- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02265809
Adaptive Study of IL-2 Dose Frequency on Regulatory T Cells in Type 1 Diabetes (DILfrequency)
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
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
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Cambridgeshire
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Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
- Wellcome Trust Clinical Research Facility, Addenbrookes Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
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
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 |
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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.
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Other Names:
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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)
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Fluorescence-activated cell sorting
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Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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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)
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Measured by fluorescence-activated cell sorting
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Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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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)
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Measured by fluorescence-activated cell sorting
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Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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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)
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Measured by fluorescence-activated cell sorting
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Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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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)
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Measured by fluorescence-activated cell sorting
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Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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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)
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Measured by fluorescence-activated cell sorting
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Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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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)
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Measured by automatic analyser
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Visits 1-12 (between day -30 and day -1 up to a maximum of approximately day 98 depending on treatment assignment)
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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)
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Measured by enzyme-linked immunosorbent assay
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Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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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)
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Blood glucose, HbA1c, C-peptide, insulin use and autoantibody status
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Visits 1-12 (between day -30 and day -1 up to a maximum of approximately day 98 depending on treatment assignment)
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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)
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Assessed by clinical history, physical examination, temperature, blood pressure, heart rate, 12-Lead electrocardiogram (ECGs), clinical laboratory tests, and adverse event recording
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Visits 1-12 (between day -30 and day -1 up to a maximum of approximately day 98 depending on treatment assignment)
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Genotype of T1D associated loci
Time Frame: Visit 1 (between day -30 and day -1)
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Measured by immunochip
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Visit 1 (between day -30 and day -1)
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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)
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Measured by RNA sequencing
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Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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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)
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Measured by fluorescence-activated cell sorting
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Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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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)
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Measured by radioactive thymidine assay and/or fluorescence-activated cell sorting
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Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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Antigen specific T cell assays
Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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Measured fluorescence-activated cell sorting and/or Enzyme-Linked ImmunoSpot (ELISPOT) assay
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Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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Sysmex® analysis of whole blood
Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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Measured by automatic analyser
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Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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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)
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Measured by Bisulphite sequencing of DNA
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Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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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)
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Measured by enzyme-linked immunosorbent assay
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Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
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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)
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Mass spectrometry
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Visits 1-12 (between day -30 and day -1 up to a maximum of approximately day 98 depending on treatment assignment)
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Recruitment analysis
Time Frame: Visit 1 (between day -30 and day -1)
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Analysis of DILfrequency recruitment database
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Visit 1 (between day -30 and day -1)
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Collaborators and Investigators
Collaborators
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
General Publications
- 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.
- 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.
- 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.
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- DILfrequency
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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