Adaptive Study of IL-2 Dose Frequency on Regulatory T Cells in Type 1 Diabetes

Study Overview
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Brief Summary
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Type 1 diabetes (T1D) is the most common severe autoimmune disease worldwide and is caused by the body's immune destruction of its own insulin producing pancreatic beta cells leading to insulin deficiency and development of elevated blood sugars. Currently, medical management of T1D focuses on intensive insulin replacement therapy to limit complications (retinopathy, nephropathy, neuropathy); nevertheless clinical outcomes remain suboptimal. 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. Genetics are in part the cause of T1D and the majority of genes contributing to T1D produce proteins involved in immune regulation (called tolerance). A key player in immune tolerance is a molecule called interleukin-2 (IL-2) which enhances the ability of cells called T regulatory (Treg) cells to suppress the destruction the insulin producing beta cells. Aldesleukin is a human recombinant IL-2 product produced by recombinant DNA technology using a genetically engineered E. coli strain expressing an analogue of the human IL-2 gene. There is substantial data to suggest that ultra-low doses (ULD) of IL-2 (aldesleukin) can arrest the autoimmune mediated destruction of pancreatic beta cells by the induction of functional Treg cells. The former study Adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D) (NCT 01827735) was a single dose mechanistic study designed to establish the doses of IL-2 (aldesleukin) required to induce a minimal Treg increase (0.1 fold from baseline) or to induce a slightly larger Treg increase (0.2 fold from baseline) (maximal increase). Following on from the DILT1D study, the goal of the DILfrequency study is to use an adaptive design to determine the optimal dose and frequency of ULD IL-2 (aldesleukin) to maximize Treg function by frequently injecting ultra-low doses of IL-2 (aldesleukin). The responsiveness of each T1D participant to a particular frequency of IL-2 (aldesleukin) administration informs the frequency of dosing given to the next patient. This strategy focuses on improving the function of regulatory T cells that are exquisitely sensitive to IL-2 (aldesleukin).

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

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Drug: Aldesleukin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 diabetes 18-70 years of age Duration of diabetes less than 60 months from diagnosis Written informed consent to participate 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 History of live vaccination two weeks prior to first treatment 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 of severely impaired liver function (ALT/AST > 3xULN at screening; alkaline phosphatase and bilirubin 2xULN at screening (isolated bilirubin >2xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%))

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aldesleukin<br>Aldesleukin will be administered subcutaneously at varying doses and frequencies for a period of up to 98 days from first administration depending on the treatment assignment. The maximum dose allowed is 0.6 X 10^6 IU/m2. | Drug: Aldesleukin<br> <br> * Other names: IL-2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline of CD4 T regulatory cells, CD4 T effector cells and CD25 expression on T regulatory cells during treatment with ultra low dose IL-2 | Fluorescence-activated cell sorting | Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| T regulatory cell number, phenotype and proliferation | Measured by fluorescence-activated cell sorting | Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment) | 
| T effector cell number, phenotype and proliferation | Measured by fluorescence-activated cell sorting | Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment) | 
| Natural Killer cell number, phenotype and proliferation | Measured by fluorescence-activated cell sorting | Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment) | 
| B lymphocyte cell number, phenotype and proliferation | Measured by fluorescence-activated cell sorting | Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment) | 
| T cell and Natural killer cell intracellular signalling | Measured by fluorescence-activated cell sorting | Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment) | 
| Full blood count | Measured by automatic analyser | Visits 1-12 (between day -30 and day -1 up to a maximum of approximately day 98 depending on treatment assignment) | 
| Blood levels of IL-2, IL-6, IL-10, TNF-alpha, soluble CD25, IP-10, soluble rIL-6, and CRP | Measured by enzyme-linked immunosorbent assay | Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment) | 
| Change in metabolic control | Blood glucose, HbA1c, C-peptide, insulin use and autoantibody status | Visits 1-12 (between day -30 and day -1 up to a maximum of approximately day 98 depending on treatment assignment) | 
| Safety and tolerability | Assessed by clinical history, physical examination, temperature, blood pressure, heart rate, 12-Lead electrocardiogram (ECGs), clinical laboratory tests, and adverse event recording | Visits 1-12 (between day -30 and day -1 up to a maximum of approximately day 98 depending on treatment assignment) | 

 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