Dose Finding Study of Il-2 at Ultra-low Dose in Children With Recently Diagnosed Type 1 Diabetes (DFIL2-Child)

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

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.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Drug: Dose D1 of interleukin-2; Drug: Dose D2 of Interleukin-2; Drug: Dose D3 of interleukin-2; Drug: placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Le Kremlin Bicetre, France, 94275
    • Service d'Endocrinologie Pédiatrique
  • Nimes, France, 30029 cedex 9
    • Service de Pédiatrie - CHU de Nîmes
  • Paris, France, 75015
    • CIC pédiatrique - CHU de Necker
  • Paris, France, 75015
    • Service d'endocrinologie pédiatrique - CHU de Necker
  • Paris, France, 75019
    • CIC 9202 CHU Rober Débré
  • Paris, France, 75019
    • Service d'endocrinologie Diabétologie pédiatrique CHU Robert Débré

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 14 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo	Drug: placebo; subcutaneous injection of Interleukin-2 during 5 days, once daily repeated administration(Induction period). At day 15 single administration of Interleukin-2 every two weeks during one year (maintenance period).
Experimental: interleukin-2; Dose D1 of interleukin-2	Drug: Dose D1 of interleukin-2; subcutaneous injection of Interleukin-2 during 5 days, once daily repeated administration(Induction period). At day 15 single administration of Interleukin-2 every two weeks during one year (maintenance period).
Experimental: Dose D2 of interleukin-2	Drug: Dose D2 of Interleukin-2; subcutaneous injection of Interleukin-2 during 5 days, once daily repeated administration(Induction period). At day 15 single administration of Interleukin-2 every two weeks during one year (maintenance period).
Experimental: Dose D3 of interleukin-2	Drug: Dose D3 of interleukin-2; subcutaneous injection of Interleukin-2 during 5 days, once daily repeated administration(Induction period). At day 15 single administration of Interleukin-2 every two weeks during one year (maintenance period).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treg response following the induction cure period	expressed as % total CD4 cells	day 5

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fasting plasma concentration of C-peptide		at Day 0, 99, 183, 267, 351, 436
C-peptide AUC response to a mixed meal tolerance test		at baseline, at months 6, 12, 15
IDAA1C score	is a score defined as A1C (percent) + [4 x insulin dose (units per kilogram per 24 h)] without unit	at baseline, at months 3, 6, 9, 12, 15
HbA1c		at baseline, at months 3, 6, 9, 12, 15
Treg response after the last administration		day 351, day 436
Treg response during the maintenance period compare to the baseline	Treg response expressed as the % / CD4 will be measured several times	day 15, day 29, day 43, day 99, day 183, day 267

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: David Klatzmann, MD, PhD, APHP

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 27, 2013
• Primary Completion (Actual): July 8, 2016
• Study Completion (Actual): March 16, 2017

Study Registration Dates

• First Submitted: December 10, 2012
• First Submitted That Met QC Criteria: May 23, 2013
• First Posted (Estimate): May 24, 2013

Study Record Updates

• Last Update Posted (Actual): November 12, 2020
• Last Update Submitted That Met QC Criteria: November 10, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Regulatory T Cells; IL-2; Paediatrics; Recently diagnosed; Tolerance Induction; Low dose
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antineoplastic Agents; Interleukin-2
• Other Study ID Numbers: P101106