Type 1 Diabetes
Conditions
Keywords
Recently diagnosed, Regulatory T Cells, Tolerance Induction, Paediatrics, Low dose, IL-2
Brief summary
Human recombinant interleukin-2 (rhIL-2) is a biological signalling protein playing a key role in the regulation of the immune system. At high doses, rhIL-2 activates the immune effectors T cells (TEFFS) while at low doses rhIL-2 induces and activates regulatory T cells (TREGS), a population of immune cells controlling the immune Teff response. In patients with Type 1 Diabetes (T1D), TREGS fail to control the autoimmune destruction by TEFFS of pancreatic beta-cells producing insulin. The investigator recently showed that rhIL-2 at low dose is well tolerated in patients with an autoimmune disease and in adults with established T1D, inducing TREGS without effects on TEFFS. The investigators aim to use rhIL-2 at low dose to induce/stimulate TREGS in young recently diagnosed T1D patients. This study will investigate the dose effect relationship of low dose rhIL-2 on TREG induction such as to optimize the risk benefit ratio of this treatment in T1D. Through Treg induction, the investigators aim to protect the remaining/regenerating pancreatic β-cells from autoimmune destruction, thus improving or even curing T1D.
Detailed description
Main objective: Define the lowest dose of rhIL-2 inducing TREGS in children with recently diagnosed type 1 diabetes. Conduct of the study: Three doses will be studied versus placebo in parallel groups of six patients. Each dose or placebo will be studied according to three periods of treatment: 1. Induction of TREGS following a cure of 5 days repeated once daily administration \[day 1 - day 5\]. 2. Maintenance of TREGS following repeated administration once every two weeks for one year \[day 15 - day 337\]. At each treatment period, Treg response and tolerance will be evaluated. In addition, overall response on T1D parameters will be assessed throughout the study.
Interventions
DRUGDose D1 of interleukin-2
subcutaneous injection of Interleukin-2 during 5 days, once daily repeated administration(Induction period). At day 15 single administration of Interleukin-2 every two weeks during one year (maintenance period).
DRUGplacebo
subcutaneous injection of Interleukin-2 during 5 days, once daily repeated administration(Induction period). At day 15 single administration of Interleukin-2 every two weeks during one year (maintenance period).
DRUGDose D2 of Interleukin-2
subcutaneous injection of Interleukin-2 during 5 days, once daily repeated administration(Induction period). At day 15 single administration of Interleukin-2 every two weeks during one year (maintenance period).
DRUGDose D3 of interleukin-2
subcutaneous injection of Interleukin-2 during 5 days, once daily repeated administration(Induction period). At day 15 single administration of Interleukin-2 every two weeks during one year (maintenance period).
Sponsors
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
7 Years to 14 Years
Healthy volunteers
No
Inclusion criteria
: * Age \[7-13\] years for girls and \[7-14\] years for boys * With a T1D diagnosis (as ADA) * Treated with insulin for ≤ 3 months, * With at least one auto-antibody among: anti-insulin, anti-GAD, anti-IA2, anti-ZnT8 ; * No clinically relevant abnormal findings for haematology, biochemistry, liver and kidney functions * Informed consent signed by the patient, the parents, and the investigator before any intervention necessary for the trial.
Exclusion criteria
: * Contra-indications to IL-2 : * Hyper sensibility to IL-2 or its excipients, * Severe cardiopathy * Previous organ allograft * Ongoing infection requiring antibiotherapy, * O2 Saturation ≤ 90 % * Severe impairment of any vital organ * Documented history of other auto-immune diseases (except for auto-antibodies for, IAA, GADA, IA-2A, anti-ZnT8A, and stable thyroiditis with normal TSH (\<10 mUI/L), T3 and, T4 levels. * Diabetes onset characteristics including: * Continuous nocturnal polyuria ≥ 3 months ; * Inaugural acidosis (with venous Ph \< 7.25) ; * HbA1c at diagnostic ≥ 13%; * Weight loss ≥ 10 % at diagnosis ; * Positive autoantibodies to 21-hydroxylase * Stage 2 obesity * Non authorized concomitant treatment : immuno-modulators, cytotoxic drugs, drug modifying plasma glycemia * vaccination ≤ 4 weeks with life vaccin * Positive serology (IgM) to the Epstein-Barr virus (EBV) and/or cytomegalovirus (CMV), reflecting an acute infection. * Participation to another clinical investigation in previous 3 months * No affiliation to National Health Insurance
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treg response following the induction cure period | day 5 | expressed as % total CD4 cells |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| C-peptide AUC response to a mixed meal tolerance test | at baseline, at months 6, 12, 15 | — |
| IDAA1C score | at baseline, at months 3, 6, 9, 12, 15 | is a score defined as A1C (percent) + \[4 x insulin dose (units per kilogram per 24 h)\] without unit |
| Fasting plasma concentration of C-peptide | at Day 0, 99, 183, 267, 351, 436 | — |
| Treg response after the last administration | day 351, day 436 | — |
| Treg response during the maintenance period compare to the baseline | day 15, day 29, day 43, day 99, day 183, day 267 | Treg response expressed as the % / CD4 will be measured several times |
| HbA1c | at baseline, at months 3, 6, 9, 12, 15 | — |
Countries
France
Outcome results
None listed