Evaluation of Ladarixin on Beta-Cell Function Preservation in Recent Onset Type 1 Diabetes: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this clinical trial is to evaluate the efficacy of **ladarixin** in preserving **β-cell** function and delaying the progression of recent onset **Type 1 Diabetes** (T1D) in adolescent and adult patients. This is clinically relevant as maintaining **β-cell** function can potentially slow the progression of T1D, thereby reducing the need for exogenous insulin and improving patient outcomes. Additionally, the study aims to assess the safety profile of ladarixin in this specific clinical setting.

The clinical trial involves a total of **186 participants** diagnosed with **recent onset Type 1 Diabetes**. The study population comprises both male and female patients aged between 14 and 45 years. Participants were selected based on their recent diagnosis of Type 1 Diabetes, with the first investigational medicinal product dose administered within 180 days from the initial insulin administration. All participants are required to be positive for at least one diabetes-related auto-antibody and must have a fasting C-peptide level of less than 0.205 nmol/L, indicating residual **β-cell function**. The trial includes individuals who have required insulin therapy through subcutaneous injections or continuous subcutaneous insulin infusion. Participants must be able to comply with all protocol procedures throughout the study duration, including scheduled follow-up visits and examinations. The trial population includes a vulnerable group, ensuring that all participants have provided written informed consent, with additional assent required for those under 18 years of age. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the effect and safety of **ladarixin** in patients with recent onset **Type 1 Diabetes**. The trial aims to assess whether ladarixin treatment can preserve **β-cell** function and delay the progression of the disease in adolescent and adult patients. The study will involve the administration of 400 mg of ladarixin twice daily in the form of hard capsules, with a maximum daily dose of 800 mg, over a treatment period of up to 12 months. The trial is expected to conclude by March 2026, with recruitment having commenced in January 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (14-45 years), recent onset of Type 1 Diabetes, and the presence of diabetes-related auto-antibodies. Following the screening, participants will be randomized to receive either ladarixin or a placebo. The primary endpoint will be the change from baseline in the 2-hour AUC of C-peptide response to the Mixed Meal Tolerance Test (MMTT) at month 6. Secondary endpoints include changes in HbA1c, time in range by Continuous Glucose Monitoring (CGM), and insulin requirements over a 24-month period.

Study visits will include regular follow-up assessments at months 6, 12, 18, and 24 to monitor safety and efficacy outcomes. The end-of-study visit will occur at the conclusion of the 24-month period. Participants are expected to remain in the study for the full duration unless they meet conditions for early termination, such as withdrawal of consent, non-compliance with study procedures, or adverse events that necessitate discontinuation. The trial is structured to ensure rigorous monitoring and data collection to evaluate the therapeutic potential of ladarixin in this patient population.

The clinical trial involves the administration of **Ladarixin**, an experimental medication, to evaluate its efficacy and safety in patients with recent onset type 1 diabetes. **Ladarixin** is provided in the form of a hard capsule, with each capsule containing the active chemical substance **Ladarixin**. The medication is administered orally at a dosage of 400 mg twice daily, resulting in a maximum daily dose of 800 mg. The treatment period extends up to 12 weeks. The pharmaceutical product is manufactured by Dompé Farmaceutici S.p.A. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen.

In addition to the experimental treatment, a **placebo** is utilized as a comparator to match **Ladarixin**. The placebo is designed to mimic the appearance of the **Ladarixin** capsules but does not contain any active pharmaceutical ingredients. The placebo is administered following the same oral route and dosing schedule as the experimental medication, ensuring the double-blind nature of the study. This allows for an unbiased assessment of the treatment's effect on preserving **β-cell** function and delaying the progression of type 1 diabetes.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline in the 2-hour area under the curve (AUC) of **C-peptide** response to the Mixed Meal Tolerance Test (MMTT) at Month 6. This measurement will help evaluate the preservation of **Beta-cell** function in patients with recent onset type 1 diabetes.

Secondary endpoints include several parameters measured at multiple time points: Month 6, 12, 18, and 24. These include changes from baseline in the 2-hour AUC of **C-peptide** response to the MMTT, changes in HbA1c levels, and time in range (TIR) as determined by Continuous Glucose Monitoring (CGM). Additional secondary endpoints involve the proportion of patients with HbA1c <7% who did not experience severe hypoglycemic events, average daily insulin requirement, and the proportion of patients with HbA1c <7% and daily insulin requirement <0.5 IU/kg/day. Other glucose variability indices derived from CGM, such as glucose AUC outside the target range, 2-hour postprandial glucose, and Mean Amplitude Glycemic Excursions (MAGE), will also be evaluated. The number of self-reported episodes of severe hypoglycemia, the percentage of patients not requiring insulin therapy, and the Estimated Glucose Disposal Rate (eGDR) will be assessed as well.

These efficacy parameters will be collected and analyzed at specified intervals throughout the trial to determine the effect of ladarixin on delaying the progression of type 1 diabetes and preserving **Beta-cell** function. The trial is designed to provide comprehensive data on the efficacy of ladarixin in this patient population.