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

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:

Genetics Home Reference related topics: type 1 diabetes

MedlinePlus related topics: Diabetes Diabetes Type 1

U.S. FDA Resources

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

Primary Outcome Measures:

Treg response following the induction cure period [ Time Frame: day 22 ] [ Designated as safety issue: No ]
expressed as % total CD4 cells

Secondary Outcome Measures:

Fasting plasma concentration of C-peptide [ Time Frame: Baseline ] [ Designated as safety issue: Yes ]
Fasting plasma concentration of C-peptide [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
Fasting plasma concentration of C-peptide [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
Fasting plasma concentration of C-peptide [ Time Frame: day 466 ] [ Designated as safety issue: Yes ]
C-peptide AUC response to a mixed meal tolerance test [ Time Frame: Baseline ] [ Designated as safety issue: Yes ]
C-peptide AUC response to a mixed meal tolerance test [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
C-peptide AUC response to a mixed meal tolerance test [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
C-peptide AUC response to a mixed meal tolerance test [ Time Frame: day 466 ] [ Designated as safety issue: Yes ]
IDAA1C score [ Time Frame: Baseline ] [ Designated as safety issue: Yes ]
is a score defined as A1C (percent) + [4 x insulin dose (units per kilogram per 24 h)] without unit
Fasting plasma concentration of C-peptide [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
Fasting plasma concentration of C-peptide [ Time Frame: 9 months ] [ Designated as safety issue: Yes ]
HbA1c [ Time Frame: Baseline ] [ Designated as safety issue: Yes ]
IDAA1C score [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
is a score defined as A1C (percent) + [4 x insulin dose (units per kilogram per 24 h)] without unit
IDAA1C score [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
is a score defined as A1C (percent) + [4 x insulin dose (units per kilogram per 24 h)] without unit
IDAA1C score [ Time Frame: 9 months ] [ Designated as safety issue: Yes ]
is a score defined as A1C (percent) + [4 x insulin dose (units per kilogram per 24 h)] without unit
IDAA1C score [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
is a score defined as A1C (percent) + [4 x insulin dose (units per kilogram per 24 h)] without unit
IDAA1C score [ Time Frame: day 466 ] [ 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: 3 months ] [ Designated as safety issue: Yes ]
HbA1c [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
HbA1c [ Time Frame: 9 months ] [ Designated as safety issue: Yes ]
HbA1c [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
HbA1c [ Time Frame: day 466 ] [ Designated as safety issue: Yes ]
Treg response during the maintenance period [ Time Frame: month 1 from month 12 ] [ Designated as safety issue: No ]
Treg response expressed as the % / CD4 will be measured several times (day 29, day 57, day 113, day 115, day 127, day 197, day 281, day 351, day 365,
Treg response after the last administration [ Time Frame: day 379 ] [ Designated as safety issue: No ]
Treg response after the last administration [ Time Frame: day 466 ] [ Designated as safety issue: No ]

Estimated Enrollment:	24
Study Start Date:	June 2013
Estimated Study Completion Date:	December 2014
Estimated Primary Completion Date:	September 2014 (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 Interleukin-2 by subcutaneous injection with: Single administration at day 1, followed at day 15 by an induction treatment of 5 days once daily repeated administration, and at day 30 by a maintenance treatment with a single administration every two weeks during one year. Other Name: IL2
Experimental: Dose D2 of interleukin-2 Dose D2 of interleukin-2	Drug: Dose D2 of Interleukin-2 Interleukin-2 by subcutaneous injection with: Single administration at day 1, followed at day 15 by an induction treatment of 5 days, and at day 30 by a maintenance treatment with a single administration every two weeks during one year.
Experimental: Dose D3 of interleukin-2 Dose D3 of interleukin-2	Drug: Dose D3 of interleukin-2 Interleukin-2 by subcutaneous injection with: Single administration at day 1, followed at day 15 by an induction treatment of 5 days, and at day 30 by a maintenance treatment with a single administration every two weeks during one year. Other Name: Il2
Placebo Comparator: placebo placebo	Drug: placebo subcutaneous injection with: Single administration at day 1, followed at day 15 by an induction treatment of 5 days, and at day 30 by a maintenance treatment with a single administration every two weeks during one year.

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:

Acute tolerance following a single administration at day 1 [day 1- day 15].
Induction of TREGS following a cure of 5 days repeated once daily administration [day 15 - day 30].
Maintenance of TREGS following repeated administration once every two weeks for one year [day 30 - day 360].

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 12 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion criteria :

Age [7-12] years;
- With a T1D diagnosis
- Treated with insulin for ≤ 3 months,
- With at least one auto-antibody among: anti-islet, 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
Non authorized concomitant treatment : immuno-modulators, cytotoxic drugs, drug modifying plasma glycemia
vaccination ≤ 4 weeks
other autoimmune disease
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

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

Contacts

Contact: David Klatzmann, MD, PhD

+33(0) 1 42 17 74 61

David.klatzmann@upmc.fr

Locations

France
Service d'Endocrinologie Pédiatrique	Not yet recruiting
Angers, France, 49033
Service d'Endocrinologie Pédiatrique	Not yet recruiting
Le Kremlin Bicetre, France, 94275
Service d'Endocrinologie Pédiatrique	Not yet recruiting
Lille, France, 59000

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

Investigators

Principal Investigator:

David Klatzmann, MD, PhD

APHP

More Information

No publications provided

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:	May 23, 2013
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

Therapeutic Uses
Pharmacologic Actions
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents

ClinicalTrials.gov processed this record on May 23, 2013

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