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

Type 1 Diabetes Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01862120
• Other study ID #: P101106
• Status: Completed
• Phase: Phase 2
• Start date: June 27, 2013
• Est. completion date: March 16, 2017

Study information

• Verified date: November 2020
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: March 16, 2017
• Est. primary completion date: July 8, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 7 Years to 14 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Type 1 Diabetes

Intervention

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).
• 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).
• 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).
• 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).

Locations

Country	Name	City	State
France	Service d'Endocrinologie Pédiatrique	Le Kremlin Bicetre
France	Service de Pédiatrie - CHU de Nîmes	Nimes
France	CIC 9202 CHU Rober Débré	Paris
France	CIC pédiatrique - CHU de Necker	Paris
France	Service d'endocrinologie Diabétologie pédiatrique CHU Robert Débré	Paris
France	Service d'endocrinologie pédiatrique - CHU de Necker	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Treg response following the induction cure period	expressed as % total CD4 cells	day 5
Secondary	Fasting plasma concentration of C-peptide		at Day 0, 99, 183, 267, 351, 436
Secondary	C-peptide AUC response to a mixed meal tolerance test		at baseline, at months 6, 12, 15
Secondary	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
Secondary	HbA1c		at baseline, at months 3, 6, 9, 12, 15
Secondary	Treg response after the last administration		day 351, day 436
Secondary	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