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 × 10 6 IU/m 2 (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.

Interleukin-2 Therapy of Autoimmunity in Diabetes (ITAD): a phase 2, multicentre, double-blind, randomized, placebo-controlled trial

“…This opens a therapeutic window for the use of ultra-low doses of IL-2 to enhance selectively the Treg response in patients with T1D or other autoimmune and inflammatory diseases 12 . IL-2 therapy is currently being investigated in many diseases, including T1D [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] and our own investigations have established the doses of IL-2 in T1D patients that stimulate Tregs but not Teffs 23,24 .…”

“…The DILT1D trial was followed by the 'Adaptive study of IL-2 dose frequency on regulatory T cells in type 1 diabetes (DILfrequency)', to establish the optimal dose and frequency of aldesleukin administration. DILfrequency was a non-randomised, open-label, response-adaptive study of 38 participants with T1D (36 completing treatment), aged 18-70 years, aiming at defining the optimal dose and frequency of IL-2 administration that would lead to sustained increased Treg responses without increasing Teff frequencies 24 .…”

“…Adverse events reported in DILT1D and DILfrequency confirmed the safety of ultra-low dose IL-2. Most participants had transient injection site reactions, consisting of erythema and nodules 23,24 .…”

“…More than 13 clinical studies in humans have been completed, including one in healthy volunteers, and others in patients with various conditions: Hepatitis C-induced vasculitis, chronic GvHD, prevention of acute GvHD, T1D, alopecia areata, systemic lupus erythematosus and amyotrophic lateral sclerosis [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] . Altogether, these studies demonstrated that the increases in Treg number/function were associated with a good tolerance, while an improvement in the clinical outcome was observed in patients with vasculitis, GvHD, alopecia areata and systemic lupus erythematosus.…”

“…Trials using low or ultra-low dose IL-2 Aldesleukin is a commercially available IL-2 produced by recombinant DNA technology, which differs from the natural cytokine by the absence of glycan residues, presence of a serine instead of a cysteine at position 125 and absence of the N-terminal alanine 31 . Aldesleukin at low dose, in the order of 1.0 × 10 6 IU per day 15,16,29,30 , or ultra-low dose, less than 1.0 × 10 6 IU per week, in adults and children 17,18,23,24 , induces Tregs in a dose-dependent manner with no drug-related adverse events except for a small temporary non-itchy rash at the site of injection 22-24 . Aldesleukin has been used for over 20 years, mainly in patients with cancer or HIV at very high doses, tens of millions of units daily, often delivered intravenously 32,33 . More recently, following promising results from preclinical studies, aldesleukin at low or ultra-low doses has been successfully and safely used in trials for the treatment of chronic graft-versus-hostdisease (cGVHD) 26,27,30 and hepatitis C virus-induced vasculitis 16 .…”