The efficacy and safety of ustekinumab in adolescents newly diagnosed with type 1 diabetes: the USTEK1D RCT
Efficacy and Mechanism Evaluation, No. 12.01
Authors
Kymberley Carter,1 Wai-Yee Cheung,2 Hayley A Hutchings,1 Greg Fegan,1 Gail Holland,1 Steve Luzio,2 Gareth Dunseath,2 Stephen Hiles,1 Susie Marques-Jones,3 John W Gregory,4 Danijela Tatovic,5 Peter Taylor,5 Jane Bowen-Morris,5 Rachel Stenson,5 Stephanie Hanna,5 Zainab Mahmood,5 Jennie Yang,6 Evangelia Williams,6 Timothy Tree,6 Ashish Marwaha,7 and Colin M Dayan5,*.Affiliations
Abstract
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.
Plain language summary
USTEK1D was a clinical trial of the immune therapy ustekinumab in teenagers (aged 12–18) who had been diagnosed in the previous 3 months with type 1 diabetes. The aim was to stop the loss of the body’s insulin-making cells. Ustekinumab was given subcutaneously (into the skin) at the start of the trial, 4 weeks later, and then every 8 weeks until week 44 (i.e. seven doses in total) and then patients were followed up at week 52. Forty-seven teenagers received ustekinumab and 25 received saltwater injections that looked the same as the medicine (the ‘control’ treatment).
The study showed that after 12 months, teenagers given ustekinumab produced 49% more insulin in their own bodies than those given the control. The treatment was very safe with no serious side effects. Laboratory studies confirmed that the ustekinumab treatment reduced the number of immune cells making the interleukin 17 protein. Interleukin 17-making immune cells are known to damage other cells. Teenagers with the greatest reduction in interleukin 17-making cells had the best protection in their insulin-making capacity. However, the treatment appeared to take up to 6 months to have an effect, and by that stage, over 40% of the insulin-making capacity had been lost. There were no differences in average blood glucose levels or low blood glucose episodes (which can lead to loss of consciousness) between the treatments.
We conclude that ustekinumab appears to slow down the autoimmune disease process in type 1 diabetes. The study also provides evidence that interleukin 17-making immune cells are important in causing type 1 diabetes. Ustekinumab had very few side effects. However, on its own, ustekinumab does not seem able to stop the autoimmune process altogether and a lot of insulin-making capacity is lost before it takes effect. For greater effect, future studies could combine ustekinumab with other treatments to protect insulin-making cells in type 1 diabetes.
About the Series
Article history
The research reported in this issue of the journal was funded by the EME programme as award number 16/36/01. The contractual start date was in November 2017. The draft manuscript began editorial review in January 2024 and was accepted for publication in September 2024. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The EME editors and production house have tried to ensure the accuracy of the authors’ manuscript and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this article.
Last reviewed: January 2024; Accepted: September 2024.
This work was produced by Carter et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.