The efficacy and safety of ustekinumab in adolescents newly diagnosed with type 1 diabetes: the USTEK1D RCT

Background Type 1 diabetes is an autoimmune disease affecting over 400,000 children and adults in the United Kingdom for which currently the only available therapy is insulin. Objective(s) To determine the efficacy and safety of the monoclonal antibody ustekinumab targeting the interleukin 12/interleukin 23 immune pathway that generates T helper 1/T helper 17 T cells to slow down the autoimmune process and preserve beta cell production in type 1 diabetes. Design Randomised, double-blind, placebo-controlled, parallel-group phase II trial. Setting Paediatric and young adult diabetes clinics across 16 sites in the United Kingdom. Participants Newly diagnosed with type 1 diabetes and aged 12–18 years. Eligibility criteria Type 1 diabetes confirmed by islet autoantibody testing, within 100 days of first insulin injection, and with residual beta cell function (stimulated C-peptide level > 0.2 nmol/l). Interventions Ustekinumab at the highest approved doses or control (saline) subcutaneously at weeks 0, 4 and 12 and subsequently every 8 weeks to week 44 (seven doses). Main outcome measures Preservation of Mixed Meal Tolerance Test stimulated 2-hour insulin C-peptide area under the curve at week 52 as compared to control (saline) treatment by analysis of covariance adjusted for baseline parameters. Randomisation 2 : 1 Remote computerised randomisation with minimisation by age and baseline C-peptide groups. Blinding Blinding of participants, investigators, laboratory and trial staff. Numbers randomised Seventy-two participants were randomised, 60% male, 18% aged 16–18 years. Recruitment Two hundred and eight potentially eligible patients were approached, and 88 patients were screened. Four participants were lost to follow-up (6%). Four participants withdrew from the treatment but attended the primary end-point assessment. Numbers analysed Six participants were missing baseline data for the primary analysis. The final analysable sample was n = 62. Outcome Ustekinumab was associated with a 49% higher endogenous stimulated insulin production than control at week 52 after adjustments for baseline factors [geometric ratio of ustekinumab to control was 1.49 (95% confidence interval 1.08 to 2.06; p = 0.02)]. Secondary analyses showed no difference in C-peptide at week 28 suggesting that the effect was ‘late’ or ‘delayed’. Ancillary analysis showed a significant reduction in activated T helper 17.1 T cells ( p < 0.001) in the treatment group which was associated with C-peptide preservation from week 28 to week 52. Harms No severe adverse events were reported and there were no differences between ustekinumab and control groups in the proportion of participants overall experiencing mild (87% vs. 88%) or moderate (32% vs. 32%) events. Limitations Sensitivity analysis showed the primary end point to be robust to exclusion of small numbers of participants with some protocol deviations and extreme values in key covariates, but not to imputation of all missing data. Conclusions Ustekinumab appears to slow down the autoimmune process providing the first clinical trial evidence that interleukin 17-secreting T cells play a pathogenic role in type 1 diabetes. Alone, it is insufficient to halt the autoimmune process. Future work Replication of this result is ongoing in a trial with a similar design in Canada. If confirmed, consideration may be given to testing other drugs targeting the interleukin 17 pathway, using ustekinumab in combination with other agents or using it earlier in the disease pathway (preclinical disease) since it is so well tolerated and simple to use. Study registration Current Controlled Trials ISRCTN14274380. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 16/36/01) and is published in full in Efficacy and Mechanism Evaluation ; Vol. 12, No. 1. See the NIHR Funding and Awards website for further award information.