DILT1D: Regulatory T Cells in Type 1 Diabetes Patients Treated With IL-2

Sponsor

Cambridge University Hospitals NHS Foundation Trust (Other)

Overall Status

Completed

CT.gov ID

NCT01827735

Collaborator

University of Cambridge (Other), Juvenile Diabetes Research Foundation (Other), National Institute for Health Research, United Kingdom (Other), Wellcome Trust (Other)

Enrollment

Location

Duration (Months)

2.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes	Drug: Aldesleukin (Proleukin)	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

40 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

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

Study Start Date :

Mar 1, 2013

Actual Primary Completion Date :

May 1, 2014

Actual Study Completion Date :

May 1, 2014

Outcome Measures

Primary Outcome Measures

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. [From Day 0 to Day 60]
Fluorescence-activated cell sorting assay

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 50 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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