Eleonora Seelig1,2,3,4, James Howlett3,5,6, Linsey Porter1,3,4, Lucy Truman3,4,7, James Heywood1,3,4, Jane Kennet1,2,3,4, Emma L Arbon3,6, Katerina Anselmiova1,2,3,4, Neil M Walker3,4,8, Ravinder Atkar3,9, Marcin L Pekalski3,4,10, Ed Rytina3,11, Mark Evans2,3, Linda S Wicker3,4,10, John A Todd3,4,10, Adrian P Mander3,5, Simon Bond3,5,6, Frank Waldron-Lynch1,2,3,4,6. 1. Experimental Medicine and Immunotherapeutics, Department of Medicine. 2. Wellcome Trust-MRC Institute of Metabolic Science, and. 3. National Institute for Health Research, Cambridge Biomedical Research Centre, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom. 4. JDRF/Wellcome Trust Diabetes and Inflammation Laboratory and. 5. MRC Biostatistics Unit Hub for Trials Methodology Research, Cambridge Institute of Public Health, University of Cambridge, Cambridge, United Kingdom. 6. National Institute for Health Research, Cambridge Clinical Trials Unit. 7. Department of Ear, Nose, and Throat Surgery. 8. Department of Clinical Informatics, and. 9. Department of Dermatology, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, United Kingdom. 10. JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Trust Center for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. 11. Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, United Kingdom.
Abstract
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.
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.
Entities:
Keywords:
Autoimmune diseases; Autoimmunity; Clinical Trials; Diabetes; T cells
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