A Double-Blind, Randomized, Placebo-Controlled Study of Wharton's Jelly-Derived Allogeneic Mesenchymal Stromal Cells for Type 1 Diabetes in Pediatric Patients

The primary objective of this study is to investigate the **safety**, tolerance, and efficacy of allogeneic infusion of Wharton's Jelly-derived Mesenchymal Stromal Cells (WJMSCs) administered intravenously in children and adolescents who have been recently diagnosed with **Type 1 diabetes** (within the last six months). This objective is clinically relevant as it aims to assess the potential of WJMSCs to provide a novel therapeutic approach for managing Type 1 diabetes, a condition characterized by the autoimmune destruction of insulin-producing beta cells.

Secondary objectives include evaluating changes in beta-cell function, metabolic control, and Diabetes Treatment Satisfaction during the first year following treatment. These assessments are crucial for understanding the broader impact of WJMSC therapy on disease progression and patient quality of life.

The clinical trial involves a study population of children and adolescents recently diagnosed with **Type 1 diabetes**. The trial includes both male and female participants, with an age range of 7 to 21 years. The study population is stratified into two age groups: 7-11 years and 12-21 years. Participants are selected based on a clinical history compatible with a diagnosis of Type 1 diabetes within the last six months. The trial population is considered vulnerable, and participants must be mentally stable and able to comply with study procedures. The trial does not specify the total number of participants, as the sponsor has not provided this information. Participants are required to have a fasting plasma C-peptide concentration greater than 0.12 nmol/L. Those of child-bearing potential must agree to use adequate contraception until one year after the administration of the treatment or placebo. The trial aims to investigate the safety, tolerance, and efficacy of allogeneic infusion of WJMSCs administered intravenously.

The clinical trial is designed as a **randomized**, double-blind, parallel, placebo-controlled study to evaluate the safety, tolerance, and efficacy of Wharton's Jelly-derived allogenic mesenchymal stromal cells (WJMSCs) in children and adolescents recently diagnosed with **Type 1 diabetes**. The trial will be conducted in two parts, with an initial cohort of six subjects aged 7-18 years, followed by a larger cohort of sixty subjects stratified by age and randomized into two treatment arms. The study will utilize **ProTrans**, a suspension for intravenous infusion, as the investigational product. The trial is expected to run from January 2021 to December 2027.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as a clinical history of Type 1 diabetes diagnosed within six months prior to enrollment and a fasting plasma C-peptide concentration greater than 0.12 nmol/L. Following randomization, participants will receive either the active treatment or placebo. Study visits will be scheduled to monitor safety and efficacy, with primary endpoints including the evaluation of safety parameters and changes in C-peptide levels at 12 months post-infusion. Secondary endpoints will assess insulin independence, insulin requirements, and glycemic control at 6 and 12 months.

The expected duration of participant involvement is up to 12 months, with conditions for early termination including the occurrence of any grade 3 or higher adverse events, as evaluated by the Data Safety Monitoring Board (DSMB). The end-of-study visit will conclude the participant's involvement, with final assessments conducted to evaluate the long-term effects of the treatment. Participants of child-bearing potential are required to use adequate contraception until one year after the administration of WJMSC or placebo. The trial aims to provide valuable insights into the potential of WJMSCs as a therapeutic option for Type 1 diabetes in the pediatric population.

The clinical trial involves the administration of **ProTrans**, a suspension for intravenous infusion, as the experimental medication. ProTrans is a cell therapy product derived from Wharton's Jelly-derived allogenic mesenchymal stromal cells. The pharmaceutical form of ProTrans is a suspension specifically designed for intravenous infusion. The maximum daily dose of ProTrans is 20,000,000 cells, with a total maximum dose of 200,000,000 cells over the course of the treatment period. The treatment is administered via intravenous infusion, and the maximum treatment period is set at one day. The product is not formulated specifically for pediatric use, although it is being tested in a pediatric population. The active substance in ProTrans is structurally diverse, classified under cell therapy, and is produced by NEXTCELL PHARMA.

In this double-blinded, randomized, parallel, placebo-controlled trial, a placebo is used as the comparator treatment. The placebo is administered in a manner identical to the experimental treatment to maintain the study's blinding and integrity. The placebo is also delivered via intravenous infusion, ensuring that the administration route and frequency are consistent with those of the experimental medication. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol and to accurately assess the safety, tolerance, and efficacy of the treatment in children and adolescents recently diagnosed with type 1 diabetes.

Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary efficacy endpoint is the change in **C-peptide** Area Under the Curve (AUC) (0-120 min) for the Mixed Meal Tolerance Test (MMTT) at 12 months following the infusion of Wharton's Jelly-derived Allogenic Mesenchymal Stromal Cells (WJMSCs) or placebo, compared to baseline measurements taken before the start of treatment. This endpoint will provide insight into the preservation of beta-cell function over the course of the study.

Secondary efficacy endpoints include several parameters measured at 6 and 12 months. These are: the proportion of study participants who are independent of insulin according to ADA criteria, the proportion of participants with daily insulin needs of less than 0.25U/kg, insulin requirement per kg of body weight, and levels of Glycosylated Hemoglobin (HbA1c) and insulin-dose adjusted HbA1c (IDAA1c). Additionally, the study will evaluate the time-in-target (4-8 mmol/l) and time-in-range (3.9-10 mmol/l) as measured by flash glucose monitoring over a 14-day period. Changes in C-peptide AUC for MMTT at 6 months and changes in peak C-peptide concentration during the first 6 months or the first year after treatment will also be assessed.