the International Physical Activity Questionnaire

Sleeping habits

Will be assessed using the single-item sleep quality scale questionnaire

Smoking habits

Will be assessed by pack years calculation. Pack-years will be calculated by dividing the average number of cigarettes smoked per day by 20 (the number of cigarettes in a standard pack) and multiplying the result by the total number of years the person has smoked.

Alcohol consumption

will be evaluated using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) questionnaire

Alcohol consumption blood biomarker

Will be assessed using the Phosphatidylethanol (PEth) test

Binge eating disorder

Will be assessed using the validated Being Eating Disorder Screener-7 (BEDS-7) questionnaire

Liver enzymes

Liver enzymes will be measured using automated enzymatic assays and will include alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP). Results will be reported in units per liter (U/L).

Fasting plasma glucose

Fasting plasma glucose will be measured using an enzymatic assay and reported in milligrams per deciliter (mg/dL)

Fasting insulin

Fasting insulin concentrations will be measured using a standardized immunoassay and reported in micro-international units per milliliter (μIU/mL).

Insulin resistance

Insulin resistance will be assessed using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). HOMA-IR will be calculated from fasting plasma glucose and fasting insulin concentrations using the following formula:

HOMA-IR = [fasting insulin (μIU/mL) × fasting glucose (mg/dL)] ÷ 405 Higher HOMA-IR values indicate greater insulin resistance. There is no universally accepted cutoff for insulin resistance, as values vary according to age, sex, ethnicity, and study population. In adults, HOMA-IR values above approximately 2.0-2.5 are often considered suggestive of insulin resistance, while values above 3.0 are generally considered indicative of significant insulin resistance.

HOMA-IR will also be analyzed as a continuous variable or categorized according to population-specific upper quartile

Hemoglobin A1c

Hemoglobin A1c (HbA1c) will be measured using a standardized assay certified according to international guidelines and reported as a percentage (%)

Estimated glomerular filtration rate (eGFR)

Estimated glomerular filtration rate (eGFR) is a widely used measure of the kidneys' ability to filter blood. The eGFR will be calculated from serum creatinine concentrations using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, which incorporates age and sex. Results will be reported in milliliters per minute per 1.73 square meters of body surface area (mL/min/1.73 m²).

Higher eGFR values indicate better kidney function, whereas lower values indicate impaired kidney function. An eGFR of 90 mL/min/1.73 m² or higher is generally considered normal, provided there is no other evidence of kidney damage. Values between 60 and 89 mL/min/1.73 m² may reflect mildly reduced kidney function, while an eGFR below 60 mL/min/1.73 m² persisting for at least three months is commonly used as a criterion for chronic kidney disease (CKD). An eGFR below 30 mL/min/1.73 m² indicates severe kidney impairment.

Complete blood count

A complete blood count (CBC) will be performed using an automated hematology analyzer. Parameters will include:

Hemoglobin (g/dL) White blood cell count (×10⁹/L) Platelet count (×10⁹/L) Red blood cell count (×10¹²/L) Hematocrit (%) Mean corpuscular volume (MCV; fL) Mean corpuscular hemoglobin (MCH; pg) Mean corpuscular hemoglobin concentration (MCHC; g/dL) Red cell distribution width (RDW; %)

Blood pressure measurements

Blood pressure will be measured using a validated automated sphygmomanometer according to standard clinical procedures. Participants will be seated comfortably with their back supported and feet flat on the floor for at least 5 minutes before the measurement. Blood pressure will be measured in the upper arm using an appropriately sized cuff. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) will be recorded in millimeters of mercury (mmHg). Blood pressure values will be analyzed as continuous variables, and participants may also be categorized according to established hypertension guidelines.

Serum free thyroxine (FT4) concentrations

Serum free thyroxine (FT4) concentrations will be measured using a standardized immunoassay. FT4 is the biologically active fraction of thyroxine and is commonly used to assess thyroid function and monitor the safety of therapies that may affect the thyroid gland. Results will be reported in nanograms per deciliter (ng/dL). Changes in FT4 concentrations from baseline to follow-up will be evaluated, and the percentage change will be analyzed as a continuous variable to assess the safety of the intervention.