Impact of Pharmacogenetic-Guided Treatment on Type 2 Diabetes.

Open-label, Double-arm, Controlled, Randomized, Multicentre Clinical Trial to Evaluate the Impact of Pharmacogenetic-guided Treatment in Patients With Insufficiently Controlled Type 2 Diabetes.

The goal of this clinical trial is to assess the efficacy of a pharmacogenetics-guided treatment, compared to standard optimized treatment, in patients with inadequately controlled type 2 diabetes. The main questions it aims to answer are:

• Is the disease better controlled when the treatment prescribed is based on the participant's pharmacogenetic profile?
• What medical problems do participants experience while taking the treatment?

Participants will:

• Take the treatment described according to the Summary of Product Characteristics (SmPC).
• Visit the clinic once every 12 weeks for checkups and tests.
• Keep a diary of their symptoms to inform the Investigator.

Rationale:

Type 2 diabetes (T2D) is a growing disease that causes serious complications and represents a significant public health burden. Despite current therapies, many patients fail to achieve adequate glycemic control, highlighting the need for more personalized approaches. This study seeks to demonstrate that pharmacogenetics, which tailors treatments according to patients' genetic variations, can improve disease control, reduce adverse effects, and ultimately optimize healthcare resources, improving patients' quality of life.

Study Design:

This is a Phase IV, multicenter, randomized, controlled, two-arm, crossover clinical trial. The study will include at least 504 patients, who will be randomized in a 1:1 ratio to receive pharmacogenetics-guided treatment or standard treatment for type 2 diabetes. Once proven to meet eligibility criteria, patients will be assigned to a treatment arm and will participate in the study for the next 24 weeks.

Primary Objective:

To evaluate the efficacy of pharmacogenetics-guided treatment, compared to optimized standard treatment, in patients with inadequately controlled type 2 diabetes.

Secondary Objective:

To evaluate pharmacogenetic markers with the effect of treatment administered prior to randomization.

Exploratory Objectives:

• To evaluate the percentage of patients achieving the target of dyslipidemia and its relationship with the genetic variations present in these subjects.
• To evaluate the percentage of patients reaching the blood pressure target and its relationship with the genetic variations present in these subjects.
• To evaluate the incidence and relationship of adverse events of glucose control drugs with genetic variations.

Safety Objective:

To evaluate the safety and tolerability of the glucose control drugs prescribed in each group of patients.

Target Population:

Patients between 40 and 70 years old, with a body mass index (BMI) between 25 and 40 kg/m² and with a diagnosis of type 2 diabetes inadequately controlled (HbA1c between 7% and 9.5%) and receiving standard non-insulin treatment for at least 6 months will be included. Patients will be visited at 12 and 24 weeks from the start of the study.

Statistical Methods:

The sample size was calculated with an alpha risk of 0.05 and a beta risk of 0.1, using a bilateral test. A total of 252 subjects in each group (standard and pharmacogenetics-guided treatment) are required to detect a significant difference in the proportion of patients achieving HbA1c ≤7%. A dropout rate of 10% is expected. Follow-up of patients will be 24 weeks, sufficient time to observe improvements in glycemic control. The goal is to achieve an HbA1c ≤7%, as recommended by the American Diabetes Association. It is estimated that 50% of patients will achieve the target with antidiabetic treatment, and it is assumed that pharmacogenetics-guided treatment will have at least a 15% greater response than conventional treatment, due to genetic variations.

The main objective is to evaluate the impact of pharmacogenetics-guided treatment in patients with type 2 diabetes, comparing proportions between groups. Analyses will be performed according to the type of variable: Student's t-test or Mann-Whitney for quantitative variables and Fisher's exact test or chi-square tests for qualitative variables. The software used will be R (version 3.6.1), with two-way tests and an alpha risk of 0.05, verifying normality with the Shapiro-Wilk test.

Inclusion Criteria:

1. Age 40-70 years old, included.

2. Body Mass Index (BMI) between 25-40 kg/m².

3. Diagnosis of Type 2 Diabetes (T2D) according to the American Diabetes Association (ADA) criteria.

4. Patients with T2D insufficiently controlled (Hemoglobin A1c (HbA1c) 7-9.5%) with current (≥6 months) "standard of care" treatment, excluding the use of insulin.

5. The subject has provided written informed consent prior to any study-specific procedure.

6. Able and willing to comply with requested study visits and procedures.

7. Contraceptive measures, only for female participants:

   • A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:
   • Is a woman of non-childbearing potential (WONCBP) OR
   • Is a woman of childbearing potential (WOCBP) and agrees to use a contraceptive method that is highly effective, with a failure rate of <1%, during the study intervention period (to be effective before starting the intervention).

A WOCBP must have a negative urine pregnancy test before the first administration of study intervention.

Exclusion Criteria:

1. Treatment with insulin at the time of screening.
2. HbA1c >9.5% at screening.
3. Treatment with more than 3 glucose-lowering drugs at the time of screening.
4. Chronic renal disease defined as estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m² (many glucose-lowering drugs are not approved or require dosage adjustments for use in these patients) at the screening visit.
5. Hepatic insufficiency, which contraindicates the use of glucose-lowering drugs.
6. Currently receiving treatment in another investigational drug study, or less than 30 days since ending treatment in another investigational drug study.
7. Pregnancy or lactation.
8. Women of childbearing potential with no effective contraceptive methods.
9. New York Heart Association (NYHA) Class III or IV congestive heart failure.
10. Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator's knowledge.
11. Subject is study staff directly involved with the study or is a family member of the investigational study staff.
12. Life expectancy predicted to be <2 years.