The DILfrequency study is an adaptive trial to identify optimal IL-2 dosing in patients with type 1 diabetes
Eleonora Seelig, James Howlett, Linsey Porter, Lucy Truman, James Heywood, Jane Kennet, Emma L. Arbon, Katerina Anselmiova, Neil M. Walker, Ravinder Atkar, Marcin L. Pekalski, Ed Rytina, Mark Evans, Linda S. Wicker, John A. Todd, Adrian P. Mander, Simon Bond, Frank Waldron-Lynch
Eleonora Seelig, James Howlett, Linsey Porter, Lucy Truman, James Heywood, Jane Kennet, Emma L. Arbon, Katerina Anselmiova, Neil M. Walker, Ravinder Atkar, Marcin L. Pekalski, Ed Rytina, Mark Evans, Linda S. Wicker, John A. Todd, Adrian P. Mander, Simon Bond, Frank Waldron-Lynch
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Clinical Research and Public Health Clinical trials

The DILfrequency study is an adaptive trial to identify optimal IL-2 dosing in patients with type 1 diabetes

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.

Authors

Eleonora Seelig, James Howlett, Linsey Porter, Lucy Truman, James Heywood, Jane Kennet, Emma L. Arbon, Katerina Anselmiova, Neil M. Walker, Ravinder Atkar, Marcin L. Pekalski, Ed Rytina, Mark Evans, Linda S. Wicker, John A. Todd, Adrian P. Mander, Simon Bond, Frank Waldron-Lynch

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Figure 4

Treg, Treg CD25, and T effector responses to aldesleukin treatment.

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Treg, Treg CD25, and T effector responses to aldesleukin treatment. (A) ...
(A) Treg proportions as a percentage of CD4+ T cells for doses administered every 3 days, with the box highlighting the final 3 trough values at steady state that were used to define the Treg primary endpoint (average response plots shown across the 4 doses; n = 1 for 0.09 × 106 IU/m2, n = 4 for 0.2 × 106 IU/m2, n = 8 for 0.32 × 106 IU/m2, n = 2 for 0.47 × 106 IU/m2). Visit number 2 (x axis) depicts first dosing visit. (B) The percentage change in Tregs at the primary endpoint for all doses administered, with the predicted dose response at the best frequency (every 3 days, red line) showing an increase in precision of the estimates around the optimal dose for the whole analysis population (0.26 × 106 IU/m2, shaded area 95% CI). (C) The increase in Tregs for all frequencies allocated, with the predicted frequency response at the optimal dose (0.26 × 106 IU/m2, red line) showing increased precision of the estimates around day 3. (D) Increase in CD25 expression on Tregs at the 3-day frequency at the primary endpoint (average response plots shown across the 4 doses; n = 1 for 0.09 × 106 IU/m2, n = 4 for 0.2 × 106 IU/m2, n = 8 for 0.32 × 106 IU/m2, n = 2 for 0.47 × 106 IU/m2). (E and F) The change in Treg CD25 at all doses and frequencies, with increased precision of the estimates around the 3-day frequency (red line). (G) The changes in the T effector (Teff) ratio of the proportion naive effectors to memory effectors at the 3-day frequency (average response plots shown across the 4 doses; n = 1 for 0.09 × 106 IU/m2, n = 4 for 0.2 × 106 IU/m2, n = 8 for 0.32 × 106 IU/m2, n = 2 for 0.47 × 106 IU/m2). (H and I) The change in Teff ratio at the primary endpoint at all doses and frequency, showing no dose-frequency response at 0.26 × 106 IU/m2 every 3 days.