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

August 20, 2018 updated by: Dr Frank Waldron-Lynch, Cambridge University Hospitals NHS Foundation Trust

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

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).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

41

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Cambridgeshire
      • Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
        • Wellcome Trust Clinical Research Facility, Addenbrookes Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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%))

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Aldesleukin
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.
Other Names:
  • Proleukin
  • IL-2

What is the study measuring?

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
Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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
Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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
Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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
Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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
Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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
Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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
Time Frame: Visits 1-12 (between day -30 and day -1 up to a maximum of approximately day 98 depending on treatment assignment)
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
Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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
Time Frame: Visits 1-12 (between day -30 and day -1 up to a maximum of approximately day 98 depending on treatment assignment)
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
Time Frame: Visits 1-12 (between day -30 and day -1 up to a maximum of approximately day 98 depending on treatment assignment)
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)

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Genotype of T1D associated loci
Time Frame: Visit 1 (between day -30 and day -1)
Measured by immunochip
Visit 1 (between day -30 and day -1)
Gene expression analysis of purified lymphocyte subsets and peripheral blood mononucleated cells
Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Measured by RNA sequencing
Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
IL-2 sensitivity of T regulatory, T effector and NK subsets
Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Measured by fluorescence-activated cell sorting
Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Treg suppression and T effector proliferation assays
Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Measured by radioactive thymidine assay and/or fluorescence-activated cell sorting
Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Antigen specific T cell assays
Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Measured fluorescence-activated cell sorting and/or Enzyme-Linked ImmunoSpot (ELISPOT) assay
Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Sysmex® analysis of whole blood
Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Measured by automatic analyser
Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Epigenetic analysis of analysis of purified lymphocyte subsets and peripheral blood
Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Measured by Bisulphite sequencing of DNA
Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Serum/plasma level of cytokines, soluble receptors and inflammatory markers
Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Measured by enzyme-linked immunosorbent assay
Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Serum/plasma and cellular metabolites
Time Frame: Visits 1-12 (between day -30 and day -1 up to a maximum of approximately day 98 depending on treatment assignment)
Mass spectrometry
Visits 1-12 (between day -30 and day -1 up to a maximum of approximately day 98 depending on treatment assignment)
Recruitment analysis
Time Frame: Visit 1 (between day -30 and day -1)
Analysis of DILfrequency recruitment database
Visit 1 (between day -30 and day -1)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Frank Waldron-Lynch, MB BChir PhD, University of Cambridge
  • Study Chair: Kevin M O'Shaughnessy, BM BCh DPhil, University of Cambridge

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 3, 2014

Primary Completion (Actual)

May 26, 2016

Study Completion (Actual)

May 26, 2016

Study Registration Dates

First Submitted

October 8, 2014

First Submitted That Met QC Criteria

October 13, 2014

First Posted (Estimate)

October 16, 2014

Study Record Updates

Last Update Posted (Actual)

August 21, 2018

Last Update Submitted That Met QC Criteria

August 20, 2018

Last Verified

August 1, 2018

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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