DILT1D

Type 1 diabetes is the most common severe chronic autoimmune disease worldwide. The incidence of type 1 diabetes is rising rapidly with a predicted increase in paediatric cases of 70% over the next 15 year in Europe. The aetiology of type 1 diabetes is the autoimmune (loss of self tolerance) mediated destruction of the insulin producing pancreatic beta cells leading to insulin deficiency and development of hyperglycaemia. At present, medical management of type 1 diabetes focuses on intensive insulin replacement therapy to limit microvascular complications (retinopathy, nephropathy, neuropathy). Despite incremental improvement over the last 90 years clinical outcomes remain suboptimal with fewer than 5% of patients in the intensively treated group of the pivotal Diabetes Control and Complications Trial achieving glycaemic targets. The limiting factor for achieving euglycemia was hypoglycaemia as a result of exogenous insulin treatment. That is the tighter the glycemic control the greater the frequency of hypoglycaemia. However, patients who had residual endogenous insulin function had a reduced level of microvascular complications and hypoglycaemia, which was most likely due to the preservation of the counter regulator responses to low blood sugars6. These findings have led to intensive efforts to arrest the autoimmune process by novel immunotherapy and thereby preserve residual insulin production leading to improved clinical outcomes in type 1 diabetes.

Previous clinical trials involving the treatment of patients with newly diagnosed type 1 diabetes with immunotherapy have embarked on large proof of concept trials without first establishing the correct dose of the experimental agent in order to achieve the desired immunological outcome. Doses have been usually derived from experience of an agent in another disease entity such as in the case of teplizumab (non Fc binding anti-CD3) where the dose used in type 1 diabetes is the same as that used in renal transplantation (OKT3). Similarly, the doses of rituximab (anti-CD20) and abatacept (CTLA-4Ig) when used to treat type 1 diabetes have been derived from clinical experience in rheumatoid arthritis. In the case of otelixizumab (non-FcR-binding anti-CD3) experience from murine models was combined with limited human data to arrive at a dose. This has led, despite considerable efforts, to suboptimal outcomes in clinical trials of these agents; and in the case of otelixizumab, a complete failure due to a lack of therapeutic effect in humans.

It is clear that new strategies need to be developed to rapidly determine the mechanisms of action of immunotherapeutic agents in patients with type 1 diabetes prior to embarking on large phase II/III clinical trials. This is a non-randomised, single dose, open label, adaptive trial. 40 patients with type 1 diabetes will be required to complete the study. The expected duration of the study is up to 2 years. Participants will be enrolled into the study for a period of approximately 9 weeks.

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