Dose-effect Relationship of Low-dose IL-2 in Type 1 Diabetes — DF-IL2  

Type 1 Diabetes Clinical Trial

Official title: Dose-effect Relationship of Repeated Administration of Low-dose IL-2 Versus Placebo on the Kinetic of Regulatory T Cells in Patients With Type 1 Diabetes

Status Completed

Clinical Trial 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.

Clinical Trial 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 ;

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 1
• Type 1 Diabetes

• NCT number: NCT01353833
• Study type: Interventional
• Source: Assistance Publique - Hôpitaux de Paris
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: May 2011
• Completion date: April 2012