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

This study has been completed.
Sponsor:
Collaborators:
University of Cambridge
Juvenile Diabetes Research Foundation
National Institute for Health Research, United Kingdom
Wellcome Trust
Information provided by (Responsible Party):
Dr Frank Waldron-Lynch, Cambridge University Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier:
NCT01827735
First received: April 4, 2013
Last updated: June 10, 2014
Last verified: June 2014
  Purpose

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 Intervention Phase
Type 1 Diabetes
Drug: Aldesleukin (Proleukin)
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D)

Resource links provided by NLM:


Further study details as provided by Cambridge University Hospitals NHS Foundation Trust:

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. [ Time Frame: From Day 0 to Day 60 ] [ Designated as safety issue: No ]
    Fluorescence-activated cell sorting assay


Secondary Outcome Measures:
  • T regulatory cell phenotype and stability [ Time Frame: From Day 0 to Day 60 ] [ Designated as safety issue: No ]
    Fluorescence-activated cell sorting assay

  • T effector cell number and phenotype [ Time Frame: From Day 0 - Day 60 ] [ Designated as safety issue: No ]
    Fluorescence-activated cell sorting assay

  • T cell subset proliferation and populations [ Time Frame: From Day 0 - Day 60 ] [ Designated as safety issue: No ]
    Fluorescence-activated cell sorting assay

  • Intracellular T cell and natural killer(NK) cell signalling [ Time Frame: From Day 0 - Day 60 ] [ Designated as safety issue: No ]
    Fluorescence-activated cell sorting assay

  • T regulatory cell function [ Time Frame: From Day 0 - Day 60 ] [ Designated as safety issue: No ]
    T suppression assay

  • IL-2 pathway genotype [ Time Frame: From Day 0 - Day 60 ] [ Designated as safety issue: No ]
    DNA sequencing

  • Lymphocyte Subsets [ Time Frame: From Day 0 to Day 60 ] [ Designated as safety issue: No ]
    Complete blood count

  • Serum Cytokines [ Time Frame: From Day 0 to Day 60 ] [ Designated as safety issue: No ]
    Enzyme-linked immuno sorbent assay

  • Glycaemic control [ Time Frame: From Day 0 to Day 60 ] [ Designated as safety issue: No ]
    Self monitoring blood glucose readings, HbA1c, insulin usage

  • Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: From Day O to Day 60 ] [ Designated as safety issue: Yes ]

Enrollment: 40
Study Start Date: March 2013
Study Completion Date: May 2014
Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Aldesleukin (Proleukin)
    A single, subcutaneous dose will be given administered with the maximum dose allowed 1.5 X 106 IU/M2.
  Eligibility

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01827735

Locations
United Kingdom
Wellcome Trust Clinical Research Facility, Addenbrooke's Hospital
Cambridge, United Kingdom, CB2 0QQ
Sponsors and Collaborators
Cambridge University Hospitals NHS Foundation Trust
University of Cambridge
Juvenile Diabetes Research Foundation
National Institute for Health Research, United Kingdom
Wellcome Trust
Investigators
Principal Investigator: Frank Waldron-Lynch University of Cambridge
  More Information

Additional Information:
Publications:
Responsible Party: Dr Frank Waldron-Lynch, Academic Consultant Endocrinologist, Cambridge University Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT01827735     History of Changes
Other Study ID Numbers: A092737, ISRCTN27852285
Study First Received: April 4, 2013
Last Updated: June 10, 2014
Health Authority: United Kingdom: Research Ethics Committee

Keywords provided by Cambridge University Hospitals NHS Foundation Trust:
Interleukin 2
Type 1 diabetes
T regulatory cells
Adaptive trial

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Autoimmune Diseases
Endocrine System Diseases
Glucose Metabolism Disorders
Immune System Diseases
Metabolic Diseases

ClinicalTrials.gov processed this record on October 23, 2014