Evaluation of Clinical and Biological Response to Repeated Low-Dose Aldesleukin in Type 1 Diabetes Patients with Residual Insulin Secretion Post-Ciclosporin Therapy

The primary objective of this study is the **evaluation** of the Tregs lymphocyte response profile between days 63 and 70, following five administrations of low-dose interleukin-2 (IL-2) at 1 million units per day in patients with newly diagnosed type 1 diabetes who have received ciclosporin treatment for two months. This objective is clinically relevant as it aims to assess the immunomodulatory effects of IL-2 on regulatory T cells (Tregs), which are crucial for maintaining immune tolerance and potentially preserving residual insulin secretion in type 1 diabetes.

Secondary objectives include:

• Monitoring the evolution of residual insulin secretion, which is important for understanding the preservation of beta-cell function.
• Assessing changes in Tregs values at multiple time points (M3, M6, M9, M12, M18, and M24) compared to baseline and post-ciclosporin values, providing insights into the long-term effects of the treatment.
• Evaluating compliance with ciclosporin and ILT-101/placebo, which is essential for ensuring the reliability of the study outcomes.
• Determining the tolerance of trial treatments from day 1 to day 719, which is critical for assessing the safety profile of the interventions.

The clinical trial involves participants diagnosed with **type 1 diabetes** stage 3, within three months of diagnosis. The study population includes both male and female subjects, aged between 16 and 45 years, who are at Tanner stage 5 of puberty. Participants must have type 1 diabetes as per ADA criteria, with at least one positive autoantibody, and must not have experienced ketoacidosis or significant weight loss. They should also have a fasting C-peptide level of at least 0.1 nmol/L after a minimum of 15 days following the start of insulin therapy. The trial requires participants to be free from clinically significant abnormalities in hematology, biochemistry, liver, kidney, and thyroid function tests, and to have no documented history of heart disease with a normal ECG. Effective contraception is mandatory for sexually active participants of childbearing age. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on these criteria, ensuring the inclusion of a vulnerable population. Participants' lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **Tregs lymphocyte** response profile in patients with newly diagnosed type 1 diabetes, specifically those who have retained residual insulin secretion. This study is a randomized, double-blind, controlled trial involving the administration of low-dose **aldesleukin** (ILT-101) and a placebo, alongside **ciclosporin** treatment. The trial is set to span approximately 24 months, with an estimated recruitment start date of September 21, 2022, and an estimated end date of April 20, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diabetes diagnosis, and absence of significant biological abnormalities. Following the screening, participants will receive **ciclosporin** treatment for two months, after which they will be administered low-dose IL-2 for five days. The primary endpoint is the variation in Tregs values at day 70 compared to post-ciclosporin values at day 63. Secondary endpoints include compliance with the treatment regimen, tolerance assessment, and the evolution of residual insulin secretion.

Study visits are scheduled at regular intervals, including follow-up visits at months 3, 6, 9, 12, 18, and 24, to monitor changes in Tregs values and assess tolerance through clinical examinations, vital sign measurements, and systematic biological check-ups. The end-of-study visit will occur at month 24, marking the conclusion of participant involvement. Participants are expected to remain in the study for the full duration unless conditions such as significant adverse events or non-compliance with the study protocol necessitate early termination.

The clinical trial involves the administration of **ILT-101 liquide**, an experimental medication containing the active substance **aldesleukin**. This medication is provided in the form of a **solution for injection** and is administered **intravenously**. The dosing regimen consists of a low-dose administration of **1 million units per day**. The maximum total dose is **46 million units**, and the treatment period extends up to **12 weeks**. The primary objective is to evaluate the Tregs lymphocyte response profile in patients with type 1 diabetes who have retained residual insulin secretion.

A **placebo** of ILT-101 is also utilized in the study as a comparator treatment. The placebo is designed to mimic the experimental medication in appearance but does not contain any active substance. The placebo is used to ensure the validity of the trial results by providing a control group for comparison against the effects of ILT-101.

Additionally, the study includes the administration of **ciclosporin**, a non-experimental treatment. Ciclosporin is a chemical substance administered **orally**. The maximum daily dose is **500 mg**, with a total maximum dose of **30 grams** over a treatment period of **60 days**. This treatment is provided to patients prior to the administration of ILT-101 to assess its impact on the clinical and biological response to the experimental medication. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

Efficacy in this clinical trial will be assessed primarily through the evaluation of the variation in **Tregs** values at Day 70 (D70) compared with post-ciclosporin values at Day 63 (D63). Secondary endpoints include compliance with ciclosporin and ILT-101/placebo, tolerance assessed from Day 1 (D1) to Day 719 (D719) through clinical examinations, vital signs measurements, systematic biological check-ups, and adverse event collection at every visit. Additionally, the evolution of residual insulin secretion and changes in **Tregs** values at multiple timepoints—Month 3 (M3, J88), Month 6 (M6, J179), Month 9 (M9, J270), Month 12 (M12, J361), and after treatment discontinuation at Month 18 (M18, J536) and Month 24 (M24, J719)—will be compared to baseline and post-ciclosporin values at Day 63 (J63).