Clinical trial NCT01827735: Regulatory T Cells in Type 1 Diabetes Patients Treated With IL-2
Official title: Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Type 1 Diabetes
Keywords: Interleukin 2
Type 1 diabetes
T regulatory cells
Adaptive trial
Lead sponsor: Cambridge University Hospitals NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: University of Cambridge
name: Juvenile Diabetes Research Foundation
name: National Institute for Health Research, United Kingdom
name: Wellcome Trust
First posted: 2013-04-10
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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.


Eligibility 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

Primary outcomes:
measure: 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.
timeFrame: From Day 0 to Day 60
Secondary outcomes:
measure: T regulatory cell phenotype and stability
timeFrame: From Day 0 to Day 60
measure: T effector cell number and phenotype
timeFrame: From Day 0 - Day 60
measure: T cell subset proliferation and populations
timeFrame: From Day 0 - Day 60
measure: Intracellular T cell and natural killer(NK) cell signalling
timeFrame: From Day 0 - Day 60
measure: T regulatory cell function
timeFrame: From Day 0 - Day 60
measure: IL-2 pathway genotype
timeFrame: From Day 0 - Day 60
measure: Lymphocyte Subsets
timeFrame: From Day 0 to Day 60
measure: Serum Cytokines
timeFrame: From Day 0 to Day 60
measure: Glycaemic control
timeFrame: From Day 0 to Day 60
measure: Number of Participants with Adverse Events as a Measure of Safety and Tolerability
timeFrame: From Day O to Day 60
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: Wellcome Trust Clinical Research Facility, Addenbrooke's Hospital
Study officials:
affiliation: University of Cambridge
name: Frank Waldron-Lynch
role: PRINCIPAL_INVESTIGATOR
References:
citation: Waldron-Lynch F, Kareclas P, Irons K, Walker NM, Mander A, Wicker LS, Todd JA, Bond S. Rationale and study design of the Adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D): a non-randomised, open label, adaptive dose finding trial. BMJ Open. 2014 Jun 4;4(6):e005559. doi: 10.1136/bmjopen-2014-005559.
citation: Heywood J, Evangelou M, Goymer D, Kennet J, Anselmiova K, Guy C, O'Brien C, Nutland S, Brown J, Walker NM, Todd JA, Waldron-Lynch F. Effective recruitment of participants to a phase I study using the internet and publicity releases through charities and patient organisations: analysis of the adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D). Trials. 2015 Mar 11;16:86. doi: 10.1186/s13063-015-0583-7.
citation: Todd JA, Evangelou M, Cutler AJ, Pekalski ML, Walker NM, Stevens HE, Porter L, Smyth DJ, Rainbow DB, Ferreira RC, Esposito L, Hunter KM, Loudon K, Irons K, Yang JH, Bell CJ, Schuilenburg H, Heywood J, Challis B, Neupane S, Clarke P, Coleman G, Dawson S, Goymer D, Anselmiova K, Kennet J, Brown J, Caddy SL, Lu J, Greatorex J, Goodfellow I, Wallace C, Tree TI, Evans M, Mander AP, Bond S, Wicker LS, Waldron-Lynch F. Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial. PLoS Med. 2016 Oct 11;13(10):e1002139. doi: 10.1371/journal.pmed.1002139. eCollection 2016 Oct.