Evaluation of the Safety, Tolerability, and Efficacy of Zimislecel (VX-880) in Type 1 Diabetes Mellitus with Impaired Hypoglycemic Awareness and Severe Hypoglycemia

The primary objective of this study is to **evaluate the efficacy** of VX-880 infusion in subjects with **Type 1 Diabetes Mellitus** (T1D) who have impaired hypoglycemic awareness (IAH) and severe hypoglycemia. This is clinically relevant as it addresses a critical need for effective treatments in managing severe hypoglycemia in T1D patients, potentially improving their quality of life and reducing the risk of hypoglycemic events.

Secondary objectives include: - Evaluating the efficacy of VX-880 infusion on **metabolic control**. - Assessing the **safety and tolerability** of VX-880 infusion in subjects with T1D, IAH, and severe hypoglycemia. These objectives are crucial for understanding the broader impact of VX-880 on metabolic parameters and ensuring the treatment's safety profile in the target population.

The clinical trial involves a total of **36 participants** diagnosed with **Type 1 Diabetes Mellitus** with impaired hypoglycemic awareness and severe hypoglycemia. The study population includes both male and female subjects, with an age range that encompasses adults and adolescents. Participants were selected based on specific criteria, including a clinical history and laboratory evidence of Type 1 Diabetes, at least two episodes of severe hypoglycemia in the 12 months prior to screening, and reduced awareness of hypoglycemia. Additionally, consistent use of a continuous glucose monitor for at least three months before screening was required, except in regions where this is not standard care. The trial also considers blood group compatibility, specifically A or AB. The population includes vulnerable groups, ensuring a comprehensive evaluation of the efficacy of VX-880 infusion in this specific cohort.

The clinical trial is designed to evaluate the **safety**, tolerability, and efficacy of VX-880, a **solution for infusion** containing the active substance **zimislecel**, in subjects with Type 1 Diabetes Mellitus with impaired hypoglycemic awareness and severe hypoglycemia. This trial is structured as a Phase 1/2/3 study, incorporating a randomized, double-blind, and controlled methodology to ensure robust and unbiased results. The trial is expected to span from May 2023 to December 2030, with participant involvement lasting up to one year post-infusion.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a clinical history of Type 1 Diabetes, episodes of severe hypoglycemia, and reduced hypoglycemic awareness. Following successful screening, participants will receive the VX-880 infusion via intraportal use. Subsequent follow-up visits will be scheduled to monitor safety and efficacy endpoints, including the incidence of treatment-emergent adverse events, changes in HbA1c levels, and insulin independence. The end-of-study visit will occur at Day 365 post-infusion to assess long-term outcomes.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include the occurrence of severe adverse events, withdrawal of consent, or non-compliance with study protocols. The primary endpoints focus on safety and tolerability, while secondary endpoints evaluate the proportion of subjects achieving insulin independence and maintaining it for at least one year. The trial aims to provide comprehensive data on the potential benefits of VX-880 for individuals with Type 1 Diabetes Mellitus experiencing severe hypoglycemic episodes.

The clinical trial involves the administration of **VX-880 solution for infusion**, an investigational medicinal product developed by Vertex Pharmaceuticals, Incorporated. The active substance in VX-880 is **zimislecel**, also known as allogeneic human stem cell-derived fully differentiated pancreatic islet cells. This product is classified as an Advanced Therapy Investigational Medicinal Product (ATIMP) and is intended for use in subjects with Type 1 Diabetes Mellitus who have impaired hypoglycemic awareness and severe hypoglycemia. VX-880 is provided in the pharmaceutical form of a solution for infusion and is administered via the **intraportal route**. The maximum daily and total dose amounts are both set at 8,000,000,000 units, with a maximum treatment period of one day.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the safety, tolerability, and efficacy of VX-880 in the target patient population. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol. The trial aims to assess the potential of VX-880 to improve glycemic control in individuals with Type 1 Diabetes Mellitus, particularly those experiencing severe hypoglycemic episodes.

The efficacy of VX-880 infusion in subjects with **Type 1 Diabetes Mellitus** (T1D) and impaired hypoglycemic awareness will be assessed through a series of primary and secondary endpoints. For Parts B and C of the trial, the primary efficacy endpoint is the proportion of subjects who achieve insulin independence at Day 365 following the VX-880 infusion. Secondary endpoints include the proportion of subjects free from severe hypoglycemic events (SHEs) from Day 90 through Day 365, the change in HbA1c levels from baseline to Day 365, and the proportion of subjects who maintain insulin independence for at least one year. Additionally, the proportion of subjects who achieve insulin independence and remain so 12 months later, without SHEs, will be evaluated.

Data collection will involve the use of clinical laboratory values, vital signs, and standard 12-lead ECGs. The analysis will focus on treatment-emergent adverse events (TEAEs), including the incidence and severity of adverse events (AEs) and serious adverse events (SAEs). The endpoints will be measured at specified timepoints, with a particular focus on Day 365 post-infusion. The trial will utilize validated laboratory tests and patient-reported outcomes to ensure the accuracy and reliability of the efficacy assessments.