ITAD

Trial Title

Interleukin-2 Therapy of Autoimmunity in Diabetes

Short Title

ITAD

Clinical Phase

IIb

Trial Design

Randomised, placebo-controlled clinical trial

Trial Patients

Children and adolescents with newly-diagnosed type 1 diabetes (T1D), aged 6-18 years, with sequential recruitment starting with age 12-18 and then expanding to the younger age group, 6-11 years.

Planned Sample Size

45 - Ratio of active drug:placebo = 2:1

Treatment duration

6 months

Follow up duration

6 months

Planned Trial Period

30 months - 18 months recruitment, 6 months treatment, 6 months follow-up

Objectives

Outcome Measures

Primary

To assess the effects of ultra low-dose (ULD) aldesleukin administration on endogenous beta-cell function as measured by frequent home-tested  dried blood spot (DBS) fasting and post-prandial C-peptide in children and adolescents with newly-diagnosed T1D.

Differences in slopes of DBS C-peptide over the 6 month-treatment period between the active and placebo groups.

Secondary

1)To assess the efficacy of regular dosing of ULD aldesleukin in increasing Treg levels

1) Change in Treg, Teff and NK56^bright cell frequencies and phenotypes from baseline

2)To confirm the clinical safety and tolerability of ULD aldesleukin

2) Safety will be assessed at each visit by:

Physical examination, including assessment of the most commonly reported reactions to low- or high-dose  aldesleukin, namely influenza-like syndrome, skin reaction, diarrhea, nausea; vital signs (temperature, weight, blood pressure, heart rate);

abnormal laboratory parameters (liver, kidney function, full blood count); reporting of adverse events.

3) To assess changes in the immune system indicating benefit or potential risk for future gains/loss in beta-cell and immune function.

3) Changes in the absolute numbers of T, B and NK cells. A whole blood 6-color BD TBNK Multitest™ assay using BD Trucount Tubes according to the manufacturers’ instructions (BD Biosciences) will be run to determine the relative and absolute concentration of lymphocyte subpopulations, including mature T, B and NK cells.

4) To assess treatment effect on glycaemic control

4) Change in HbA1c and daily insulin requirements during the trial period.

5) To assess treatment effect on the immune activity and inflammatory marker C-reactive protein (CRP), measured by frequent home-tested DBS fasting.

5) Change in CRP levels during the trial period

Summary of eligibility criteria

Inclusion Criteria:

• Have given written informed consent to participate or assent with parental consent
• Be aged 6-18 years
• Being diagnosed with T1D (at least 1 autoantibody positive) requiring insulin treatment
• Be within 6 weeks from diagnosis of T1D
• Have a random C-peptide >200 pmol/l
• Normal full blood count

Exclusion Criteria:

• Non-T1D (type 2 or monogenic diabetes) and secondary diabetes
• Pre-exisitng autoimmune disease (excluding type 1 diabetes)
• Hypersensitivity to aldesleukin or any of the excipients
• History of severe cardiac disease (NYHA Class III or IV)
  • See Appendix D
• History of malignancy within the past 5 years (with the exception of adequately treated basal or squamous cell carcinoma or cervical carcinoma in situ)
• Clinically significant abnormal laboratory values (out of range and associated with clinical symptoms or signs) in haematology, biochemistry, thyroid, liver and kidney function
• Pre-existing severe major organ dysfunction or seizure disorders
• Participation in another clinical trial (CTIMP) within 4 months prior to screening
• Females who are pregnant, lactating or intend to get pregnant during the trial
• Females of childbearing potential who are unwilling or unable to comply with contraceptive advice and regular pregnancy testing throughout the trial
• Current use of immunosuppressive agents or steroids
• Current treatment with hepatotoxic, nephrotoxic, myelotoxic, or cardiotoxic products
• Active clinical infections – patients can be recruited after a minimum period of 48 h  after last day of feeling unwell or last day of antibiotic/anti-viral treatment
• Immunisations – patients can be recruited after a minimum of 14 days following immunisation. Routine vaccinations should be avoided for the 6-month duration of treatment and for 30 days afterwards
• Any medical history or clinically relevant abnormality that is deemed by the Principal Investigator and/or medical monitor to make the patientnt ineligible for inclusion because of a safety concern.
• Children with compliance problems