Evaluation of Pharmacogenetic-Guided Therapy Versus Standard Treatment in Patients with Uncontrolled Type 2 Diabetes Using Dapagliflozin, Dulaglutide, and Metformin

The primary objective of this clinical trial is to evaluate the **efficacy** of pharmacogenetic-guided treatment compared to optimized standard treatment in patients with insufficiently controlled **Type 2 Diabetes Mellitus**. This is clinically relevant as it aims to determine whether personalized treatment based on genetic information can improve glycemic control, potentially leading to better management of the disease and reduction in diabetes-related complications.

Secondary objectives include:

• Assessing the impact of treatment on HbA1c response according to genetic variants.
• Evaluating the percentage of patients achieving the goal of dyslipidemia and its relationship with genetic variations.
• Evaluating the percentage of patients achieving the goal of blood pressure and its relationship with genetic variations.
• Evaluating the incidence and relatedness of glucose-lowering drugs' adverse events with genetic variations.
• Evaluating the safety and tolerability of the glucose-lowering drugs prescribed in each patient group.

These secondary objectives aim to provide insights into the broader implications of pharmacogenetic-guided treatment, including its impact on other metabolic parameters and safety profile, which are crucial for comprehensive diabetes management.

The clinical trial focuses on individuals diagnosed with **Type 2 Diabetes Mellitus** who are experiencing insufficient control of their condition. The study population includes both male and female participants aged between 40 and 70 years, with a **Body Mass Index (BMI)** ranging from 25 to 40 kg/m². Participants are required to have been on a standard treatment regimen for at least six months without the use of insulin, and their **HbA1c** levels must be between 7% and 9.5%. The trial does not involve a vulnerable population. Participants are expected to comply with study visits and procedures, and female participants of childbearing potential must adhere to specific contraceptive measures. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed as an open-label, double-arm, controlled, randomized, multicentre study aimed at evaluating the efficacy of **pharmacogenetic**-guided treatment compared to optimized standard treatment in patients with insufficiently controlled **Type 2 Diabetes Mellitus**. The trial will involve participants aged 40-70 years with a **Body Mass Index (BMI)** of 25-40 kg/m², who have been diagnosed with Type 2 Diabetes according to the American Diabetes Association criteria and have not achieved adequate glycemic control (HbA1c 7-9.5%) despite at least six months of standard care treatment without insulin. The study will commence with a screening visit to confirm eligibility based on the inclusion criteria, including the provision of written informed consent and the ability to comply with study procedures.

Participants will be randomly assigned to either the experimental arm receiving pharmacogenetic-guided treatment or the control arm receiving optimized standard treatment. The trial will span a total duration of 24 weeks, with the primary endpoint being the proportion of patients achieving an HbA1c level of ≤7% at Week 24. Secondary endpoints include the achievement of dyslipidemia and blood pressure goals, as well as the incidence of adverse events related to glucose-lowering drugs. Study visits will be scheduled at baseline, mid-study, and at the end of the study to monitor progress, assess treatment efficacy, and record any adverse events. The end-of-study visit will involve a comprehensive evaluation of the participant's health status and the collection of final data for analysis.

Participant involvement is expected to last for the entire 24-week period unless early termination is warranted due to adverse events, non-compliance with study procedures, or withdrawal of consent. The trial is categorized as a Phase IV low-interventional study, with the justification for this classification being attached to the trial documentation. The study will utilize a range of glucose-lowering medications, including **dapagliflozin**, **dulaglutide**, **metformin hydrochloride**, **empagliflozin**, **pioglitazone**, **semaglutide**, **linagliptin**, **canagliflozin**, **vildagliptin**, and **sitagliptin**, administered either orally or via injection, depending on the specific medication. The trial is set to begin recruitment on April 15, 2025, with an estimated end date of June 30, 2026.

The clinical trial involves the administration of several **experimental medications** to evaluate their efficacy in patients with insufficiently controlled type 2 diabetes. The first medication is Forxiga, which contains the active substance **dapagliflozin**. It is provided in the form of film-coated tablets, with a dosage of 10 mg. The route of administration is oral, and the maximum daily dose is 10 mg. The treatment period is up to 24 months.

Trulicity, containing **dulaglutide**, is administered as a solution for injection in a pre-filled pen. The dosage is 1.5 mg, with a maximum daily dose of 1.5 mg. The route of administration is injection, and the treatment period is also up to 24 months.

GLUCOPHAGE, with the active substance **metformin hydrochloride**, is provided as film-coated tablets. The dosage is 1000 mg, administered orally, with a maximum daily dose of 1000 mg. The treatment period extends to 24 months.

Jardiance, containing **empagliflozin**, is available in film-coated tablet form with a dosage of 10 mg. It is administered orally, with a maximum daily dose of 25 mg, and the treatment period is up to 24 months.

Pioglitazone Mylan, with the active substance **pioglitazone**, is provided as tablets. The dosage is 15 mg, administered orally, with a maximum daily dose of 45 mg. The treatment period is up to 24 months.

Ozempic, containing **semaglutide**, is administered as a solution for injection in a pre-filled pen. The dosage is 0.5 mg, with a maximum daily dose of 2 mg. The route of administration is injection, and the treatment period is up to 24 months.

Trajenta, with the active substance **linagliptin**, is available in film-coated tablet form. The dosage is 5 mg, administered orally, with a maximum daily dose of 5 mg. The treatment period extends to 24 months.

Invokana, containing **canagliflozin**, is provided as film-coated tablets. The dosage is 100 mg, administered orally, with a maximum daily dose of 300 mg. The treatment period is up to 24 months.

Galvus, with the active substance **vildagliptin**, is available in tablet form. The dosage is 50 mg, administered orally, with a maximum daily dose of 100 mg. The treatment period extends to 24 months.

Sitagliptin, provided as film-coated tablets, contains the active substance **sitagliptin**. The dosage is 50 mg, administered orally, with a maximum daily dose of 100 mg. The treatment period is up to 24 months.

All medications are administered according to the specified dosing schedules, and participant compliance is monitored throughout the trial. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this study.

The efficacy of the pharmacogenetic-guided treatment in patients with insufficiently controlled type 2 diabetes will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of patients achieving a goal **HbA1c** level of ≤7% at Week 24 in the experimental arm compared to the control arm. Secondary endpoints include the comparison of patients who have achieved the goal of HbA1c ≤7% at baseline with those who did not, the percentage of patients achieving dyslipidemia goals at Week 24, and the percentage of patients achieving the target blood pressure of <140/90 mmHg at Week 24.

Additional secondary endpoints involve the number of adverse events related to glucose-lowering drugs for each genetic variation identified, and the proportion of patients in each group presenting various clinical outcomes over the study period. These outcomes include adverse events, serious adverse events, changes in clinical laboratory parameters such as renal and hepatic function, and changes in vital signs. The efficacy parameters will be measured and collected at specified timepoints, with the primary assessment occurring at Week 24.