Efficacy and Safety of Oral Semaglutide Versus Placebo in Combination with Metformin and/or Basal Insulin in Pediatric Type 2 Diabetes Patients

The primary objective of this study is to confirm the superiority of oral **semaglutide** at the maximum tolerated dose (3 mg, 7 mg, or 14 mg) compared to placebo in improving glycaemic control in children and adolescents aged 10 to less than 18 years with type 2 diabetes, who are also receiving background treatment with metformin, basal insulin, or both. This objective is clinically relevant as it aims to establish the efficacy of semaglutide in managing blood glucose levels in a pediatric population, potentially offering a new therapeutic option for young patients with type 2 diabetes.

Secondary objectives include: - Assessing and comparing the efficacy of oral semaglutide at the maximum tolerated dose versus placebo on parameters of body composition, which is important for understanding the broader metabolic effects of the treatment. - Evaluating and comparing the safety and tolerability of oral semaglutide at the maximum tolerated dose versus placebo, which is crucial for determining the risk-benefit profile of the medication in this demographic.

The clinical trial involves a total of **112 participants** diagnosed with **type 2 diabetes**. The study population consists of both male and female subjects aged between 10 to less than 18 years. Participants are required to have a stable treatment regimen of metformin, basal insulin, or both. The trial population was selected based on specific criteria, including an HbA1c range of 6.5% to 11.0% and a diagnosis according to the American Diabetes Association criteria. The study focuses on children and adolescents, a vulnerable population, to assess the efficacy of oral semaglutide in improving glycaemic control. Lifestyle factors such as diet and physical activity are not specified, but the inclusion of stable medication regimens suggests a focus on maintaining consistent treatment conditions.

The clinical trial is designed to evaluate the **efficacy** and safety of oral **semaglutide** in children and adolescents with **type 2 diabetes**. This is a randomized, double-blind, placebo-controlled trial involving participants aged 10 to less than 18 years. The trial will compare the effects of semaglutide at doses of 3 mg, 7 mg, and 14 mg against a placebo, all administered orally. The trial is expected to last for a total duration of 52 weeks, with the primary endpoint being the change in glycosylated hemoglobin (HbA1c) from baseline to week 26. Secondary endpoints include changes in fasting plasma glucose, body mass index, and other metabolic parameters over the same period and extending to week 52.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, HbA1c levels, and a confirmed diagnosis of type 2 diabetes. Following randomization, participants will attend regular follow-up visits to monitor their response to the treatment and any adverse events. These visits will include assessments of glycemic control, body measurements, and laboratory tests. The end-of-study visit will occur at week 52, where final evaluations will be conducted to assess the long-term effects of the treatment.

The expected length of participant involvement is approximately 57 weeks, accounting for the treatment period and follow-up assessments. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with the study protocol, or withdrawal of consent by the participant or their legal representative. The trial aims to provide comprehensive data on the safety and efficacy of semaglutide in a pediatric population, contributing to the understanding of its potential as a treatment option for type 2 diabetes in this age group.

The clinical trial involves the administration of **Rybelsus** tablets, which contain the active substance **semaglutide**. The trial includes three different dosages of Rybelsus: 3 mg, 7 mg, and 14 mg. These tablets are manufactured by Novo Nordisk A/S and are administered orally. The tablets are designed for blinding purposes, with "M8" debossed on one side and no debossment on the other. The maximum treatment period for each dosage is 52 weeks. The pharmaceutical form of these medications is a tablet, and they are not formulated specifically for pediatric use. The trial aims to evaluate the efficacy and safety of these dosages in children and adolescents with type 2 diabetes, in combination with metformin and/or basal insulin.

A **placebo** tablet is also used in this study as a comparator treatment. The placebo is designed to mimic the appearance of the semaglutide tablets to maintain blinding. It does not contain any active substance and is administered in the same manner as the active treatment, orally. The placebo serves as a control to assess the efficacy of the semaglutide tablets in managing glycemic control in the study population.

The efficacy of oral **semaglutide** in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change in glycosylated hemoglobin (HbA1c) levels from baseline (week 0) to week 26. Secondary endpoints include changes in fasting plasma glucose (FPG), body mass index (BMI) standard deviation score (SDS), body weight, waist circumference, and blood pressure, measured at both week 26 and week 52. Additionally, the trial will evaluate the percentage of participants achieving specific HbA1c targets at weeks 26 and 52, as well as the time to additional anti-diabetic medication and rescue medication.

Biochemical and hormonal changes will also be monitored, including levels of insulin-like growth factor 1 (IGF-1), calcitonin, estradiol, testosterone, prolactin, thyroid stimulating hormone (TSH), and other relevant biomarkers. The presence and titer of anti-semaglutide antibodies, along with their potential neutralizing effects, will be assessed over a 57-week period. Pharmacokinetic sampling of semaglutide will be conducted at eight visits throughout the 52-week treatment period, with specific focus on apparent clearance and average concentration, compared to historical adult data.

Measurements will be collected at specified time points, including baseline, week 26, and week 52, using validated laboratory tests and clinical assessments. The trial will also include safety assessments such as changes in height velocity, bone age, pubertal development, and pulse rate. The data collected will be analyzed to determine the efficacy of semaglutide in improving glycemic control and other metabolic parameters in children and adolescents with type 2 diabetes.