Regulatory T Cells in Type 1 Diabetes Patients Treated With IL-2

Study Overview
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Brief Summary
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Type 1 diabetes is the most common severe chronic autoimmune disease worldwide and is caused by the autoimmune (loss of self tolerance) mediated destruction of the insulin producing pancreatic beta cells thus leading to insulin deficiency and development of hyperglycaemia. Currently, medical management of type 1 diabetes focuses on intensive insulin replacement therapy to limit complications (retinopathy, nephropathy, neuropathy); nevertheless clinical outcomes remain sub optimal. There are intensive efforts to design novel immunotherapies that can arrest the autoimmune process and thereby preserve residual insulin production leading to fewer complications and better clinical outcomes. The vast majority of genes that contribute to susceptibility to type 1 diabetes have been found to encode proteins involved in immune regulation and function. In particular, several susceptibility proteins are involved in the interleukin 2 (IL-2) pathway that regulates T cell activation and tolerance to self antigens. Aldesleukin is a human recombinant IL-2 product produced by recombinant DNA technology using genetically engineered E. coli stain containing an analog of the human interleukin-2 gene. There is substantial nonclinical, preclinical and clinical data that ultra low dose IL-2 (aldesleukin) therapy can arrest the autoimmune mediated destruction of pancreatic beta cells by induction of functional T regulatory cells. However, prior to embarking on large proof of concept trials in type 1 diabetes it is essential that the optimum dose of IL-2 (aldesleukin) is determined. The objective of this study is to establish in patients with type 1 diabetes the optimal dose of IL-2 (aldesleukin) to administer in order to increase T regulatory cell response.

Official Title
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Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D)

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Drug: Aldesleukin (Proleukin)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Type 1 diabetes 18-50 years Duration of diabetes less than 24 months from diagnosis One positive autoantibody (anti-islet cell, anti-GAD, anti-IA2, anti-ZnT8) Exclusion Criteria: Hypersensitivity to aldesleukin or any of the excipients History of severe cardiac disease History of malignancy within the past 5 years (with the exception of localized carcinoma of the skin that had been resected for cure or cervical carcinoma in situ) History or concurrent use of immunosuppressive agents or steroids History of unstable diabetes with recurrent hypoglycaemia Active autoimmune, hyper or hypothyroidism Active clinical infection Major pre-existing organ dysfunction or previous organ allograft Females who are pregnant, lactating or intend to get pregnant during the study - Males who intend to father a pregnancy during the study Donation of more than 500 ml of blood within 2 months prior to aldesleukin administration Participation in a previous therapeutic clinical trial within 2 months prior to aldesleukin administration Abnormal ECG Abnormal full blood count, chronic renal failure (Stage 3,4,5) and/or evidence impaired liver function Positive Hepatitis B surface Antigen (HBsAg) or Hepatitis C serology or Human Immunodeficiency Virus (HIV) test Any medical history or clinically relevant abnormality that is deemed by the principal investigator and/or medical monitor to make the patient ineligible for inclusion because of a safety concern

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Aldesleukin (Proleukin)|A single, subcutaneous dose will be given administered with the maximum dose allowed 1.5 X 106 IU/M2.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary endpoint is based upon the percentage of CD4+T regulatory (defined as CD3+CD4+CD25highCD127low) cells within the CD3+CD4+T cell gate following treatment with IL-2. | Fluorescence-activated cell sorting assay | From Day 0 to Day 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| T regulatory cell phenotype and stability | Fluorescence-activated cell sorting assay | From Day 0 to Day 60 | 
| T effector cell number and phenotype | Fluorescence-activated cell sorting assay | From Day 0 - Day 60 | 
| T cell subset proliferation and populations | Fluorescence-activated cell sorting assay | From Day 0 - Day 60 | 
| Intracellular T cell and natural killer(NK) cell signalling | Fluorescence-activated cell sorting assay | From Day 0 - Day 60 | 
| T regulatory cell function | T suppression assay | From Day 0 - Day 60 | 
| IL-2 pathway genotype | DNA sequencing | From Day 0 - Day 60 | 
| Lymphocyte Subsets | Complete blood count | From Day 0 to Day 60 | 
| Serum Cytokines | Enzyme-linked immuno sorbent assay | From Day 0 to Day 60 | 
| Glycaemic control | Self monitoring blood glucose readings, HbA1c, insulin usage | From Day 0 to Day 60 | 
| Number of Participants with Adverse Events as a Measure of Safety and Tolerability |  | From Day O to Day 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Interleukin 2, Type 1 diabetes, T regulatory cells, Adaptive trial