A drug already used for psoriasis is being tested in a clinical trial to see if it can preserve insulin production in teenagers newly diagnosed with type 1 diabetes. Less than 20% of UK patients with type 1 diabetes achieve good blood sugar control, and adolescents fare worst. In the first year after diagnosis, however, over half of teenagers still produce some of their own insulin, which makes control easier. No immunotherapy is currently licensed to slow the autoimmune attack that destroys insulin-producing cells. This trial tests ustekinumab, a monoclonal antibody that blocks two key immune pathways (Th1 and Th17) implicated in the disease. If the drug preserves even modest levels of natural insulin production, it could reduce severe hypoglycaemia by 50% or more and lower the risk of costly long-term complications—blindness, kidney failure, amputation—that typically strike these patients between ages 30 and 50. The trial will randomise 72 adolescents aged 12–18, diagnosed within the previous 100 days, to receive high-dose, low-dose, or placebo injections over 52 weeks. The primary measure is the change in stimulated C-peptide levels, a direct marker of the body’s own insulin output.
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Type 1 diabetes (T1D) can be diagnosed at any age from 6 months, most commonly around age 12. T1D is associated with severe long-term complications including blindness, renal failure, peripheral neuropathy with foot ulceration or amputation and reduced QoL. Although good blood glucose control can reduce these risks, less than 20% of patients with T1D in the UK achieve target levels, control being worst in adolescents. By contrast, in the first 1-2 years after diagnosis, over 50% of individuals including adolescents achieve optimal levels of glycaemic control due to residual endogenous insulin secretion. Interventions to slow the autoimmune process (immunotherapy) and preserve endogenous insulin therefore have immense potential to improve outcomes, particularly in adolescents, but none are currently licensed. We and others have shown that CD4 T cells that secrete IFNgamma (Th1) and IL-17 (Th17) are likely to be important to T1D pathogenesis. Ustekinumab is a monoclonal antibody that blocks two key cytokines involved in the generation of Th1 and Th17 cells. It can be self-administered, with low infection risk and is already licensed for psoriasis in children > 12 years of age. In a recent pilot study in adults with recent-onset T1D we have shown that usketinumab has a good safety profile, with reduction in a measureable biomarker of Th1/Th17 cells and evidence of beta cell preservation at higher doses. HYPOTHESIS: Blockade of the IL17/IFNgamma axes with ustekinumab in adolescents recently-diagnosed with T1D will result in significant preservation of endogenous insulin (c-peptide) production. AIM: To provide evidence to address our hypothesis in an appropriately powered, adequately dosed randomised controlled trial with relevant mechanistic assessment and evaluation of clinical relevant outcomes. DESIGN: Stage 1 – setup; Stage 2 – All sites open and feasibility review; Stage 3 randomised, multicentre masked placebo controlled study – 2:1 drug:placebo. POPULATION: Adolescents aged 12-18 diagnosed with T1D in the previous 100 days. INTERVENTION: Treatment with ustekinumab (anti-IL12/23) at “high” or “low” dose (as determined from dose finding study) or placebo injections, subcutaneously at weeks 0, 4 and then every 8 or 12 weeks to week 52. OUTCOMES/ASSESSMENTS: PRIMARY change in 2-hour area under the curve (AUC) insulin c-peptide (endogenous) levels following standard mixed meal tolerance test (MMTT) stimulation at week 52. EXPLORATORY– changes in AUC c-peptide at week 28; insulin dose/kg; insulin dose adjusted HbA1c; hypoglycaemia rates, PROMs, adverse events, infections; Th1 and Th17 cell numbers; multicolour T,B, NK subset profile; antigen specific T cell responses; drug levels. SAMPLE SIZE: A sample size of 72 in a 2:1 ratio has >85% power to detect a 0.2nml/L/min difference between AUC values of the intervention and control arms at twelve months allowing for 10% loss to follow-up. STATISTICAL ANALYSIS (primary outcome): Analysis of covariance that accounts for the baseline value of the AUC mean values. ECONOMIC BENEFIT: Preservation of c-peptide is expected to result in a 50% or greater reduction in severe hypoglycaemia and a similar reduction in long-term complications including the very costly complications of renal replacement therapy, blindness and amputation as well as increased QoL. For teenagers these occur during working age (age 30-50). Health economic benefits will not be assessed in the current study.
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