Journal
BMJ OPEN
Volume 5, Issue 12, Pages -Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/bmjopen-2015-009799
Keywords
DIABETES & ENDOCRINOLOGY; IMMUNOLOGY; GENETICS
Categories
Funding
- Sir Jules Thorn Award for Biomedical Research [13/JTA]
- JDRF [9-2011-253]
- Wellcome Trust [091157]
- National Institute for Health Research Cambridge Biomedical Research Centre
- Wellcome Trust Strategic Award [100140]
- Medical Research Council [G0800860]
- National Institute for Health Research [NF-SI-0513-10143, NF-SI-0508-10275] Funding Source: researchfish
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Introduction Type 1 diabetes (T1D) is caused by autoimmune destruction of the insulin-producing cells in the pancreatic islets, leading to insulinopenia and hyperglycaemia. Genetic analyses indicate that alterations of the interleukin-2 (IL-2) pathway mediating immune activation and tolerance predispose to T1D, specifically the polymorphic expression of the IL-2 receptor- chain (CD25) on T lymphocytes. Replacement of physiological doses of IL-2 could restore self-tolerance and prevent further autoimmunity by enhancing the function of CD4(+) T regulatory cells (Tregs) to limit the activation of auto reactive T effector cells (Teffs). In this experimental medicine study, we use an adaptive trial design to determine the optimal dosing regimen for IL-2 to improve Treg function while limiting activation of Teffs in participants with T1D. Methods and analysis The Adaptive study of IL-2 dose frequency on Tregs in type 1 diabetes(DILfrequency) is a mechanistic, non-randomised, repeat dose open-label, response-adaptive study of 36 participants with T1D. The objective is to establish the optimal dose and frequency of ultra-low dose IL-2: to increase Treg frequency within the physiological range, to increase CD25 expression on Tregs, without increasing CD4(+) Teffs. DILfrequency has an initial learning phase where 12 participants are allocated to six different doses and frequencies followed by an interim statistical analysis. After analysis of the learning phase, the Dose and Frequency Committee will select the optimal targets for Treg frequency, Treg CD25 expression and Teff frequency. Three groups of eight participants will be treated consecutively in the confirming phase. Each dose and frequency selected will be based on statistical analysis of all data collected from the previous groups. Ethics Ethical approval for DILfrequency was granted on 12 August 2014. Results The results of this study will be reported, through peer-reviewed journals, conference presentations and an internal organisational report. Trial registration numbers NCT02265809, ISRCTN40319192, CRN17571.
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