Efficacy and Safety of Gliclazide MR and Dapagliflozin, with or without Metformin, in Type 2 Diabetes Patients Inadequately Controlled on Dapagliflozin

The primary objective of this phase 3, randomized, double-blind, placebo-controlled study is to demonstrate the **superiority** of the free combination of gliclazide MR and dapagliflozin, with or without metformin, in reducing HbA1c levels after 24 weeks of treatment. This is compared to placebo and dapagliflozin, with or without metformin, in participants with **Type 2 Diabetes** (T2D) who are not optimally controlled with dapagliflozin, with or without metformin. The clinical relevance of this objective lies in its potential to offer a more effective treatment regimen for patients with inadequately controlled T2D, thereby improving glycemic control and reducing the risk of diabetes-related complications.

Secondary objectives include:

• Assessing the effect of the free combination of gliclazide MR and dapagliflozin compared to placebo and dapagliflozin, with or without metformin, over 24 weeks of treatment on different secondary endpoints in participants with T2D not optimally controlled with dapagliflozin, with or without metformin.
• Evaluating the safety and tolerability of the free combination of gliclazide MR and dapagliflozin compared with placebo and dapagliflozin, with or without metformin, over 24 weeks of treatment.

The clinical trial involves a total of **105 participants** diagnosed with **Type 2 Diabetes** that is inadequately controlled with dapagliflozin, with or without metformin. The study population includes both male and female subjects, aged 18 years and older, with a body mass index (BMI) ranging from 25 to 40 kg/m². Participants were selected based on their stable regimen of diet and exercise, and their current treatment with either metformin monotherapy at a stable daily dose of at least 1500 mg or dapagliflozin or empagliflozin, in monotherapy or in combination with metformin, with stable doses for at least 12 weeks prior to the screening visit. The trial includes individuals with HbA1c levels ranging from 7.0% to 10.5% and fasting plasma glucose (FPG) levels of 15 mmol/L or less. The study population is characterized by a vulnerable group, indicating the inclusion of individuals who may require additional considerations during the trial. The selection criteria ensure that participants are on a stable treatment regimen and have specific glycemic control parameters, which are crucial for assessing the efficacy of the treatment under investigation.

The clinical trial is a **randomized, double-blind, placebo-controlled** study designed to evaluate the efficacy and safety of **gliclazide** modified-release in patients with **type 2 diabetes** inadequately controlled with **dapagliflozin** with or without **metformin**. The primary objective is to demonstrate the superiority of the combination of gliclazide MR and dapagliflozin, with or without metformin, in reducing HbA1c levels after 24 weeks of treatment compared to placebo and dapagliflozin, with or without metformin. The trial is expected to commence recruitment on June 30, 2024, and conclude by February 28, 2026.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as a diagnosis of type 2 diabetes for more than six months, a body mass index between 25 and 40 kg/m², and specific HbA1c and fasting plasma glucose levels. The screening period will ensure participants are on a stable regimen of diet and exercise and currently treated with either metformin or dapagliflozin, with or without metformin, at stable doses for at least 12 weeks prior to the screening visit. Following successful screening, eligible participants will be enrolled in the randomized treatment period.

The trial will include follow-up visits to monitor the participants' health and treatment efficacy, with assessments of HbA1c and fasting plasma glucose levels as primary and secondary endpoints, respectively. Additional secondary endpoints include the proportion of participants achieving specific HbA1c targets, the need for rescue therapy, and the incidence of adverse events such as hypoglycemic events, genital infections, and urinary tract infections. Vital signs, body weight, and clinical laboratory measures will also be evaluated.

The expected duration of participant involvement is 24 weeks, with conditions for early termination including failure to meet specific glycemic control criteria or the occurrence of significant adverse events. Participants will conclude their involvement with an end-of-study visit, where final assessments will be conducted to evaluate the overall outcomes of the treatment regimen.

The clinical trial involves the administration of **DIAMICRON 60MG**, a modified-release tablet containing the active substance **gliclazide**. This medication is produced by LES LABORATOIRES SERVIER (SURESNES) and is authorized for use in France. The pharmaceutical form is a modified-release tablet, designed to be taken orally. The maximum daily dose is 60 mg, with a total treatment period of up to 24 weeks. The administration of gliclazide is intended to assess its efficacy in reducing HbA1c levels in patients with type 2 diabetes who are inadequately controlled with dapagliflozin, with or without metformin.

Another experimental medication used in the trial is **Forxiga 10 mg**, a film-coated tablet containing the active substance **dapagliflozin**. Manufactured by ASTRAZENECA AB, this medication is authorized for use in the European Union. The film-coated tablet is administered orally, with a maximum daily dose of 10 mg. The treatment period for dapagliflozin extends up to 38 weeks. This medication is used in combination with gliclazide to evaluate its effectiveness in managing blood glucose levels in the target patient population.

**METFORMIN** is included as a non-experimental treatment in the study. It is provided in a prolonged-release tablet form and is administered orally. Although the specific dosage and treatment period are not detailed, metformin is commonly used as a standard-of-care therapy for type 2 diabetes. Its inclusion in the trial allows for the assessment of the combined effects of gliclazide and dapagliflozin, with or without metformin, on glycemic control.

A **placebo** is also utilized in this study, identified as Placebo S05762. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know which treatment is being administered. This control measure is critical for accurately assessing the efficacy and safety of the experimental medications.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the change from baseline to week 24 in **HbA1c** levels. Secondary endpoints include the change from baseline to week 24 in centralised fasting plasma glucose (FPG), the proportion of participants at week 24 achieving specific HbA1c targets (<7.0%, ≤6.5%, and <7% without clinically important and/or severe hypoglycaemia), the proportion of participants requiring rescue therapy over 24 weeks, and the incidence of adverse events such as hypoglycaemic events, genital infections, and urinary tract infections (UTIs). Additionally, vital signs (systolic blood pressure, diastolic blood pressure, heart rate), body weight, and clinical laboratory measures (biochemistry and haematology) will be monitored.

Measurements will be collected at baseline and at the 24-week mark to assess changes in the specified parameters. The trial is designed to demonstrate the superiority of the combination of gliclazide MR and dapagliflozin, with or without metformin, in reducing HbA1c compared to placebo and dapagliflozin, with or without metformin, in participants with type 2 diabetes not optimally controlled with dapagliflozin, with or without metformin. The data collected will be analyzed to determine the efficacy of the treatment regimen in achieving the desired outcomes.