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

Primary Purpose

Type 1 Diabetes

Status
Completed
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Dose D1 of interleukin-2
placebo
Dose D2 of Interleukin-2
Dose D3 of interleukin-2
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Type 1 Diabetes focused on measuring Recently diagnosed, Regulatory T Cells, Tolerance Induction, Paediatrics, Low dose, IL-2

Eligibility Criteria

7 Years - 14 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Service d'Endocrinologie Pédiatrique
  • Service de Pédiatrie - CHU de Nîmes
  • CIC pédiatrique - CHU de Necker
  • Service d'endocrinologie pédiatrique - CHU de Necker
  • CIC 9202 CHU Rober Débré
  • Service d'endocrinologie Diabétologie pédiatrique CHU Robert Débré

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Placebo Comparator

Arm Label

interleukin-2

Dose D2 of interleukin-2

Dose D3 of interleukin-2

placebo

Arm Description

Dose D1 of interleukin-2

Dose D2 of interleukin-2

Dose D3 of interleukin-2

placebo

Outcomes

Primary Outcome Measures

Treg response following the induction cure period
expressed as % total CD4 cells

Secondary Outcome Measures

Fasting plasma concentration of C-peptide
C-peptide AUC response to a mixed meal tolerance test
IDAA1C score
is a score defined as A1C (percent) + [4 x insulin dose (units per kilogram per 24 h)] without unit
HbA1c
Treg response after the last administration
Treg response during the maintenance period compare to the baseline
Treg response expressed as the % / CD4 will be measured several times

Full Information

First Posted
December 10, 2012
Last Updated
November 10, 2020
Sponsor
Assistance Publique - Hôpitaux de Paris
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1. Study Identification

Unique Protocol Identification Number
NCT01862120
Brief Title
Dose Finding Study of Il-2 at Ultra-low Dose in Children With Recently Diagnosed Type 1 Diabetes
Acronym
DFIL2-Child
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

2. Study Status

Record Verification Date
November 2020
Overall Recruitment Status
Completed
Study Start Date
June 27, 2013 (Actual)
Primary Completion Date
July 8, 2016 (Actual)
Study Completion Date
March 16, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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: Induction of TREGS following a cure of 5 days repeated once daily administration [day 1 - day 5]. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 1 Diabetes
Keywords
Recently diagnosed, Regulatory T Cells, Tolerance Induction, Paediatrics, Low dose, IL-2

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
Participant
Allocation
Randomized
Enrollment
24 (Actual)

8. Arms, Groups, and Interventions

Arm Title
interleukin-2
Arm Type
Experimental
Arm Description
Dose D1 of interleukin-2
Arm Title
Dose D2 of interleukin-2
Arm Type
Experimental
Arm Description
Dose D2 of interleukin-2
Arm Title
Dose D3 of interleukin-2
Arm Type
Experimental
Arm Description
Dose D3 of interleukin-2
Arm Title
placebo
Arm Type
Placebo Comparator
Arm Description
placebo
Intervention Type
Drug
Intervention Name(s)
Dose D1 of interleukin-2
Intervention Description
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).
Intervention Type
Drug
Intervention Name(s)
placebo
Intervention Description
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).
Intervention Type
Drug
Intervention Name(s)
Dose D2 of Interleukin-2
Intervention Description
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).
Intervention Type
Drug
Intervention Name(s)
Dose D3 of interleukin-2
Intervention Description
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).
Primary Outcome Measure Information:
Title
Treg response following the induction cure period
Description
expressed as % total CD4 cells
Time Frame
day 5
Secondary Outcome Measure Information:
Title
Fasting plasma concentration of C-peptide
Time Frame
at Day 0, 99, 183, 267, 351, 436
Title
C-peptide AUC response to a mixed meal tolerance test
Time Frame
at baseline, at months 6, 12, 15
Title
IDAA1C score
Description
is a score defined as A1C (percent) + [4 x insulin dose (units per kilogram per 24 h)] without unit
Time Frame
at baseline, at months 3, 6, 9, 12, 15
Title
HbA1c
Time Frame
at baseline, at months 3, 6, 9, 12, 15
Title
Treg response after the last administration
Time Frame
day 351, day 436
Title
Treg response during the maintenance period compare to the baseline
Description
Treg response expressed as the % / CD4 will be measured several times
Time Frame
day 15, day 29, day 43, day 99, day 183, day 267

10. Eligibility

Sex
All
Minimum Age & Unit of Time
7 Years
Maximum Age & Unit of Time
14 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David Klatzmann, MD, PhD
Organizational Affiliation
APHP
Official's Role
Principal Investigator
Facility Information:
Facility Name
Service d'Endocrinologie Pédiatrique
City
Le Kremlin Bicetre
ZIP/Postal Code
94275
Country
France
Facility Name
Service de Pédiatrie - CHU de Nîmes
City
Nimes
ZIP/Postal Code
30029 cedex 9
Country
France
Facility Name
CIC pédiatrique - CHU de Necker
City
Paris
ZIP/Postal Code
75015
Country
France
Facility Name
Service d'endocrinologie pédiatrique - CHU de Necker
City
Paris
ZIP/Postal Code
75015
Country
France
Facility Name
CIC 9202 CHU Rober Débré
City
Paris
ZIP/Postal Code
75019
Country
France
Facility Name
Service d'endocrinologie Diabétologie pédiatrique CHU Robert Débré
City
Paris
ZIP/Postal Code
75019
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
32607749
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.
Results Reference
derived

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

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