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This randomized control trial aims to evaluate the effectiveness of combining resmetirom therapy (first approved pharmacological therapy for treating metabolic dysfunction-associated steatohepatitis (MASH)) with a nutritional intervention compared to resmetirom therapy alone over one year in improving liver health among 120 patients living with non-cirrhotic MASH. We hypothesize that patients receiving resmetirom and nutritional intervention will experience more significant improvements in liver function than those receiving only resmetirom therapy.
On March 14, 2024, resmetirom, a selective thyroid hormone receptor-β agonist, became the first pharmacological therapy approved by the US Food and Drug Administration (FDA) for treating metabolic dysfunction-associated steatohepatitis (MASH). Although, lifestyle modification remains first-line MASH treatment the provision of resmetirom is rarely accompanied by structured non-pharmacological interventions, and evidence guiding the integration of nutrition-based strategies with pharmacotherapy is limited. This study aims to evaluate the effectiveness of a nutrition-based intervention, including medically tailored meal (MTM) and nutrition education provision combined with resmetirom therapy, compared with resmetirom therapy combined with standard-of-care lifestyle recommendations, in improving liver function.
This multi-site, prospective, randomised controlled trial will enroll 120 adults (18-75 years) with non-cirrhotic MASH and fibrosis stages F2-F3. Recruited participants will undergo baseline assessments including evaluation of medical history and lifestyle behaviors, completion of a food frequency questionnaire, blood pressure measurement, blood sampling, anthropometric measurements (weight, height, and waist and hip circumference), and assessment of liver steatosis and fibrosis using imaging methods. Upon completion of baseline evaluations, participants will be randomised 1:1 to receive either: (1) resmetirom plus standard-of-care lifestyle education (control); or (2) resmetirom plus a structured nutritional intervention consisting of MTM delivery and lifestyle education (intervention).
The primary endpoints are changes in liver steatosis and fibrosis at 12 months, assessed by imaging methods. Secondary endpoints include changes in blood-circulating lipids, alanine aminotransferase levels, metabolic parameters, anthropometrics, dietary quality, and lifestyle behaviours. Analyses will follow an intention-to-treat approach using regression models adjusted for relevant covariates.
Adherence assessments will be conducted at 3, 6, and 9 months, with outcome evaluations at 6 months and at the end of the study (12 months).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Resmetirom plus medically tailored meals and lifestyle education | Experimental | 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. |
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| Resmetirom plus standard-of-care lifestyle education | Active Comparator | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Resmetirom therapy | Drug | All participants involved in the study will receive treatment according to resemetirom protocol: For patients weighing:
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| Measure | Description | Time Frame |
|---|---|---|
| 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 | Baseline and 12 months |
| 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 | Baseline and 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | Baseline, 6 months and 12 months |
| Vibration-controlled transient elastography (VCTE) responder |
| Measure | Description | Time Frame |
|---|---|---|
| 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) | Baseline, 6 months and 12 months |
| Waist to hip ratio |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Jeffrey V. Lazarus | Contact | +1 646-364-9600 | Jeffrey.Lazarus@sph.cuny.edu |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CUNY Graduate School of Public Health and Health Policy | New York | New York | 10027 | United States |
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| Comprehensive nutritional intervention | Behavioral | The nutritional intervention will consist of two components:
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| Standard dietary support | Behavioral | 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. |
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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) |
| Baseline, 6 months and 12 months |
| 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 | Baseline, 6 months and 12 months |
| 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 | Baseline, 6 and 12 months |
| Apolipoprotein B change | Change (%) from baseline in directly measured apolipoprotein B at months 6 and 12 | Baseline, 6 and 12 months |
| 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 | Baseline, 6 and 12 months |
| 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 | Baseline, 6 and 12 months |
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.
| Baseline, 6 months and 12 months |
| 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. | Baseline, 6 and 12 months |
| 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. | 3 months, 6 months, 9 months and 12 months |
| 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. | 3 months, 6 months, 9 months and 12 months |
| Dietary intake | Will be measured using a Food Frequency Questionnaire (FFQ) | Baseline, 6 months and 12 months |
| Physical activity | Will be evaluated using the International Physical Activity Questionnaire | Baseline, 6 and 12 months |
| Sleeping habits | Will be assessed using the single-item sleep quality scale questionnaire | Baseline, 6 months and 12 months |
| 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. | Baseline, 6 months and 12 months |
| Alcohol consumption | will be evaluated using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) questionnaire | Baseline, 6 months and 12 months |
| Alcohol consumption blood biomarker | Will be assessed using the Phosphatidylethanol (PEth) test | Baseline, 6 months and 12 months |
| Binge eating disorder | Will be assessed using the validated Being Eating Disorder Screener-7 (BEDS-7) questionnaire | Baseline, 6 months and 12 months |
| 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). | Baseline, 6 and 12 months |
| Fasting plasma glucose | Fasting plasma glucose will be measured using an enzymatic assay and reported in milligrams per deciliter (mg/dL) | Baseline, 6 and 12 months |
| Fasting insulin | Fasting insulin concentrations will be measured using a standardized immunoassay and reported in micro-international units per milliliter (μIU/mL). | Baseline, 6 and 12 months |
| 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 | Baseline, 6 and 12 months |
| Hemoglobin A1c | Hemoglobin A1c (HbA1c) will be measured using a standardized assay certified according to international guidelines and reported as a percentage (%) | Baseline, 6 and 12 months |
| 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. | Baseline, 6 and 12 months |
| 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; %) | Baseline, 6 and 12 months |
| 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. | Baseline, 6 and 12 months |
| 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. | Baseline, 6 and 12 months |