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

NCT02265809 | Completed Phase 1

• 1 other identifier: DILfrequency
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Type 1 Diabetes

Keywords

Interleukin 2; Type 1 diabetes; T regulatory cells; Adaptive trial

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (9)

• T regulatory cell number, phenotype and proliferation

  Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)

• T effector cell number, phenotype and proliferation

  Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)

• Natural Killer cell number, phenotype and proliferation

  Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)

• B lymphocyte cell number, phenotype and proliferation

  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

  Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)

Other Outcomes (10)

• Genotype of T1D associated loci

  Visit 1 (between day -30 and day -1)

• Gene expression analysis of purified lymphocyte subsets and peripheral blood mononucleated cells

  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

  Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)

Study Arms (1)

Aldesleukin

EXPERIMENTAL

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

Interventions

Aldesleukin DRUG

Also known as: Proleukin, IL-2

Aldesleukin

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Type 1 diabetes
• years of age
• Duration of diabetes less than 60 months from diagnosis
• Written informed consent to participate

You may not qualify if:

• 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%))

Sponsors & Collaborators

• Cambridge University Hospitals NHS Foundation Trust: lead
• University of Cambridge: collaborator
• Sir Jules Thorn Charitable Trust: collaborator
• Juvenile Diabetes Research Foundation: collaborator
• Wellcome Trust: collaborator
• National Institute for Health Research, United Kingdom: collaborator

Study Sites (1)

Wellcome Trust Clinical Research Facility, Addenbrookes Hospital

Cambridge, Cambridgeshire, CB2 0QQ, United Kingdom

Location

Related Publications (4)

• 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.

  PMID: 24898091 BACKGROUND

• Truman LA, Pekalski ML, Kareclas P, Evangelou M, Walker NM, Howlett J, Mander AP, Kennet J, Wicker LS, Bond S, Todd JA, Waldron-Lynch F. Protocol of the adaptive study of IL-2 dose frequency on regulatory T cells in type 1 diabetes (DILfrequency): a mechanistic, non-randomised, repeat dose, open-label, response-adaptive study. BMJ Open. 2015 Dec 8;5(12):e009799. doi: 10.1136/bmjopen-2015-009799.

  PMID: 26646829 BACKGROUND

• Zhang JY, Whalley JP, Knight JC, Wicker LS, Todd JA, Ferreira RC. SARS-CoV-2 infection induces a long-lived pro-inflammatory transcriptional profile. Genome Med. 2023 Sep 12;15(1):69. doi: 10.1186/s13073-023-01227-x.

  PMID: 37700317 DERIVED

• Seelig E, Howlett J, Porter L, Truman L, Heywood J, Kennet J, Arbon EL, Anselmiova K, Walker NM, Atkar R, Pekalski ML, Rytina E, Evans M, Wicker LS, Todd JA, Mander AP, Bond S, Waldron-Lynch F. The DILfrequency study is an adaptive trial to identify optimal IL-2 dosing in patients with type 1 diabetes. JCI Insight. 2018 Oct 4;3(19):e99306. doi: 10.1172/jci.insight.99306.

  PMID: 30282826 DERIVED

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MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

aldesleukin; Interleukin-2

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors

Study Officials

• Frank Waldron-Lynch, MB BChir PhD

  University of Cambridge

  PRINCIPAL INVESTIGATOR

• Kevin M O'Shaughnessy, BM BCh DPhil

  University of Cambridge

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Academic Consultant Endocrinologist

Study Record Dates

• First Submitted: October 8, 2014
• First Posted: October 16, 2014
• Study Start: October 3, 2014
• Primary Completion: May 26, 2016
• Study Completion: May 26, 2016
• Last Updated: August 21, 2018

Record last verified: 2018-08

Locations

GB (1)