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
Author(s)Truman, Lucy A.
Pekalski, Marcin L.
Walker, Neil M.
Mander, Adrian P.
Wicker, Linda S.
Todd, John A.
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AbstractThis is the final version of the article. It was first available from BMJ via http://dx.doi.org/10.1136/bmjopen-2015-009799
Introduction: Type 1 diabetes (T1D) is caused by autoimmune destruction of the insulin-producing β cells in the pancreatic islets, leading to insulin deficiency and hyperglycaemia. Genetic analyses indicate that deficiencies in the interleukin-2 (IL-2) pathway in immune activation and tolerance predispose to T1D, in particular in the polymorphic expression of the IL-2 receptor α chain (CD25) on T lymphocytes. Replacement of physiological doses of IL-2 may help to maintain self-tolerance and prevent further autoimmunity by specifically enhancing the suppressive function of CD4+ T regulatory cells (Tregs), which 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 administering IL-2 to improve Treg function whilst limiting activation of Teffs in patients with T1D.
Method 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 recently diagnosed T1D. The aim is to establish the optimal dose and frequency of administration of ultra-low dose IL-2. The three co-primary objectives are: to increase Treg frequencies within the physiological normal range, to increase CD25 expression on Tregs, whilst not causing increases in CD4+ Teff frequencies. DILfrequency is designed to have an initial learning phase in which 12 participants are allocated to six different doses and frequencies followed by an interim statistical analysis. After examining the results of the learning phase, the Dose and Frequency Committee will select the optimal targets of Treg frequency, Treg CD25 expression and lack of Teff proliferation, for the remaining 24 participants. A confirming phase comprising three groups of participants will be treated with Proleukin consecutively. Each dose and frequency selected will based on analysis of all data collected from the previous groups.
Ethics and dissemination: DILfrequency was approved by UK ethics (REC reference 14/EE/1057). Study results will be published.
Trial registration numbers: NCT02265809, ISRCTN40319192, CRN17571.
Strengths and limitations of this study:
- This non randomised, repeat dose, open label, response adaptive study has three co-primary objectives to determine the optimal dose and frequency of interleukin-2 administration in patients with type 1 diabetes to preferentially stimulate T regulatory cells over T effector cells.
- The study is not designed to test the effects of interleukin-2 on pancreatic beta-cell function and insulin secretion.
This work is funded by The Sir Jules Thorn Award for Biomedical Research 2013 (13/JTA), the JDRF (9-2011-253), the Wellcome Trust (091157) and the National Institute for Health Research Cambridge Biomedical Research Centre. The Cambridge Institute for Medical Research is in receipt of a Wellcome Trust Strategic Award (100140). AM was supported by the Medical Research Council [grant number G0800860] and the National Institute for Health Research Cambridge Biomedical Research Centre.