Effect of an Early Time Restricted Eating Mediterranean Diet Compared to Naltrexone/Bupropion on Liver Fibrosis in People With Cardiometabolic Risk Factors in a Hospital Outpatient Clinic (MEDFAST-study) (MEDFAST)

Effect of Mediterranean Diet Combined With Intermittent Fasting on Liver Fibrosis Compared to Naltrexone/Bupropion in People With Cardiometabolic Risk Factors

In the Netherlands, there are many people with cardiometabolic diseases. More than half of these people also have fatty liver. This is a build-up of fat in the liver (steatosis) and can lead to long-term scarring (fibrosis) and even death of the liver. Losing weight can help reduce this. Losing weight can be done with medication such as naltrexone/bupropion, which is often prescribed to people with cardiometabolic diseases, but losing weight can also be done with diet. In this study, the investigators want to combine a Mediterranean diet (with lots of vegetables, fruits, whole grain products, nuts and olive oil) with intermittent fasting. In addition participants are not allowed to eat after the evening meal. The investigators will compare this with a group of participants receiving naltrexone/bupropion, to see if a diet with intermittent fasting might be better for reducing liver steatosis and fibrosis in people with cardiometabolic diseases.

Study Overview

• Status: Enrolling by invitation
• Conditions: Hypertension; Diabetes Mellitus, Type 2; Hepatic Fibrosis; Hepatic Steatosis; Overweight or Obesity; Liver Fibrosis; Cardio-metabolic Risk; Dyslipidaemia; Liver Steatoses; Cardio-metabolic Health; MASLD; MASLD - Metabolic Dysfunction-Associated Steatotic Liver Disease
• Intervention / Treatment: Other: early time restricted Mediterranean diet; Drug: Mysimba

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Rotterdam, Netherlands, 3045 PM
    • Franciscus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• BMI > 30 kg/m2 or BMI > 27 kg/m2 and at least one cardiometabolic risk factor (T2D, hypertension, dyslipidaemia)
• Moderate to severe liver fibrosis, measured as liver stiffness by transient elastography (LSM > 7.0 kPa and < 13.6 kPa)
• Aged 18-75 years
• Written informed consent

Exclusion Criteria:

• An insufficient comprehension of the Dutch language (spoken and written)
• Female who is pregnant, breast-feeding or intends to become pregnant
• Participants with an established diagnosis of liver pathology like, but not limited to: Hepatitis B, Hepatitis C, Autoimmune hepatitis, Wilson's disease, Hemochromatosis, Primary biliary cholangitis, Primary sclerosing cholangitis, Alcoholic liver disease
• History of liver transplant, or current placement on a liver transplant list
• History of cirrhosis and/or hepatic decompensation, including ascites, hepatic encephalopathy or variceal bleeding
• Participants with active HIV infection and/or treatment
• Participants with diagnosed malignancies with or without active treatment
• Participants with history or pre-existing renal disease (eGFR <30 mL/min/1.73 m2)
• Participants with corticosteroid induced diabetes (while still using corticosteroids)
• Participants using GLP-1 agonists for less than 3 months or not yet on a stable dose
• Participants using MAO-inhibitors, opioids and/or methadone (due to contraindication)
• Known or suspected excessive alcohol consumption (>30 grams/day for males or >20 grams/day for females. One drink is equivalent to 10 grams of alcohol)
• Previous or planned (during the trial period) obesity treatment with surgery. However, previous interventions that, due to reversal or removal, do not have any influence on the patient's weight, in the opinion of the investigator, are allowed.
• Participants with 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 complete the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dietary arm; Calorie restricted Mediterranean diet, with an eating window between 8AM till 6PM (early time-restricted eating)	Other: early time restricted Mediterranean diet; Participants will start with a calorie restricted Mediterranean diet, with an eating window between 8AM till 6PM (early time-restricted eating) for a period of six months. Participants are asked to stop eating at 6PM. This results in a daily fasting window of approximately 14 hours. A daily calorie restriction of 500 kcal will be applied, based on the estimated energy requirement calculated using the WHO equation for participants with a BMI ≤ 30 and the Harris-Benedict equation for those with a BMI > 30.; Other Names: intermittent fasting; dietary intervention; mediterranean diet; early time restricted eating
Active Comparator: Pharmacological arm; 32 mg/360 mg naltrexone/bupropion (Mysimba)	Drug: Mysimba; Participants will take Mysimba twice daily at a total dose of 32 mg/360 mg naltrexone/bupropion per day for a duration of six months. The dosage will be built up in the first month following the stepped care approach used in the Summary of Product Characteristics (SmPC), up to maximally tolerated doses. Compliance with N/B intake is monitored by pill counting at the three and six-month visits. Participants receive usual care, including the advice of 60 minutes of exercise per day and standard dietary recommendations according to the guidelines for the Dutch population.; Other Names: naltrexone/bupropion; pharmacological intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Between-group difference in absolute change in liver fibrosis during six months	Measured as liver stiffness in kilopascals (kPa) by transient elastography with FibroScan. For a value between 0 and 8 kPa, no liver fibrosis is assumed. Anything above 8 kPa means liver fibrosis. The highest possible result is 75 kPa.	Change from baseline to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Between-group difference in weight during six months	Measured in kilograms (kg) with Seca 888 compact digital flat scale. Along with height, BMI is calculated by dividing weight by height squared. BMI should be at least 27 kg/m^2.	Change from baseline to 6 months
Between-group difference in height during six months	Measured in centimeters (cm) with a yardstick. Along with weight, BMI is calculated by dividing weight by height squared. BMI should be at least 27 kg/m^2.	Change from baseline to 6 months
Between-group difference in waist circumference during six months	Measured in centimeters (cm) with measuring tape. A healthy waist circumference for women is between 68 and 80 cm and for men between 79 and 94 cm.	Change from baseline to 6 months
Between-group difference in body composition during six months	Impedance, resistance and reactance are measured in Ohm at 50 kHz with bioelectrical impedance analysis (Bodystat 500). The impedance measuring range is between 20 and 1300 Ohm.	Change from baseline to 6 months
Between-group difference in grip strength during six months	Measured in kilograms (kg) with a hand dynamometer (Jamar). The grip strength can be measured between 0 and 90 kg. Normal values depend on gender and age. In people aged 20-29, the average grip strength is 46 kg for men and 29 kg for women.	Change from baseline to 6 months
Between-group difference in glycaemic regulation during six months	Glycaemic regulation is determined from values measured in the blood. These include fasting blood glucose measured in millimoles per litre (mmol/l), haemoglobin A1c (HbA1c) measured in millimoles per mole (mmol/mol) and fasting insulin measured in milligrams per decilitre (mg/dl). Normal values are below 6.1 mmol/l for fasting glucose, below 53 mmol/mol for HbA1c and between 60-110 mg/dl for fasting insulin.	Change from baseline to 6 months
Between-group differences in cholesterol during six months	Total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides are measured in millimoles per litre (mmol/l) through blood samples. Normal values are <5.0 mmol/l for total cholesterol, <2.6 for LDL cholesterol, >0.8 for HDL cholesterol and <2.0 for triglycerides	Change from baseline to 6 months
Between-group differences in lipoproteins during six months	Apolipoprotein B (ApoB), apolipoprotein AI (ApoAI), lipoprotein a (Lp(a)) and Apolipoproteïne B48 are measured in grams per litre (g/l) through blood samples. Normal values are: ApoB 0.55-1.4 g/l for men and 0.55-1.25 g/l for women; ApoAI 1.1-2.05 g/l for men and 1.25-2.15 g/l for women; Lp(a) <0.5 g/l. There are no normal values for Apolipoprotein B48 yet.	Change from baseline to 6 months
Between-group difference in blood pressure during six months	Systolic and diastolic blood pressure measured in millimetres of mercury pressure (mmHg). Normal values are 120-140 mmHg for systolic pressure and <90 mmHg for diastolic pressure.	Change from baseline to 6 months
Between-group difference in liver enzymes during six months	Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are measured in units per litre (U/L). Normal values are <50 U/L for men and <35 U/L for women for ALT and <40 U/L for men and <32 U/L for women for AST.	Change from baseline to 6 months
Between-group difference in renal function during six months	Renal function is determined by measuring creatinine in micromol per litre (µmol/L) and eGFR in mL/min/1.73m^2. Normal values are 62-106 µmol/L for men and 44-80 µmol/L for women for creatinine; >90 mL/min/1.73m^2 for eGFR.	Change from baseline to 6 months
Between-group difference in blood count during six months	Blood count is determined by thrombocytes and leukocytes in x10⁹/L. Normal values are 150-400 x10⁹/L for thrombocytes and 4.0-10.0 x10⁹/L for leukocytes.	Change from baseline to 6 months
Between-group difference in physical activity during six months	Physical activity will be measured with Activ8 Activity Tracker GEN2. Activity is measured in time (seconds), Metabolic equivalent (MET) and kilocalories (kcal). All for sitting, standing, walking, cycling, running and total/average. In addition, step count is also measured.	Change from baseline to 6 months
Between-group difference in lifestyle factors during six months	Food intake, demographic variables, drug use, smoking and drinking habits, (diabetes) medication use and compliance to the time restriction will be administered with a self-developed questionnaire	Change from baseline to 6 months
Between-group difference in quality of life during six months	Measured with SF-36 Questionnaire. This is a 36-item patient-reported questionnaire that covers eight health domains: physical functioning (10 items), bodily pain (2 items), role limitations due to physical health problems (4 items), role limitations due to personal or emotional problems (4 items), emotional well-being (5 items), social functioning (2 items), energy/fatigue (4 items), and general health perceptions (5 items). Scores for each domain range from 0 to 100, with a total higher score defining a more favorable health state.	Change from baseline to 6 months
Between group difference in absoulte change in liver steatosis during six months	Measured as Controlled Attenuation Parameter (CAP) score with FibroScan. This score will range from 100 to 400 decibels per meter (dB/m). A score below 238 dB/m means the amount of fatty change in the liver is not higher than normal.	Change from baseline to 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Shift in liver fibrosis severity during six months	Liver fibrosis is categorized in fibrosis score F0, F1, F2 or F3. The scores are classified according to liver stiffness (kPa). Fibrosis score F0 and F1 means normal (no scarring), F2 means moderate scarring and F3 means severe scarring. The lower the score the better.	Change from baseline to 6 months
Drop-outs during six months	Number of participants that drop-out (categorized by reason for drop-out)	Change from baseline to 6 months
Side effects during six months	Side effects will be self-reported	Change from baseline to 6 months

Collaborators and Investigators

• Sponsor: Carmen Dietvorst
• Investigators: Principal Investigator: Manuel Castro Cabezas, Dr., Franciscus

Study record dates

Study Major Dates

• Study Start (Actual): April 14, 2025
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: February 17, 2025
• First Submitted That Met QC Criteria: February 24, 2025
• First Posted (Actual): February 25, 2025

Study Record Updates

• Last Update Posted (Actual): April 21, 2026
• Last Update Submitted That Met QC Criteria: April 16, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: diabetes; obesity; liver fibrosis; intermittent fasting; liver diseases; lifestyle; mediterranean diet; cardiometabolic diseases; mysimba
• Additional Relevant MeSH Terms: Endocrine System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Nutrition Disorders; Metabolic Diseases; Overnutrition; Body Weight; Digestive System Diseases; Glucose Metabolism Disorders; Lipid Metabolism Disorders; Fibrosis; Pathological Conditions, Signs and Symptoms; Behavior; Nutritional and Metabolic Diseases; Signs and Symptoms; Feeding Behavior; Fasting; Overweight; Obesity; Hypertension; Diabetes Mellitus, Type 2; Diabetes Mellitus; Liver Diseases; Fatty Liver; Liver Cirrhosis; Dyslipidemias; Intermittent Fasting; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Therapeutics; Diet, Food, and Nutrition; Physiological Phenomena; Alkaloids; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Nutritional Physiological Phenomena; Diet, Plant-Based; Nutrition Therapy; Diet; Heterocyclic Compounds, 4 or More Rings; Naloxone; Morphinans; Opiate Alkaloids; Heterocyclic Compounds, Bridged-Ring; Phenanthrenes; Ketones; Propiophenones; Naltrexone; Bupropion; Diet, Mediterranean; Diet Therapy; bupropion hydrochloride, naltrexone hydrochoride drug combination
• Other Study ID Numbers: 2024-519774-40-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: All individual data will be encrypted and shared only with the research team.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No