Comparative Study of Early Time-Restricted Eating Mediterranean Diet Versus Bupropion Hydrochloride and Naltrexone Hydrochloride in Type 2 Diabetes with Liver Fibrosis

The primary objective of this study is to determine the difference in effectiveness of an early time-restricted eating **Mediterranean diet** (eTRE-MD) over a six-month intervention period on the improvement of liver fibrosis, compared to the administration of Mysimba in overweight and obese patients with type 2 diabetes and significant liver fibrosis (LSM >8.0 kPa by Fibroscan). This is clinically relevant as liver fibrosis is a critical factor in the progression of liver disease, and effective management can significantly impact patient outcomes.

Secondary objectives include:

• Comparing the effect of the intervention and control group on liver steatosis over six months in overweight adults with type 2 diabetes.
• Determining the difference in weight loss and body composition between the intervention and control group after six months.
• Assessing the difference in cardiovascular risk factors between the intervention and control group after six months.
• Evaluating the difference in blood biomarkers associated with MASLD between the intervention and control group after six months.
• Evaluating the difference in lifestyle factors between the two groups.
• Evaluating the difference in quality of life between the two groups.
• Evaluating the difference in treatment satisfaction between the two groups.
• Evaluating the difference in compliance and adherence between the two groups.
• Studying the associations between patient characteristics and the effectiveness of the two groups.

The clinical trial involves a study population comprising both **male** and **female** participants aged between 18 and 75 years. The participants are individuals with a **Body Mass Index (BMI)** of over 27 kg/m², specifically targeting those who are overweight or obese. The trial focuses on individuals with type 2 diabetes and moderate to severe liver fibrosis, characterized by a liver stiffness measurement (LSM) greater than 8.0 kPa and less than 13.6 kPa. The selection criteria ensure that the participants are not part of a vulnerable population. The sponsor has not provided the total number of participants involved in the study. Lifestyle considerations such as diet and physical activity are integral to the trial, as the intervention includes an early time-restricted eating Mediterranean diet. The trial does not specify any exclusion criteria beyond the outlined inclusion parameters.

The clinical trial is designed to evaluate the effectiveness of an early time-restricted eating Mediterranean diet compared to **Mysimba** (bupropion hydrochloride, naltrexone hydrochloride) in improving liver fibrosis in overweight and obese patients with type 2 diabetes. This study is a randomized, controlled trial with a double-blind design, ensuring that neither the participants nor the researchers know which treatment the participants are receiving, thus minimizing bias. The trial is expected to last until January 4, 2027, with recruitment starting on January 6, 2025.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility criteria are assessed. These criteria include having type 2 diabetes, moderate to severe liver fibrosis, a **Body Mass Index (BMI)** greater than 27 kg/m², and being aged between 18 and 75 years. Follow-up visits will occur throughout the six-month intervention period to monitor progress and collect data on primary and secondary endpoints. The primary endpoint is the between-group difference in liver fibrosis, measured by liver stiffness using transient elastography. Secondary endpoints include assessments of liver steatosis, nutritional status, cardiovascular risk factors, and other laboratory measurements.

The end-of-study visit will conclude the trial for each participant, where final assessments will be conducted. The expected length of participant involvement is six months, with conditions for early termination including non-compliance with the study protocol or adverse events that may compromise participant safety. The trial aims to provide valuable insights into the comparative effectiveness of dietary intervention versus pharmacological treatment in managing liver fibrosis in this patient population.

The clinical trial involves the administration of **Mysimba 8 mg/90 mg prolonged-release tablets**, which contain the active substances **bupropion hydrochloride** and **naltrexone hydrochloride**. These tablets are formulated as prolonged-release tablets, designed to release the active ingredients over an extended period. The route of administration is oral. The maximum daily dose is 50 mg, with a total maximum dose of 32 mg. The treatment period is set for a maximum of 56 days. The pharmaceutical product is manufactured by Orexigen Therapeutics Ireland Limited and is not a pediatric formulation. The trial aims to evaluate the effectiveness of Mysimba in comparison to a Mediterranean diet combined with intermittent fasting in patients with type 2 diabetes and significant liver fibrosis.

In addition to the experimental treatment, the study includes a comparator treatment involving a Mediterranean diet combined with intermittent fasting. This non-experimental treatment serves as a standard-of-care therapy to assess its impact on liver fibrosis in the target population. The study does not utilize a placebo. Compliance with the dosing schedule and administration is monitored throughout the trial to ensure adherence to the protocol. Participants' adherence to the treatment regimen is crucial for the accurate assessment of the trial's outcomes.

Efficacy in this clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the between-group difference in **liver fibrosis** over a six-month period, measured as liver stiffness (kPa) using transient elastography (TE) with FibroScan®. Secondary endpoints include liver steatosis assessed by the Controlled Attenuation Parameter (CAP) score using FibroScan, and a comprehensive nutritional assessment involving body weight, height, waist circumference, fat mass, and lean body mass measured with bioelectrical impedance analysis, as well as grip strength. Cardiovascular risk factors will be evaluated through routine laboratory procedures measuring total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, apolipoprotein B (ApoB), apolipoprotein AI (ApoAI), lipoprotein (a), HbA1c, fasting blood glucose, fasting insulin, and blood pressure.

Additional laboratory measurements will include creatinine, estimated GFR (eGFR), alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), thrombocytes, hemoglobin (Hb), leukocytes, transferrin, ferritin, total iron binding capacity, apolipoprotein B48 (ApoB48), fibroblast growth factor 19 (FGF19) and 21 (FGF21), C-reactive protein (CRP), and the fibrosis-4 index score (Fib-4). Other parameters such as physical activity, sleep patterns, quality of life, patient satisfaction, food intake, and adherence to the dietary intervention will also be assessed. Demographic variables, drug use, smoking and drinking habits, diabetes medication use, and compliance with the time restriction will be documented. These assessments will be conducted at specified intervals throughout the trial to ensure comprehensive data collection and analysis.