Low-Dose Interleukin 2 in Children with Recently Diagnosed Type 1 Diabetes: A Phase 1/2 Randomised, Double-Blind, Placebo-Controlled Dose Finding Study
113 Pages Posted: 10 May 2019More...
Background: Low-dose interleukin 2 (ld-IL2) selectively activates and expands regulatory T cells (Tregs) and thus has the potential to skew the regulatory/effector T (Treg/Teff) cell balance towards improved regulation. Regimens of ld-IL2 are actively investigated as a treatment for various autoimmune diseases, including type 1 diabetes (T1D). We previously reported a dose-dependent specific activation and expansion of Tregs in adults with established T1D receiving a short 5-day treatment with ld-IL2. We report results from the DF-Child trial, in which we investigated which low doses of IL2 would more effectively activate Treg cells during a 1-year treatment in children with recently diagnosed T1D.
Methods: DF-Child was a multicentre, double-blinded, phase 1/2 clinical trial: 24 children (7-14 years-old) with T1D diagnosed within the previous 3 months were randomized in a 1:1:1:1 ratio to s.c. injection of placebo or IL2, at doses of 0.125, 0.250, or 0.500 MIU/m2, given daily for a 5-day course and then fortnightly for 1 year. The primary outcome was change in Treg cells expressed as a percentage of CD4+ T cells at day-5, and pre-specified that an increased on Tregs â‰¥60% from baseline would identify Treg high responders. This trial is registered with ClinicalTrials.gov, NCT01862120.
Findings: Twenty-four patients were randomized between June 27, 2013, and Jan 1, 2016. IL2 was well tolerated at all doses, with no serious adverse events. Non-serious adverse events were transient and mild to moderate. Ld-IL2 induced a dose dependent increase in the proportion of Tregs. Although the mean Treg responses of all dose-groups were significantly different from placebo, the individual Treg responses to IL-2 were variable and fluctuated over time. All treated subjects showed an increase in Tregs, and we identified 7 Treg high responders among those treated with the 0.250 and 0.500 MIU/m2/day doses (3 and 4, respectively). There was no significant change in glycaemic control in any of the dose-groups compared to placebo, and no differences reported in insulin doses. However, there was a trend for an improved maintenance of induced C-peptide production at one year in the 7 Treg high responders.
Interpretation: The good safety profile at all doses, the dose-dependent effects on Tregs and the observed variability of the Treg response to ld-IL2 in newly diagnosed T1D children call for using the highest dose in future developments. The better preservation of insulin production in Treg high responders supports the potential of Tregs in regulating autoimmunity in T1D and warrants pursuing the investigation of ld-IL2 for its treatment and prevention.
Trial Registration Number: This trial is registered with ClinicalTrials.gov, NCT01862120.
Funding: Assistance Publique-Hôpitaux de Paris, Investissements d’Avenir programme (ANR-11-IDEX-0004-02, LabEx Transimmunom and ANR-16-RHUS-0001, RHU iMAP) and European Research Council Advanced Grant (FP7-IDEAS-ERC-322856, TRiPoD).
Declaration of Interest: DK, MR and CB are co-inventor of a patent entitled “IL 2 based therapy” (OEB 11 305269.0) and DK and MR are shareholders in ILTOO pharma, the exclusive licensee of this patent.
Ethical Approval: The study was approved by the institutional review board of Pitié-Salpêtrière Hospital, and conducted in accordance with the Declaration of Helsinki and good clinical practice guidelines. Written informed consent was obtained from all participants before enrolment in the study.
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