Adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes

Research summary

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.


Main inclusion criteria

  1. Type 1 diabetes

  2. 18-50 years of age

  3. Duration of diabetes less than 24 months from diagnosis

  4. One positive autoantibody (anti-islet cell, anti-GAD, anti-IA2, anti-ZnT8)

  5. Written informed consent

Main exclusion criteria

The presence of any of the following will preclude patient inclusion:

  1. Hypersensitivity to aldesleukin or any of the excipients

  2. History of severe cardiac disease History of malignancy within the past 5 years (with the exception of localized carcinoma of the skin that had been resected for cure or cervical carcinoma in situ

  3. History or concurrent use of immunosuppressive agents or steroids.

  4. History of unstable diabetes with recurrent hypoglycaemia

  5. Active auto immune, Hyper or hypothyroidism

  6. Active clinical infection Major pre-existing organ dysfunction or previous organ allograft

  7. Females who are pregnant, lactating or intend to get pregnant during the study

  8. Males who intend to father a pregnancy during the study

  9. Donation of more than 500 ml of blood within 2 months prior to aldesleukin administration

  10. Participation in a previous therapeutic clinical trial within 2 months prior to aldesleukin administration

  11. Abnormal ECG Abnormal full blood count, chronic renal failure (Stage 3,4,5) and/or evidence impaired liver function

  12. Positive HBsAg or HepC serology or HIV test

  13. Any medical history or clinically relevant abnormality that is deemed by the principal investigator and/or medical monitor to make the patient ineligible for inclusion because of a safety concern.

Chief investigator

Dr Frank Waldron-Lynch

Contact details

Clinical Trials ManagerDr Paula Kareclas

Telephone: 01223 596473 | Email: [email protected]