Award Title: Phase II multi-centre, double-blind, randomised trial of Ustekinumab in adolescents with new-onset Type 1 Diabetes (USTEKID)
Funder: Medical Research Council

Abstract: Type 1 diabetes (T1D) is an “autoimmune condition” in which the body’s immune system selectively destroys the insulin making “beta cells” of the pancreas. Unlike the more common type 2 diabetes, it is not related to obesity or lifestyle. Affected individuals are permanently dependent on insulin injections. The condition can be diagnosed at any time from 6 months of age. Around half of all cases are first diagnosed in childhood, and the commonest time to be diagnosed is age 12. Controlling blood sugar levels accurately with insulin injections when there is no insulin produced by the body is very difficult, requiring daily dose adjustments and blood fingerprick testing many times a day. As a result, despite the development of new ways of giving insulin, less than 20% of people with T1D achieve levels of blood sugar control sufficient to prevent the long-term complications of diabetes: blindness, kidney failure, foot problems and heart disease. Blood sugar control is worst during the teenage years, when adolescents find it hard to focus on healthy behaviours and taking medication reliably. At the time of diagnosis, most people have around 10-20% of their body’s insulin making capacity remaining, but this “last bit” of insulin disappears within 1 - 5 years due to continued attack by the immune system. In this initial period, sometimes referred to as a “honeymoon”, the remaining insulin, although limited, makes blood sugar control much easier. Recent evidence suggests that treatments that could slow the loss of insulin by half, would allow 50% rather than < 20% of people to achieve ideal levels of blood sugar control and reduce long-term complications by half. _x000D_
Immunotherapy aims to stop the destruction of the beta-cells, preserving the individual’s ability to make their own insulin. Such treatment would need to be used immediately after diagnosis before the insulin is lost. Since blood sugar control is worst in teenage, and early teenage is the most common age to be newly-diagnosed, developing an immunotherapy for use in adolescents with new-onset T1D is a very high priority and likely to have the greatest long-term benefit. _x000D_
Ustekinumab is an immunotherapy treatment that has been licensed for use in psoriasis, a non-fatal skin condition where it has proved safe as well as very effective, including in adolescents aged 12-18. It works by blocking the development of certain forms of white blood cells, referred to as CD4 T helper cells (Th). Since these same T cells have been implicated in causing type 1 diabetes, we believe it may be beneficial in preserving insulin in T1D. Ustekinumab is very easy to take – it is an injection under the skin (like insulin) that can be given by patients themselves at home. It is given at the start, after 4 weeks and then every 8 to 12 weeks. We recently conducted a small scale study in adults with newly-diagnosed T1D and found that ustekinumab at higher doses (used in psoriasis) has few side effects, reduces the level of Th cells and appears to preserve insulin production. _x000D_
Here we propose a study of ustekinumab in adolescents age 12- 18 with newly diagnosed T1D in 13 paediatric specialist centres across the UK, coordinated by the newly-formed T1D UK immunotherapy consortium. If ustekinumab proves effective, this will pave the way for the introduction of this therapy into clinical practice improving outcomes and quality of life and making blood sugar control easier for adolescents with newly-diagnosed T1D.

Lay Abstract: 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. _x000D_
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._x000D_
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. _x000D_
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. _x000D_
DESIGN: Stage 1 – setup; Stage 2 – All sites open and feasibility review; Stage 3 randomised, multicentre masked placebo controlled study – 2:1 drug:placebo. _x000D_
POPULATION: Adolescents aged 12-18 diagnosed with T1D in the previous 100 days._x000D_
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._x000D_
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. _x000D_
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. _x000D_
STATISTICAL ANALYSIS (primary outcome): Analysis of covariance that accounts for the baseline value of the AUC mean values. _x000D_
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.

Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: METABOLIC AND ENDOCRINE