Effect of orlistat on LIVER fat content in obese subjects with NAFLD and High concEntrAtion of pLasma proneurotensin THrough inhibition of neurotensin secretion and action

The primary objective of this study is to evaluate whether a 24-week treatment with **orlistat** significantly reduces the percentual Liver Fat Content (LFC%) in individuals with obesity, defined as a Body Mass Index (BMI) of 30 kg/m² or greater, who also have Non-Alcoholic Fatty Liver Disease (NAFLD) and elevated plasma concentrations of proneurotensin (pro-NTS) exceeding 150 pmol/L. This is clinically relevant as reducing liver fat content can potentially mitigate the progression of NAFLD, a condition associated with increased risk of liver-related morbidity and mortality.

Secondary objectives include assessing the impact of orlistat treatment on various metabolic parameters in the same population. These include:

• Reduction in body weight
• Improvement in insulin sensitivity, as measured by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)
• Reduction in fasting plasma glucose levels
• Reduction in plasma glucose levels 2 hours after an oral glucose load
• Reduction in plasma triglycerides
• Reduction in plasma LDL-cholesterol
• Reduction in systolic blood pressure
• Increase in HDL-cholesterol levels

These secondary outcomes are important as they address various cardiovascular and metabolic risk factors associated with obesity and NAFLD, potentially leading to improved overall health outcomes in this patient population.

The clinical trial involves participants diagnosed with **Non-Alcoholic Fatty Liver Disease** (NAFLD) and aims to evaluate the efficacy of orlistat in reducing liver fat content over a 24-week period. The study population includes both male and female subjects aged between 20 and 65 years, with a body mass index (BMI) of 30 kg/m² or higher, and elevated plasma concentrations of pro-NTS (>150 pmol/L). Participants are required to have a liver fat content percentage greater than 5.6% in the absence of other causes of steatosis. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria include obtaining written informed consent and a negative pregnancy test for women of childbearing potential. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **orlistat** in reducing liver fat content in individuals with **Non-Alcoholic Fatty Liver Disease** (NAFLD) and high plasma proneurotensin levels. This is a phase 4, randomized, double-blind, controlled trial with an estimated duration of 24 weeks for each participant. The trial aims to compare the effects of orlistat with a control therapy over this period. Participants will be randomly assigned to either the orlistat group or the control group, ensuring that neither the participants nor the investigators are aware of the group assignments, thus maintaining the double-blind nature of the study.

The study will commence with an inclusion visit, where potential participants will undergo screening to ensure they meet the principal inclusion criteria, such as being aged 20-65 years, having a body mass index (BMI) of 30 kg/m² or higher, and a liver fat content percentage (LFC%) greater than 5.6% without other causes of steatosis. Women of childbearing potential must have a negative pregnancy test. Following successful screening, participants will be enrolled and begin the treatment phase.

Throughout the trial, participants will attend regular follow-up visits to monitor their health and assess the primary and secondary endpoints. The primary endpoint is the difference in the change of absolute LFC% between the treatment and control groups after 24 weeks. Secondary endpoints include changes in body weight, insulin sensitivity, fasting plasma glucose, plasma glucose after an oral glucose load, plasma triglycerides, LDL-cholesterol, systolic blood pressure, and HDL-cholesterol over the same period.

The end-of-study visit will occur at the conclusion of the 24-week treatment period, where final assessments will be conducted to evaluate the outcomes. Participant involvement is expected to last for the entire 24-week duration unless conditions arise that necessitate early termination, such as adverse events or withdrawal of consent. The trial is expected to conclude by December 31, 2025, with recruitment having started on August 15, 2023.

The clinical trial involves the administration of **Orlistat**, a pharmaceutical compound utilized in the study to evaluate its effects on liver fat content in obese subjects with non-alcoholic fatty liver disease (NAFLD) and elevated plasma proneurotensin levels. The experimental medication, **Orlistat STADA 120 mg**, is provided in the form of hard capsules. The active substance, **Orlistat**, is a chemical compound with the ATC code A08AB01. The medication is administered orally, with a maximum daily dose of 360 mg, divided into three doses of 120 mg each. The treatment period extends over 24 weeks, during which participant compliance is monitored to ensure adherence to the dosing schedule.

In this study, the control therapy serves as the comparator treatment. The control group will receive standard-of-care therapy, which may include lifestyle modifications and dietary advice, but will not include the administration of **Orlistat**. The objective is to compare the effects of **Orlistat** with the control therapy in reducing the percentage of liver fat content in the specified patient population. Compliance with the control therapy will also be monitored to ensure the integrity of the study results.

Efficacy in this clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the treatment group difference in the 6-month change of absolute **Liver Fat Content (LFC%)**. This will be measured by comparing the LFC% at week 24 to the baseline measurement at week -1. Secondary endpoints include the between-group differences (orlistat vs control) in the 24-week changes in several parameters: body weight, insulin sensitivity (assessed by the Homeostatic Model Assessment of insulin resistance, HOMA-IR), fasting plasma glucose, plasma glucose 2-hours after a 75 gram oral glucose load, plasma triglycerides, plasma LDL-cholesterol, systolic blood pressure, and HDL-cholesterol. These parameters will be collected and analyzed at the end of the 24-week treatment period to determine the efficacy of orlistat in reducing liver fat content and improving metabolic markers in individuals with obesity and non-alcoholic fatty liver disease (NAFLD) with high plasma concentration of pro-neurotensin.