Low-dose rhIL-2 in Patients With Recently-diagnosed Type 1 Diabetes
Condition: Type 1 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1
Study type: Interventional
Phase: Phase 2

Summary: 
      Type 1diabetes (T1D) is caused by autoimmune destruction of the pancreatic islet ß-cells,
      leading to an absolute deficiency in insulin.

      In health, regulatory T cells (Tregs) suppress immune responses against normal tissues, and
      likewise prevent autoimmune diseases. Tregs are insufficient in T1D.

      The investigators previously showed that administration of low doses of IL-2 induces
      selective expansion and activation of Tregs in mice and humans.

      The investigators hypothesize that Tregs expansion and activation with low doses of IL2 could
      block the ongoing autoimmune destruction of insulin producing cells in patients with recently
      diagnosed T1D.
    

Detailed description: 
      Scientific justification:

      Clinical and preclinical studies, together with supportive mechanistic data showing that
      Tregs are activated by much lower IL-2 concentration than effector T cells (Teffs), provide a
      strong rationale for studying efficacy of low dose IL2 to stop the autoimmune destruction of
      insulin-secreting beta cells in patient with recently diagnosed with T1D.

      Primary objective:

        1. To evaluate efficacy of low dose IL-2 for the preservation of residual pancreatic β
           cells function

        2. To select the optimal regimen of administration of IL-2

      Primary assessment criterion:

      AUC (T0-T120) of serum C-peptide, determined after a mixed meal tolerance test at month 12,
      compared to baseline.

      Secondary objectives:

        1. To assess Tregs expansion after an induction period and during maintenance therapy

        2. To assess safety of IL-2 during the treatment period (1 year) and 1 year after its
           discontinuation

        3. To assess the relation between Tregs expansion and preservation of residual pancreatic β
           cells function

        4. To assess clinical and biological responses according to (i) pubertal stage group, (i)
           time from diagnosis to treatment initiation, (iii) biomarkers of responses

        5. To assess effects of IL-2 on disease-specific immune responses

        6. To identify biomarkers for predicting/monitoring safety and efficacy of IL-2.

      Secondary assessment criteria:

        -  Serum concentrations of C-peptide

        -  AUC (T0-T120) of serum C-peptide after a mixed meal tolerance test after treatment
           discontinuation

        -  Diabetic monitoring (insulin use)

        -  HbA1c and IDAA1c score

        -  Number of hypoglycaemic episodes (< 0.5 g/L on capillary sample) over 15 days before
           each visit.

        -  Number of clinically significant symptomatic episodes of hypoglycaemia between each
           visit.

        -  Change in Tregs (expressed as percentage of CD4 and absolute numbers) at day 5 compared
           to baseline.

        -  Change in trough level of Tregs (%CD4+ and absolute numbers) at month 1, month 3, month
           6, month 9, month 12, compared to baseline; and then month 15 and 24 after treatment
           discontinuation.

        -  Change in Foxp3 gene methylation

        -  Cytokines and chemokines assays at day 5, month 1, month 3, month 6, month 9, and month
           12 compared to baseline and then month 15 and month 24 after treatment discontinuation.

        -  Transcriptome analysis.

        -  Genotyping at baseline

        -  Treg phenotype and functionality in adults and adolescents only including pStat5
           analysis

      Pharmacokinetic of IL2 will be performed (in patients from regimen A only) on day 1 at T0,
      T60min (1h), T120min (2h), T240min (4h), T360min (6h), T600min (10h), T1440min (24h=day2) on
      day 4, V8 (D29±1day) and V54 (day 351±3 days) at the same time points in 27 patients of
      regimen A.

      • Safety parameters will be evaluated by clinical examination (including height/weight and
      pubertal stage especially for children and adolescents), routine laboratory tests, ILT-101
      auto-antibodies, ancillary investigations and adverse event.

      Experimental design:

      This is a multicenter European, sequential-group, randomized, double-blind trial evaluating
      IL-2 versus placebo

      Population involved:

      Male or female, aged between 6 and 35 years, with type 1 diabetes diagnosed for less than two
      months.

      Number of subjects: 138

      Inclusion period: 49 months

      Duration of patient participation: 24 months (treatment period: 12 months, follow-up period:
      12months)

      Total duration of the study: 73 months

      Statistical analysis:

      The principal efficacy analysis will be drawn from the intention to treat group.

      The per-protocol analysis will be used to confirm the intention to treat analysis.

      For each regimen:

      - MMTT: C-peptide concentrations will be summarized by the AUC from T0 to T+120 min. Before
      statistical analysis, log (x+1) normalizing transformation will be used, and IL-2 and placebo
      treated patients will be compared using a mixed model of ANCOVA including baseline value as
      covariate and factor pubertal stage group.

      Quantitative endpoints will be analyzed using same methods as primary endpoint. Categorical
      endpoints will be analyzed using multivariate logistic regression models.

      Subgroups analyses: Response to treatment will be analysed according to criteria such as:

        -  Pubertal stage, age, gender, BMI…

        -  Biomarkers (identified in previous studies as predictive of patients' response to
           treatment)

      Funding source: European Commission under the Health Cooperation Programme of the Seventh
      Framework Programme (Grant Agreement n°305380-2).
    

Intervention name(s): rhIL-2; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Subcutaneous injections of IL2 according to regimen A Subcutaneous injections of IL2 according to regimen B; Subcutaneous injections of Placebo according to regimen A Subcutaneous injections of Placebo according to regimen B
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: IL2; Interleukin 2; IL-2; Auto-immune disease; Insulin; Diabetes; Regulatory T cells; Treg; Immunoregulation; Immune tolerance; Immunotherapy