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.
INTRODUCTION
Type 1 diabetes (T1D) is caused by autoimmune destruction of the insulin-producing β 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-α 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.
['Truman|Lucy A|LA|', 'Pekalski|Marcin L|ML|', 'Kareclas|Paula|P|', 'Evangelou|Marina|M|', 'Walker|Neil M|NM|', 'Howlett|James|J|', 'Mander|Adrian P|AP|', 'Kennet|Jane|J|', 'Wicker|Linda S|LS|', 'Bond|Simon|S|', 'Todd|John A|JA|', 'Waldron-Lynch|Frank|F|']
D000293:Adolescent D000328:Adult D000368:Aged D003922:Diabetes Mellitus, Type 1 D005260:Female D006801:Humans D007376:Interleukin-2 D053645:Interleukin-2 Receptor alpha Subunit D008297:Male D008875:Middle Aged D050378:T-Lymphocytes, Regulatory D055815:Young Adult
GENETICS DIABETES & ENDOCRINOLOGY IMMUNOLOGY