Safety, Tolerability, and Efficacy of Immunomodulation With AT-1501 in Combination With Transplanted Islet Cells in Adults With Brittle T1D

Study Overview
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Brief Summary
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This study will evaluate the safety, tolerability and efficacy of AT-1501 in an immunomodulation regimen in adult patients with T1D undergoing an islet cell transplant.

Detailed Description
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This study will evaluate the safety, tolerability and efficacy of transplantation of experimental islet cells as a potential treatment for brittle type 1 diabetes mellitus. It will also assess the safety, tolerability and efficacy of AT-1501 in an immunomodulation regimen in adult patients with brittle T1D undergoing an islet cell transplant. This is a single arm open-label study and up to 6 participants will be recruited at a single center in the United States. The objectives include: To assess the safety and tolerability of transplanted islet cells and immunomodulation with AT-1501, in combination (AT+) with rabbit anti-thymoglobulin (ATG), etanercept and mycophenolate mofetil (MMF/EC-MPS) in adults with T1D undergoing islet cell transplant. To assess the efficacy of transplanted islet cells and immunomodulation with AT-1501 in adults with brittle T1D undergoing islet cell transplant. The duration of treatment may vary from participant to participant and could be up to 2 years. Participants may receive up to 2 islet cell transplants.

Official Title
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AT-1501-I206: An Open-Label Study to Evaluate the Safety, Tolerability and Efficacy of Transplanted Islet Cells and AT-1501 Immunomodulation in Adults With Brittle Type 1 Diabetes

Conditions
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Brittle Type 1 Diabetes Mellitus

Intervention / Treatment
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* Biological: AT-1501 IV Infusion
* Biological: Isolated cadaveric islet cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women 18-65 years of age A diagnosis of T1D ≥5 years with onset of disease at <40 years of age Involvement in appropriate diabetes management in accordance with the standard of care, as directed by an endocrinologist or diabetologist with at least 3 clinical evaluations within the 12 months prior to Screening; using an insulin pump or multiple daily injection (MDI) insulin therapy; and, unable to achieve acceptable metabolic control because of the occurrence of unexplained SHEs At least 3 unexplained SHEs not secondary to a missed meal or dosing error, in the 12 months prior to Screening Glycosylated hemoglobin (HbA1c) level greater than 7% (53 mmol/mol) and less than 9.5% (80 mmol/mol) inclusive Absence of stimulated C peptide (< 0.3 ng/mL) in response to a mixed meal tolerance test (MMTT) measured at 60 and 90 minutes after the start of consumption Impaired awareness of hypoglycemia (IAH) as defined by a Clarke Score [Clarke 1995] of 4 or more at the time of Screening, during the Screening period, and within the last 6 months prior to the transplant Exclusion Criteria: Any previous solid organ or islet allotransplant Body mass index (BMI) >30 kg/m2 Insulin requirement >1.0 unit/kg/day or <15 units/day

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Single-arm, open-label trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm AT-1501<br>Single-arm, open-label trial | Biological: AT-1501 IV Infusion<br>* Investigational study drug<br>Biological: Isolated cadaveric islet cells<br>* Infusion of human cadaveric islet cells into the portal vein<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety - Adverse Events (AE) and Adverse Events of Special Interest (AEoSI) | Incidence of adverse events | Accessed from date of transplant through Day 364 post final transplant for approximately 2 years | 
| Efficacy - Insulin independence | The proportion of participants that become insulin independent at Days 75 and 365 post-first, and final transplant | Date of transplant through Day 364 post- final transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy - HbA1c | Proportion of participants with HbA1c <7.0% (53 mmol/mol) and free of serious hypoglycemic events (SHEs) from Day 28 to Day 364 post first and final transplant. | Date of transplant through Day 364 post-final transplant | 
| Efficacy - Graft failure | Date of transplant through Day 364 post final transplant | Proportion of participants with graft failure at Day 364 post final transplant | 
| Efficacy - Durability of insulin independence | The proportion of participants that become insulin independent at Day 364 post-transplant | Date of transplant through Day 364 post final transplant | 
| Efficacy - Durability of insulin independence - long term | The proportion of participants that become insulin independent at year 2 and year 3 | 2 and 3 years after discontinuation of AT- 1501 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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T1D, AT-1501, Type 1 Diabetes, Islet Cell Transplant, humanized blocking antibody to CD40L, CD40L inhibitor, monoclonal antibody, Glucose Metabolism Diseases, Diabetes Mellitus, Type 1, Endocrine System Diseases, Graft, Metabolic Diseases, Immune System Diseases, Autoimmune Diseases, Hypoglycemia, Hyperglycemia, Brittle T1D, Brittle Type 1 Diabetes