Evaluation of the Efficacy and Safety of Semaglutide with Reduced-Dose Insulin Glargine Versus Titrated Insulin Glargine in Type 2 Diabetes with Overweight

The primary objective of this study is to confirm that the efficacy of once-weekly **semaglutide** 2.0 mg subcutaneously, as an add-on to dose-reduced **insulin glargine** U100, is not unacceptably worse (i.e., non-inferior) compared to titrated insulin glargine U100. This is measured by the change in HbA1c (%-point) from baseline to week 40 in participants with type 2 diabetes and overweight, who are treated with a once-daily basal insulin up to 40 units per day. The clinical relevance of this objective lies in establishing a treatment option that maintains glycemic control without increasing the insulin dose, which is crucial for managing type 2 diabetes effectively.

Secondary objectives include confirming the superiority of once-weekly semaglutide 2.0 mg as an add-on to dose-reduced insulin glargine U100 versus titrated insulin glargine U100 in terms of change in body weight (kg) from baseline to week 40 in the same participant population. This objective is clinically significant as it addresses the challenge of weight management in individuals with type 2 diabetes, which is a critical factor in the overall management of the disease.

The clinical trial involves a total of **170 participants** diagnosed with **Type 2 Diabetes (T2D)** and who are also overweight. The study population includes both male and female subjects, with age categories ranging from 18 to 64 years. Participants were selected based on specific criteria, including a diagnosis of T2D at least 180 days prior to screening, an HbA1c level between 7-10%, and a body mass index (BMI) of 25 kg/m² or higher. All participants have been on a stable daily dose of anti-diabetic medication, including metformin formulations or combinations, for at least 90 days before screening. Additionally, they have been treated with a once-daily basal insulin regimen of 40 units or less per day for the same duration. The trial does not include a vulnerable population, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **efficacy** and safety of once-weekly **semaglutide** 2.0 mg as an add-on to dose-reduced **insulin glargine** compared to titrated insulin glargine in participants with type 2 diabetes and overweight. This is a randomized, double-blind, controlled trial with a duration of 40 weeks. The primary objective is to confirm that the change in HbA1c from baseline to week 40 with semaglutide is not unacceptably worse than that with titrated insulin glargine, with a non-inferiority margin of 0.3%-point. Secondary endpoints include changes in body weight, daily insulin dose, and diabetes treatment satisfaction.

Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of type 2 diabetes at least 180 days prior, HbA1c levels between 7-10%, and a body mass index of at least 25 kg/m². Following the screening, participants will be randomized to receive either semaglutide or insulin glargine. Follow-up visits will occur periodically to monitor safety, efficacy, and adherence to the treatment regimen. The end-of-study visit will assess the primary and secondary endpoints.

The expected length of participant involvement is approximately 40 weeks, with conditions for early termination including significant adverse events or non-compliance with the study protocol. The trial will utilize pre-filled pen devices for subcutaneous administration of the investigational products, ensuring precise dosing and ease of use. The study aims to provide valuable insights into the management of type 2 diabetes in individuals with overweight, potentially influencing future therapeutic strategies.

The clinical trial involves the administration of **Lantus SoloStar**, a **solution for injection** containing **insulin glargine** as the active substance. This medication is provided in a pre-filled pen designed for subcutaneous injection. The pen, known as SoloSTAR, is a dial-a-dose device with an integrated 3 mL cartridge, allowing for dose adjustments. The trial aims to evaluate the efficacy and safety of this long-acting insulin analogue in participants with type 2 diabetes and overweight. The maximum treatment period for this medication is 40 weeks, with the dosing schedule determined by the trial protocol. Participant compliance is monitored through regular assessments and dose adjustments as necessary.

**Ozempic** is another investigational product used in this trial, available in two formulations: 2 mg and 1 mg solutions for injection in pre-filled pens. The active substance in Ozempic is **semaglutide**, a protein-based compound. The PDS290 pen-injector, used for administering semaglutide, is a dial-a-dose device with an integrated 1.5 mL cartridge. It allows for subcutaneous administration of semaglutide or placebo, with adjustable doses of 0.25 mg, 0.5 mg, and 1 mg. The trial product is provided in a clinical variant of the pen-injector, and the batch size may vary from the approved marketed batch size. The maximum treatment period for Ozempic is also 40 weeks, with dosing schedules tailored to the study's requirements.

In this trial, the comparator treatment involves the use of titrated insulin glargine U100, which serves as the standard-of-care therapy. The objective is to assess the non-inferiority of once-weekly semaglutide 2.0 mg as an add-on to dose-reduced insulin glargine compared to titrated insulin glargine in terms of efficacy, specifically the change in HbA1c levels from baseline to week 40. The trial ensures rigorous monitoring of participant compliance and adherence to the dosing regimen, with adjustments made based on individual responses and safety assessments.

The efficacy of the clinical trial will be assessed by evaluating the change in **HbA1c** levels from baseline (week 0) to the end of treatment (week 40). This primary endpoint will determine the non-inferiority of once-weekly semaglutide 2.0 mg as an add-on to dose-reduced insulin glargine compared to titrated insulin glargine in participants with type 2 diabetes and overweight. The clinically acceptable margin for non-inferiority is set at 0.3%-point for the mean treatment difference in **HbA1c**.

Secondary endpoints include the change in body weight from baseline to week 40, the relative change in daily insulin dose, and the score of the Diabetes Treatment Satisfaction Questionnaire – change version (DTSQc) at the end of treatment. These parameters will be measured and collected at specified timepoints, with the primary focus on the end of the treatment period at week 40. The assessments will utilize validated scales and laboratory tests to ensure accuracy and reliability in the data collected.