Clinical trial NCT01862120: Dose Finding Study of Il-2 at Ultra-low Dose in Children With Recently Diagnosed Type 1 Diabetes
Official title: Induction of Regulatory T Cells for the Treatment of Recently Diagnosed Type 1 Diabetes: Dose Finding Study of the Lowest Active Dose of IL-2 in Children
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Type 1 Diabetes
Keywords: Recently diagnosed
Regulatory T Cells
Tolerance Induction
Paediatrics
Low dose
IL-2
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2013-05-24
Enrollment: 24
Sex: ALL
Minimum age (years): 7
Maximum age (years): 14
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility 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

Primary outcomes:
measure: Treg response following the induction cure period
timeFrame: day 5
Secondary outcomes:
measure: Fasting plasma concentration of C-peptide
timeFrame: at Day 0, 99, 183, 267, 351, 436
measure: C-peptide AUC response to a mixed meal tolerance test
timeFrame: at baseline, at months 6, 12, 15
measure: IDAA1C score
timeFrame: at baseline, at months 3, 6, 9, 12, 15
measure: HbA1c
timeFrame: at baseline, at months 3, 6, 9, 12, 15
measure: Treg response after the last administration
timeFrame: day 351, day 436
measure: Treg response during the maintenance period compare to the baseline
timeFrame: day 15, day 29, day 43, day 99, day 183, day 267
Other outcomes:
Locations:
city: Le Kremlin Bicetre
country: France
facility: Service d'Endocrinologie Pédiatrique
city: Nimes
country: France
facility: Service de Pédiatrie - CHU de Nîmes
city: Paris
country: France
facility: CIC pédiatrique - CHU de Necker
city: Paris
country: France
facility: Service d'endocrinologie pédiatrique - CHU de Necker
city: Paris
country: France
facility: CIC 9202 CHU Rober Débré
city: Paris
country: France
facility: Service d'endocrinologie Diabétologie pédiatrique CHU Robert Débré
Study officials:
affiliation: APHP
name: David Klatzmann, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rosenzwajg M, Salet R, Lorenzon R, Tchitchek N, Roux A, Bernard C, Carel JC, Storey C, Polak M, Beltrand J, Amouyal C, Hartemann A, Corbeau P, Vicaut E, Bibal C, Bougneres P, Tran TA, Klatzmann D. Low-dose IL-2 in children with recently diagnosed type 1 diabetes: a Phase I/II randomised, double-blind, placebo-controlled, dose-finding study. Diabetologia. 2020 Sep;63(9):1808-1821. doi: 10.1007/s00125-020-05200-w. Epub 2020 Jul 1.