Clinical trial NCT02265809: Adaptive Study of IL-2 Dose Frequency on Regulatory T Cells in Type 1 Diabetes
Official title: Adaptive Study of IL-2 Dose Frequency on Regulatory T Cells in Type 1 Diabetes (DILfrequency)
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: Sir Jules Thorn Charitable Trust
name: Juvenile Diabetes Research Foundation
name: Wellcome Trust
name: National Institute for Health Research, United Kingdom
First posted: 2014-10-16
Enrollment: 41
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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).


Eligibility criteria: 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%))

Primary outcomes:
measure: 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
timeFrame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
Secondary outcomes:
measure: T regulatory cell number, phenotype and proliferation
timeFrame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
measure: T effector cell number, phenotype and proliferation
timeFrame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
measure: Natural Killer cell number, phenotype and proliferation
timeFrame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
measure: B lymphocyte cell number, phenotype and proliferation
timeFrame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
measure: T cell and Natural killer cell intracellular signalling
timeFrame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
measure: Full blood count
timeFrame: Visits 1-12 (between day -30 and day -1 up to a maximum of approximately day 98 depending on treatment assignment)
measure: Blood levels of IL-2, IL-6, IL-10, TNF-alpha, soluble CD25, IP-10, soluble rIL-6, and CRP
timeFrame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
measure: Change in metabolic control
timeFrame: Visits 1-12 (between day -30 and day -1 up to a maximum of approximately day 98 depending on treatment assignment)
measure: Safety and tolerability
timeFrame: Visits 1-12 (between day -30 and day -1 up to a maximum of approximately day 98 depending on treatment assignment)
Other outcomes:
measure: Genotype of T1D associated loci
timeFrame: Visit 1 (between day -30 and day -1)
measure: Gene expression analysis of purified lymphocyte subsets and peripheral blood mononucleated cells
timeFrame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
measure: IL-2 sensitivity of T regulatory, T effector and NK subsets
timeFrame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
measure: Treg suppression and T effector proliferation assays
timeFrame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
measure: Antigen specific T cell assays
timeFrame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
measure: Sysmex® analysis of whole blood
timeFrame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
measure: Epigenetic analysis of analysis of purified lymphocyte subsets and peripheral blood
timeFrame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
measure: Serum/plasma level of cytokines, soluble receptors and inflammatory markers
timeFrame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment)
measure: Serum/plasma and cellular metabolites
timeFrame: Visits 1-12 (between day -30 and day -1 up to a maximum of approximately day 98 depending on treatment assignment)
measure: Recruitment analysis
timeFrame: Visit 1 (between day -30 and day -1)
Locations:
city: Cambridge
country: United Kingdom
facility: Wellcome Trust Clinical Research Facility, Addenbrookes Hospital
state: Cambridgeshire
Study officials:
affiliation: University of Cambridge
name: Frank Waldron-Lynch, MB BChir PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Cambridge
name: Kevin M O'Shaughnessy, BM BCh DPhil
role: STUDY_CHAIR
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: 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.
citation: 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.