title: 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.
abstract: BACKGROUND
  CD4 T regulatory cells (Tregs) are crucial for the maintenance of self-tolerance and are deficient in many common autoimmune diseases such as type 1 diabetes (T1D). Interleukin 2 (IL-2) plays a major role in the activation and function of Tregs and treatment with ultra-low dose (ULD) IL-2 could increase Treg function to potentially halt disease progression in T1D. However, prior to embarking on large phase II/III clinical trials it is critical to develop new strategies for determining the mechanism of action of ULD IL-2 in participants with T1D. In this mechanistic study we will combine a novel trial design with a clinical grade Treg assay to identify the best doses of ULD IL-2 to induce targeted increases in Tregs.
  
  
  METHODS
  Adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D) is a single centre non-randomised, single dose, open label, adaptive dose-finding trial. The primary objective of DILT1D is to identify the best doses of IL-2 to achieve a minimal or maximal Treg increase in participants with T1D (N=40). The design has an initial learning phase where pairs of participants are assigned to five preassigned doses followed by an interim analysis to determine the two Treg targets for the reminder of the trial. This will then be followed by an adaptive phase which is fully sequential with an interim analysis after each participant is observed to determine the choice of dose based on the optimality criterion to minimise the determinant of covariance of the estimated target doses. A dose determining committee will review all data available at the interim(s) and then provide decisions regarding the choice of dose to administer to subsequent participants.
  
  
  BACKGROUND
  Ethical approval for the study was granted on 18 February 2013.
  
  
  RESULTS
  The results of this study will be reported through peer-reviewed journals, conference presentations and an internal organisational report.
  
  
  BACKGROUND
  NCT01827735, ISRCTN27852285, DRN767.
authors.affiliation: JDRF/Wellcome Trust Diabetes & Inflammation Laboratory, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Waldron-Lynch
authors.affiliation: 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: Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Irons
authors.affiliation: JDRF/Wellcome Trust Diabetes & Inflammation Laboratory, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Neil M
authors.initials: NM
authors.lastname: Walker
authors.affiliation: MRC Biostatistics Unit Hub for Trials Methodology Research, Cambridge Institute of Public Health, Cambridge, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Mander
authors.affiliation: JDRF/Wellcome Trust Diabetes & Inflammation Laboratory, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Wicker
authors.affiliation: JDRF/Wellcome Trust Diabetes & Inflammation Laboratory, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.affiliation: 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
mesh_terms: D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology; D054796:Drug Dosage Calculations; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000494:pharmacology; D012107:Research Design; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000502:physiology
chemical_list: D007376:Interleukin-2