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

Sponsor
Assistance Publique - Hôpitaux de Paris (Other)
Overall Status
Completed
CT.gov ID
NCT01353833
Collaborator
(none)
25
Enrollment
1
Location
4
Arms
11
Duration (Months)
2.3
Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

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

Study Design

Study Type:
Interventional
Actual Enrollment :
25 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Care Provider)
Primary Purpose:
Treatment
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
Study Start Date :
May 1, 2011
Actual Primary Completion Date :
Oct 1, 2011
Actual Study Completion Date :
Apr 1, 2012

Arms and Interventions

Arm Intervention/Treatment
Placebo Comparator: IL2-4

Drug: Aldesleukin
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 Names:
  • IL2

    		•
    Experimental: IL2-2

    1 millions IU of IL-2 per day

    Drug: Aldesleukin
    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 Names:
  • IL2

    		•
    Experimental: IL2-3

    3 millions IU of IL-2 per day

    Drug: Aldesleukin
    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 Names:
  • IL2

    		•
    Experimental: IL2-1

    0.33 millions IU of IL-2 per day

    Drug: Aldesleukin
    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 Names:
  • IL2

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Kinetic parameters of Treg proportions variation within CD4+ T cells in peripheral blood [from Day+0 to Day+60]

    Secondary Outcome Measures

    1. Improvement of residual secretion of insulin assessed by the AUC of peptide C during a standardized test meal in IL-2 vs placebo treated patients [at Day+0 and Day+60]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 50 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Age [18-50] years;

    • With a T1D:

    • Treated with insulin for ≤ 2 years,

    • With at least one auto-antibody among: anti-islet, anti-GAD, anti-IA2, anti-ZnT8 ;

    • No clinically relevant abnormal value for hematology, biochemistry, liver and kidney function

    • Lymphocyte [1000-4000]/ mm3

    • Informed consent signed by the patient and the investigator before any intervention necessary for the trial.

    Exclusion Criteria:

    • Contra-indications to IL2 :

    • Hypersensibility to IL-2 or its excipients,

    • Severe cardiopathy

    • Ongoing infection requiring antibiotherapy,

    • O2 Saturation ≤ 90 %

    • Severe impairment of a vital organ

    • Previous organ allograft

    • Non authorized concomitant treatment : i.e. immuno-modulators, cytotoxic, drug modifying glycemia

    • Cancer progressing or cured for less than 5 years except for primary basal cell carcinoma or carcinoma in situ of the uterine cervix.

    • Participation to another clinical investigation in < 3 months

    • Pregnant or lactating women

    • Male or female in age of procreation without efficient contraception during the study

    • No affiliation to National Health Insurance

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Hôpital Pitié-Salpêtrière Paris France 75013

    Sponsors and Collaborators

    • Assistance Publique - Hôpitaux de Paris

    Investigators

    • Principal Investigator: Davis Klatzmann, MD, PhD, Assistance Publique - Hôpitaux de Paris

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Assistance Publique - Hôpitaux de Paris
    ClinicalTrials.gov Identifier:
    NCT01353833
    Other Study ID Numbers:
    • P101101
    • 2010-024499-24
    First Posted:
    May 16, 2011
    Last Update Posted:
    Apr 23, 2012
    Last Verified:
    May 1, 2011
    Additional relevant MeSH terms:
    Diabetes Mellitus
    Diabetes Mellitus, Type 1
    Aldesleukin

    Study Results

    No Results Posted as of Apr 23, 2012