Long-Term Evaluation of Semaglutide for BMI Maintenance in Adolescents with Obesity Following Initial Weight Reduction

The primary objective of this study is to evaluate the **maintenance** of a body mass index (BMI) below the obesity threshold in adolescents treated with **semaglutide** following a dose-tapering algorithm. This is clinically relevant as it addresses the long-term management of obesity in adolescents, a critical factor in reducing the risk of obesity-related comorbidities and improving overall health outcomes.

Secondary objectives include:

• Investigating the maintenance of improved BMI category in adolescents who have reduced their obesity class but still have a BMI above the obesity threshold after 1.5 years of initial treatment with semaglutide.
• Examining the doses of semaglutide administered according to a dose-tapering algorithm in adolescents who have achieved a BMI below the obesity threshold and are still on treatment after 1.5 years.
• Describing outcomes with semaglutide administered according to a response-dependent strategy in adolescents with obesity concerning weight-related parameters, glucose metabolism, cardiometabolic risk factors, and body composition.
• Investigating the long-term safety of semaglutide administered according to a response-dependent strategy in adolescents with obesity.

The clinical trial involves a total of **206 participants** who are adolescents aged between **12 to less than 15 years**. The study population includes both **male and female** subjects who are classified as a vulnerable population. Participants were selected based on specific criteria, including a **body mass index (BMI)** at or above the 95th percentile according to sex- and age-specific growth charts, and a body weight greater than 60 kg at screening. The trial focuses on adolescents who have achieved a BMI below the obesity threshold and are still undergoing treatment after 1.5 years of initial therapy. The study does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not provided additional information regarding the general health status or other lifestyle habits of the participants.

The clinical trial is designed to evaluate the long-term efficacy of **semaglutide** in maintaining weight loss in adolescents with **obesity**. This study employs a randomized, double-blind, controlled trial design to ensure the reliability and validity of the results. The trial is expected to span approximately six years, with the estimated recruitment start date in March 2025 and an anticipated end date in November 2031. Participants will be involved in the study for a maximum treatment period of 312 weeks, which is approximately six years, depending on their response to the treatment and adherence to the protocol.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility is assessed based on criteria such as age, body mass index (BMI), and body weight. Following successful screening, participants will undergo a series of follow-up visits to monitor their progress and adjust the dosage of **semaglutide** as needed. The primary objective is to maintain a BMI below the obesity threshold over the course of the study. Secondary endpoints include improvements in BMI category, changes in waist circumference, and various metabolic parameters. The end-of-study visit will conclude the trial, assessing the long-term impact of the treatment on weight maintenance and metabolic health.

Participants are expected to adhere to the study protocol, which includes regular subcutaneous administration of **semaglutide** using a pre-filled pen injector. The trial allows for dose adjustments based on individual tolerance and response, with the possibility of tapering to a zero dose if necessary. Conditions that may lead to early termination from the study include non-compliance with the treatment regimen, adverse reactions to the medication, or withdrawal of consent. The trial aims to provide valuable insights into the management of obesity in adolescents, with a focus on sustainable weight loss and metabolic health improvements.

The clinical trial involves the administration of **semaglutide**, a protein-based active substance, in the form of a solution for injection. The experimental medication is provided in pre-filled pens under the brand name Wegovy, manufactured by Novo Nordisk A/S. The pharmaceutical form is a solution for injection in a pre-filled pen, specifically designed for subcutaneous administration. The trial includes multiple dosage strengths of Wegovy: 0.25 mg, 0.5 mg, 1 mg, 1.7 mg, and 2.4 mg. Each dosage is delivered using the PDS290 pen-injector, a dial-a-dose prefilled device with an integrated 1.5 mL cartridge. This device allows for dose adjustments by dialing up or down, facilitating precise administration of the required dose. The maximum treatment period for the trial is 312 weeks.

The PDS290 pen-injector is utilized for the administration of semaglutide or placebo in clinical trials. It is designed to deliver semaglutide doses of 0.25 mg, 0.5 mg, and 1 mg, with the flexibility to adjust the dose as needed. The pen-injector does not have a CE mark, indicating it is specifically intended for clinical trial use. The administration route for all doses is subcutaneous, ensuring consistent delivery of the medication. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

In addition to the experimental medication, the trial may include the use of a placebo as a comparator treatment. The placebo is administered using the same PDS290 pen-injector to maintain consistency in the administration process. This approach allows for a controlled comparison of the effects of semaglutide against a non-active substance, providing valuable data on the efficacy and safety of the experimental treatment. The trial does not involve any other non-experimental treatments or standard-of-care therapies.

Efficacy in the clinical trial will be assessed through a series of primary and secondary endpoints focused on the maintenance and improvement of **Body Mass Index (BMI)** in adolescents with obesity. The primary endpoint is the maintenance of BMI below the obesity threshold, evaluated from 1.5 years to 3 years, with the count of participants as the measurement parameter. Secondary endpoints include the maintenance of an improved BMI category, tapering to zero dose, and the time/dose steps before ending dose tapering, all measured from 1.5 years to 3 years. Additionally, achieving BMI below the obesity threshold and any improvement in BMI category will be assessed from baseline to 1.5, 3 years, and the end of the continued treatment phase, up to 6 years.

Further secondary endpoints involve changes in various health parameters, such as BMI percentage of the 95th percentile, BMI SDS, waist-to-height ratio, waist circumference, and metabolic markers like HbA1c, fasting plasma glucose, fasting insulin, and HOMA-IR. These will be measured at baseline, 1.5 years, 3 years, and the end of the treatment phase. Changes in cardiovascular and body composition metrics, including blood pressure, fat mass, lean body mass, and visceral fat mass, will also be evaluated using DXA scans. The trial will utilize a dose-tapering algorithm for semaglutide administration, with assessments scheduled at specific intervals to monitor efficacy and safety outcomes.