The DILfrequency study is an adaptive trial to identify optimal IL-2 dosing in patients with type 1 diabetes.
Arbon, Emma L
Walker, Neil M
Pekalski, Marcin L
Wicker, Linda S
Todd, John A
American Society for Clinical Investigation
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Seelig, E., Howlett, J., Porter, L., Truman, L., Heywood, J., Kennet, J., Arbon, E. L., et al. (2018). The DILfrequency study is an adaptive trial to identify optimal IL-2 dosing in patients with type 1 diabetes.. JCI Insight, 3 (19) https://doi.org/10.1172/jci.insight.99306
BACKGROUND: Type 1 diabetes (T1D) results from loss of immune regulation, leading to the development of autoimmunity to pancreatic β cells, involving autoreactive T effector cells (Teffs). Tregs, which prevent autoimmunity, require IL-2 for maintenance of immunosuppressive functions. Using a response-adaptive design, we aimed to determine the optimal regimen of aldesleukin (recombinant human IL-2) to physiologically enhance Tregs while limiting expansion of Teffs. METHODS: DILfrequency is a nonrandomized, open-label, response-adaptive study of participants, aged 18-70 years, with T1D. The initial learning phase allocated 12 participants to 6 different predefined regimens. Then, 3 cohorts of 8 participants were sequentially allocated dose frequencies, based on repeated interim analyses of all accumulated trial data. The coprimary endpoints were percentage change in Tregs and Teffs and CD25 (α subunit of the IL-2 receptor) expression by Tregs, from baseline to steady state. RESULTS: Thirty-eight participants were enrolled, with thirty-six completing treatment. The optimal regimen to maintain a steady-state increase in Tregs of 30% and CD25 expression of 25% without Teff expansion is 0.26 × 106 IU/m2 (95% CI -0.007 to 0.485) every 3 days. Tregs and CD25 were dose-frequency responsive, Teffs were not. The commonest adverse event was injection site reaction (464 of 694 events). CONCLUSIONS: Using a response-adaptive design, aldesleukin treatment can be optimized. Our methodology can generally be employed to immediately access proof of mechanism, thereby leading to more efficient and safe drug development. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number Register, ISRCTN40319192; ClinicalTrials.gov, NCT02265809. FUNDING: Sir Jules Thorn Trust, the Swiss National Science Foundation, Wellcome, JDRF, and NIHR Cambridge Biomedical Research Centre.
Humans, Diabetes Mellitus, Type 1, Recombinant Proteins, Interleukin-2, Lymphocyte Count, Treatment Outcome, Drug Administration Schedule, Feasibility Studies, Lymphocyte Activation, Dose-Response Relationship, Drug, Adolescent, Adult, Aged, Middle Aged, Female, Male, T-Lymphocytes, Regulatory, Interleukin-2 Receptor alpha Subunit, Young Adult
Sir Jules Thorn Trust Swiss National Science Foundation, Wellcome Trust JDRF, NIHR Cambridge Biomedical Research Centre.
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Wellcome Trust (091157/Z/10/B)
External DOI: https://doi.org/10.1172/jci.insight.99306
This record's URL: https://www.repository.cam.ac.uk/handle/1810/285685
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/