Efficacy and safety of low-dose IL-2 in people with newly diagnosed type 1 diabetes (DIABIL-2): a double-blind, multicentre, randomised, placebo-controlled, phase 2b trial.

Authors

Michelle Rosenzwajg, Agnès Hartemann, Marine Halbron, Chloé Amouyal, Charles Thivolet, Vincent Rigalleau, Pierre Fontaine, Brigitte Mignot, Rachel Reynaud, Jean-Claude Carel, Elise Bismuth, Caroline Storey, Karine Bourdet, Emmanuel Sonnet, Sabine Baron, Marc Nicolino, Kevin Perge, Lucy Chaillous, Laurence Kessler, Marie Mansilla, Peter Achenbach, Anette-Gabriele Ziegler, Henk-Jan Aanstoot, Thierry Mouraux, Kristina Casteels, Marc Y Donath, Bart O Roep, Roberta Lorenzon, Claire Ribet, Joe-Elie Salem, Fabien Pitoiset, Alexandra Roux, Eric Vicaut, David Klatzmann, DIABIL-2 investigators

Published in

The lancet. Diabetes & endocrinology. Oct 01, 2026. Epub Oct 01, 2026.

Abstract

Type 1 diabetes results from immune-mediated destruction of pancreatic β cells, driven partly by regulatory T-cell (Treg) insufficiency. We previously showed that low-dose interleukin-2 (IL-2) selectively activates Tregs in people with type 1 diabetes. We aimed to evaluate the efficacy of low-dose IL-2 in preserving residual pancreatic β-cell function and select an optimal regimen of administration in this patient population.
This double-blind, multicentre, randomised, placebo-controlled, phase 2b trial was done in 19 academic hospital centres across Belgium, France, Germany, Switzerland, and the Netherlands. Eligible participants were aged 6-35 years; had a diagnosis of type 1 diabetes; received insulin for less than 3 months; and had a peak C-peptide concentration of at least 0·2 pmol/mL. Participants were randomly assigned (1:1:1) to a maintenance course of regimen A, regimen B, or placebo (with a 2:1 allocation ratio of IL-2 to placebo within each regimen) and were stratified by pubertal stage (children and adolescents with a Tanner score ≤4 [stratum 1] and adults with a Tanner score of ≥5 [stratum 2]). Both regimens started with an induction course of once per day subcutaneous injections for 5 consecutive days (days 1-5), then a maintenance course of injections (once per 2 weeks [regimen A] or once per week [regimen B]) from day 15 to 351. Adults received 1 million IU per injection, whereas children and adolescents received 0·5 million IU/m² per injection. The primary endpoint was the change from baseline to month 12 in serum C-peptide area under the curve (AUC) from 0 to 120 min during a mixed meal tolerance test, analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02411253 (completed).
Between June 18, 2015, and Nov 19, 2020, 159 people were assessed for eligibility, of whom 18 were ineligible and 141 were enrolled (48 randomly assigned to regimen A, 46 to regimen B, and 47 to placebo). 66 participants were in stratum 1 and 75 in stratum 2. 125 (89%) of 141 participants completed the study and 16 (11%) ended participation early. 54 (38%) participants were female and 87 (62%) were male. For log-transformed C-peptide AUC at month 12, there was no statistically significant difference in the overall population between placebo and IL-2 groups (geometric mean ratio 1·06 [95% CI 0·56 to 2·01]; p=0·85), with similar results when considering each regimen separately and by pubertal status. A marked Treg expansion was observed shortly after treatment initiation, peaking at day 5, with adjusted means of 1·31 (1·24 to 1·37) in the IL-2 group versus 1·04 (0·95 to 1·14) in the placebo group (difference -0·27 [-0·38 to -0·15]). Low-dose IL-2 was well tolerated across all age groups and treatment regimens. Nine (20%) of 46 participants in the placebo group and nine (10%) of 94 in the IL-2 group reported serious adverse events; one in each group was considered probably related to treatment.
Despite robust Treg expansion confirming target engagement, low-dose IL-2 did not preserve β-cell function in people with newly diagnosed type 1 diabetes. The inflammatory environment at diagnosis might be too intense for this monotherapy, but the observed safety profile and confirmed biological activity support further investigation of low-dose IL-2 in earlier disease stages or combination strategies.
Assistance Publique-Hôpitaux de Paris (European Research Network), ILTOO Pharma, and the Investissements d'Avenir programme.
For the French translation of the abstract see Supplementary Materials section.

PMID:
42822480
Bibliographic data and abstract were imported from PubMed on 02 Oct 2026.

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