Dose Finding Study of Il-2 at Ultra-low Dose in Children With Recently Diagnosed Type 1 Diabetes (DFIL2-Child)

Assistance Publique - Hôpitaux de Paris

Status and phase: Completed; Phase 2

Conditions: Type 1 Diabetes

Treatments: Drug: Dose D2 of Interleukin-2; Drug: Dose D1 of interleukin-2; Drug: Dose D3 of interleukin-2; Drug: placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT01862120

P101106

Details and patient eligibility

About

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.

Full 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.

Enrollment: 24 patients

Sex: All

Ages: 7 to 14 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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24 participants in 4 patient groups, including a placebo group

interleukin-2

Experimental group

Description:

Dose D1 of interleukin-2

Treatment:

Drug: Dose D1 of interleukin-2

Dose D2 of interleukin-2

Experimental group

Description:

Dose D2 of interleukin-2

Treatment:

Drug: Dose D2 of Interleukin-2

Dose D3 of interleukin-2

Experimental group

Description:

Dose D3 of interleukin-2

Treatment:

Drug: Dose D3 of interleukin-2

placebo

Placebo Comparator group

Description:

placebo

Treatment:

Drug: placebo