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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:
NCT01862120
First received: December 10, 2012
Last updated: April 18, 2016
Last verified: April 2016
  Purpose
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.

Condition Intervention Phase
Type 1 Diabetes
Drug: Dose D1 of interleukin-2
Drug: placebo
Drug: Dose D2 of Interleukin-2
Drug: Dose D3 of interleukin-2
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Assistance Publique - Hôpitaux de Paris:

Primary Outcome Measures:
  • Treg response following the induction cure period [ Time Frame: day 5 ] [ Designated as safety issue: No ]
    expressed as % total CD4 cells


Secondary Outcome Measures:
  • Fasting plasma concentration of C-peptide [ Time Frame: at Day 0, 99, 183, 267, 351, 436 ] [ Designated as safety issue: Yes ]
  • C-peptide AUC response to a mixed meal tolerance test [ Time Frame: at baseline, at months 6, 12, 15 ] [ Designated as safety issue: Yes ]
  • IDAA1C score [ Time Frame: at baseline, at months 3, 6, 9, 12, 15 ] [ Designated as safety issue: Yes ]
    is a score defined as A1C (percent) + [4 x insulin dose (units per kilogram per 24 h)] without unit

  • HbA1c [ Time Frame: at baseline, at months 3, 6, 9, 12, 15 ] [ Designated as safety issue: Yes ]
  • Treg response after the last administration [ Time Frame: day 351, day 436 ] [ Designated as safety issue: No ]
  • Treg response during the maintenance period compare to the baseline [ Time Frame: day 15, day 29, day 43, day 99, day 183, day 267 ] [ Designated as safety issue: No ]
    Treg response expressed as the % / CD4 will be measured several times


Enrollment: 24
Study Start Date: June 2013
Estimated Study Completion Date: March 2017
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
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
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).
Placebo Comparator: placebo
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).

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

Ages Eligible for Study:   7 Years to 14 Years   (Child)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01862120

Locations
France
Service d'Endocrinologie Pédiatrique
Le Kremlin Bicetre, France, 94275
Service de Pédiatrie - CHU de Nîmes
Nimes, France, 30029 cedex 9
CIC pédiatrique - CHU de Necker
Paris, France, 75015
Service d'endocrinologie pédiatrique - CHU de Necker
Paris, France, 75015
CIC 9202 CHU Rober Débré
Paris, France, 75019
Service d'endocrinologie Diabétologie pédiatrique CHU Robert Débré
Paris, France, 75019
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
Principal Investigator: David Klatzmann, MD, PhD APHP
  More Information

Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT01862120     History of Changes
Other Study ID Numbers: P101106 
Study First Received: December 10, 2012
Last Updated: April 18, 2016
Health Authority: France: Ministry of Health

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Recently diagnosed
Regulatory T Cells
Tolerance Induction
Paediatrics
Low dose
IL-2

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Interleukin-2
Antineoplastic Agents
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 21, 2016