title: 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.
abstract: BACKGROUND
  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
  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.
  
  
  METHODS
  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.
  
  
  BACKGROUND
  NCT02265809, ISRCTN40319192, CRN17571.
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Truman
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
authors.forename: Marcin L
authors.initials: ML
authors.lastname: Pekalski
authors.affiliation: National Institute for Health Research Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Paula
authors.initials: P
authors.lastname: Kareclas
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK Department of Mathematics, Imperial College, London, UK.
authors.forename: Marina
authors.initials: M
authors.lastname: Evangelou
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
authors.forename: Neil M
authors.initials: NM
authors.lastname: Walker
authors.affiliation: National Institute for Health Research Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK MRC Biostatistics Unit Hub for Trials Methodology Research, Cambridge Institute of Public Health, Cambridge, UK.
authors.forename: James
authors.initials: J
authors.lastname: Howlett
authors.affiliation: MRC Biostatistics Unit Hub for Trials Methodology Research, Cambridge Institute of Public Health, Cambridge, UK.
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Mander
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Kennet
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Wicker
authors.affiliation: National Institute for Health Research Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK MRC Biostatistics Unit Hub for Trials Methodology Research, Cambridge Institute of Public Health, Cambridge, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Bond
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Waldron-Lynch
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*; D055815:Young Adult; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D065228:Non-Randomized Controlled Trials as Topic
chemical_list: D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit
keywords: DIABETES & ENDOCRINOLOGY; GENETICS; IMMUNOLOGY