Evaluation of Semaglutide and Pramlintide Acetate on Metabolic Parameters in Obesity and Pre-diabetes: A Randomized Controlled Trial

The primary objectives of this study are twofold: to evaluate the **efficacy** of **semaglutide**, with or without **pramlintide**, on metabolism, body composition, gastric emptying, and various aspects of appetite and satiety in individuals with **obesity** and **pre-diabetes**; and to determine if phenotyping of obesity can predict the treatment response to semaglutide and pramlintide. These objectives are clinically relevant as they aim to enhance treatment strategies and outcomes for this population, potentially leading to more personalized and effective therapeutic approaches.

The secondary objective is to compare the effects of semaglutide alone or in combination with pramlintide on bone turnover in obese individuals with pre-diabetes. This aspect of the study is significant as it may provide insights into the broader metabolic effects of these treatments, beyond their primary targets.

The clinical trial involves participants diagnosed with **obesity** (BMI ≥ 30kg/m²) and **pre-diabetes** (HbA1c 39-47 mmol/mol). The study population includes both male and female subjects, aged over 18 years. Participants are required to have a negative pregnancy test and must agree to use contraceptives during the study period. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. The selection criteria focus on individuals with specific health conditions, and no additional lifestyle considerations such as diet or physical activity are specified.

The clinical trial is designed to evaluate the efficacy of **semaglutide** with or without **pramlintide** in individuals with obesity and prediabetes. This study is a randomized, double-blind, controlled trial, with an estimated duration from January 1, 2025, to December 31, 2025. Participants will be randomly assigned to receive either semaglutide alone or in combination with pramlintide. The trial aims to assess changes in metabolism, body composition, gastric emptying, and appetite and satiety sensations. The primary endpoint is the change in kilocalorie consumption at an ad libitum meal test from baseline to 25 weeks and after 26 weeks of treatment. Secondary endpoints include total weight loss, differences in weight loss between phenotypes, and changes in gastric emptying rate.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a BMI ≥ 30 kg/m², prediabetes status, age over 18 years, and a negative pregnancy test. Follow-up visits will occur at baseline, after 25 weeks, and at the end of the study. These visits will involve assessments of weight, appetite, and gastric emptying, among other parameters. The end-of-study visit will conclude the participant's involvement, which is expected to last approximately 26 weeks.

Participants may be withdrawn from the study early if they experience adverse effects, fail to comply with study procedures, or withdraw consent. The trial is conducted in accordance with regulatory standards, ensuring the safety and well-being of participants throughout the study duration.

The clinical trial involves the administration of three distinct treatments, each with specific roles and characteristics. **Paracetamol** is utilized as a comparator in this study. It is provided in the form of a dispersible tablet, with a maximum daily dose of 4 grams. The administration route is oral, and the treatment period is limited to a maximum of 2 days. Paracetamol serves as a mild analgesic and antipyretic, and its use in the trial is to provide a baseline for comparison against the experimental treatments.

**Semaglutide** is one of the primary experimental medications in this trial. It is administered via subcutaneous injection, with a pharmaceutical form identified as PHF00231MIG. The maximum daily dose is 0.34 milligrams, with a total maximum dose of 2.4 milligrams over a treatment period of up to 26 weeks. Semaglutide is classified as an anti-diabetic and anti-obesity medication, and its efficacy is being evaluated in the context of metabolism, body composition, gastric emptying, and appetite regulation in individuals with obesity and prediabetes.

**Pramlintide acetate** is another experimental treatment used in conjunction with semaglutide. It is administered as an injectable, with a maximum daily dose of 360 micrograms and a total maximum dose of 1980 micrograms over a treatment period of up to 1 week. Pramlintide acetate functions as an anti-diabetic and blood glucose-stabilizing medication. The trial aims to assess its impact on metabolic parameters and its potential synergistic effects when combined with semaglutide.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The study's objective is to evaluate the efficacy of semaglutide, with or without pramlintide, in improving metabolic outcomes in obese individuals with prediabetes, as well as to explore the potential predictive value of obesity phenotyping on treatment response.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change in kilocalorie (kCal) consumption during an ad libitum meal test, measured from baseline to after 25 weeks, and after 26 weeks of treatment with **semaglutide**, with the last week including the addition of **pramlintide**. Secondary endpoints include total weight loss from baseline, measured after 25 weeks and at the end of the study, expressed both in kilograms and as a percentage of total body weight. Additionally, the difference in total weight loss between different phenotypes will be evaluated.

Further secondary endpoints involve changes in appetite and satiety sensations, which will be measured using a Visual Analogue Scale (VAS) before and after meal tests conducted at baseline, after 25 weeks, and at the end of the study. The rate of gastric emptying will also be assessed using a **paracetamol** test at the same time points. These efficacy parameters will be collected and analyzed to determine the impact of the treatment regimen on individuals with obesity and prediabetes.