Dose-effect Relationship of Low-dose IL-2 in Type 1 Diabetes
Condition: Type 1 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      IL-2 is an inducer of regulatory T cells (Treg), a population of lymphocytes that fail to
      control the autoimmune destruction of beta-cells in patients with Type 1 Diabetes (T1D). The
      investigators recently showed that low dose IL-2 is well tolerated in patients with an
      autoimmune disease. The investigators aim to use IL-2 to induce/stimulate Treg in T1D
      patients. This study will investigate the dose effect relationship of low dose IL-2 for Treg
      induction such as to optimize the risk benefit ratio for this treatment in T1D. By Treg
      induction, the investigators aim to protect the remaining/regenerating β-cells from
      autoimmune destruction, thus improving or even curing T1D.
    

Detailed description: 
      Rationale:

      Type 1 diabetes (T1D) results from an autoimmune destruction of beta-pancreatic cells that
      regulatory T cells (Treg) fail to control. This is in part due to a deficit in production of,
      or response to, interleukin 2 (IL-2). This cytokine is essential to Treg development,
      survival and function. Importantly, while IL-2 also contributes to the activation of effector
      T cells (Teff), IL-2/IL-2 receptor signal transduction threshold is much lower for Treg than
      Teff. Thus low-dose IL-2 could be a specific Treg inducer/stimulator.

      The investigators then recently showed that low-dose IL-2 could cure recent onset diabetes in
      NOD mice that develop spontaneous diabetes considered as the best model of human T1D. A 5-day
      treatment with IL-2 could cure over 30% of the mice versus 0% for controls.

      With these premises, the investigators propose to explore if Treg induction could be obtained
      in patients who may have a deficit in production of, or response to, IL-2. Defining the dose
      effect relationship of low dose IL-2 for Treg induction will optimize the risk benefit ratio
      for IL-2 in T1D.

      Principal objective:

      To define the dose-effect relationship of low dose IL-2 for Treg induction in patient with
      recent onset diabetes

      Evaluation Criteria:

        -  Efficacy Kinetic variation of Treg proportions within CD4+ T cells in peripheral blood
           from Day+0 to Day+60.

        -  Tolerance Evaluation by clinical exams, laboratory tests and monitoring of side effects.
           The criterion for terminating the study will be the occurrence of one serious unexpected
           side effect in the month following IL-2 first administration in at least 2 patients.

      Study plan:

      After inclusion (Day0), the patient receives a 5-day course of IL-2 or placebo. Patients are
      randomized in 4 arms receiving either a placebo, or IL-2 doses of 0,33 - 1 or 3 millions
      UI/day. Laboratory follow-up of peripheral blood T cell subsets will be performed at D0 to D6
      (daily), D15, D22 and D60 by immunophenotyping and transcriptomics.

      Tolerance will be evaluated at D0-6, D15, D22 and D60.

      Methodology:

      Double blind placebo controlled randomized study, with 4 parallel groups. Patients will have
      T1D of autoimmune origin attested by the presence of auto-antibodies (at least one of:
      anti-islet, anti-GAD, anti-IA2 or anti-ZnT8), with a diagnostic inferior or equal to 24
      months.

      Study length:

      Study length = 9 months Patient participation = 2 months Inclusion period = 6 months
    

Intervention name(s): Aldesleukin
Intervention type(s): Drug
Intervention description(s): 0.33 ; 1 ; 3 ; 0 millions IU of IL-2 per day for arm 1 to 4, respectively. 1 s.c. injection per day for 5 days.
Other intervention name(s): IL2
Intervention MeSH terms: Aldesleukin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary purpose: Treatment