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

Type 1 Diabetes Clinical Trial

— DILfrequency  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02265809
• Other study ID #: DILfrequency
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: October 3, 2014
• Est. completion date: May 26, 2016

Study information

• Verified date: August 2018
• Source: Cambridge University Hospitals NHS Foundation Trust
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 41
• Est. completion date: May 26, 2016
• Est. primary completion date: May 26, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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%))

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Type 1 Diabetes

Intervention

Drug:
• Aldesleukin

Locations

Country	Name	City	State
United Kingdom	Wellcome Trust Clinical Research Facility, Addenbrookes Hospital	Cambridge	Cambridgeshire

Sponsors (6)

Lead Sponsor	Collaborator
Cambridge University Hospitals NHS Foundation Trust	Juvenile Diabetes Research Foundation, National Institute for Health Research, United Kingdom, Sir Jules Thorn Charitable Trust, University of Cambridge, Wellcome Trust

Country where clinical trial is conducted

United Kingdom, 

References & Publications (2)

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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Genotype of T1D associated loci	Measured by immunochip	Visit 1 (between day -30 and day -1)
Other	Gene expression analysis of purified lymphocyte subsets and peripheral blood mononucleated cells	Measured by RNA sequencing	Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Other	IL-2 sensitivity of T regulatory, T effector and NK subsets	Measured by fluorescence-activated cell sorting	Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Other	Treg suppression and T effector proliferation assays	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)
Other	Antigen specific T cell assays	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)
Other	Sysmex® analysis of whole blood	Measured by automatic analyser	Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Other	Epigenetic analysis of analysis of purified lymphocyte subsets and peripheral blood	Measured by Bisulphite sequencing of DNA	Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Other	Serum/plasma level of cytokines, soluble receptors and inflammatory markers	Measured by enzyme-linked immunosorbent assay	Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Other	Serum/plasma and cellular metabolites	Mass spectrometry	Visits 1-12 (between day -30 and day -1 up to a maximum of approximately day 98 depending on treatment assignment)
Other	Recruitment analysis	Analysis of DILfrequency recruitment database	Visit 1 (between day -30 and day -1)
Primary	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	T regulatory cell number, phenotype and proliferation	Measured by fluorescence-activated cell sorting	Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Secondary	T effector cell number, phenotype and proliferation	Measured by fluorescence-activated cell sorting	Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Secondary	Natural Killer cell number, phenotype and proliferation	Measured by fluorescence-activated cell sorting	Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Secondary	B lymphocyte cell number, phenotype and proliferation	Measured by fluorescence-activated cell sorting	Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Secondary	T cell and Natural killer cell intracellular signalling	Measured by fluorescence-activated cell sorting	Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Secondary	Full blood count	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)
Secondary	Blood levels of IL-2, IL-6, IL-10, TNF-alpha, soluble CD25, IP-10, soluble rIL-6, and CRP	Measured by enzyme-linked immunosorbent assay	Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Secondary	Change in metabolic control	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)
Secondary	Safety and tolerability	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)

External Links

•   DILfrequency trial website
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