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Low-dose rhIL-2 in Patients With Recently-diagnosed Type 1 Diabetes (DIABIL-2)

This study is currently recruiting participants.
Verified September 2016 by Assistance Publique - Hôpitaux de Paris
Sponsor:
ClinicalTrials.gov Identifier:
NCT02411253
First Posted: April 8, 2015
Last Update Posted: November 9, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Iltoo Pharma
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris
  Purpose

Type 1diabetes (T1D) is caused by autoimmune destruction of the pancreatic islet ß-cells, leading to an absolute deficiency in insulin.

In health, regulatory T cells (Tregs) suppress immune responses against normal tissues, and likewise prevent autoimmune diseases. Tregs are insufficient in T1D.

The investigators previously showed that administration of low doses of IL-2 induces selective expansion and activation of Tregs in mice and humans.

The investigators hypothesize that Tregs expansion and activation with low doses of IL2 could block the ongoing autoimmune destruction of insulin producing cells in patients with recently diagnosed T1D.


Condition Intervention Phase
Type 1 Diabetes Drug: rhIL-2 Drug: Placebo Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: European Phase-IIb Clinical Trial Evaluating Efficacy of Low Dose rhIL-2 in Patients With Recently-diagnosed Type 1 Diabetes DIABIL-2

Resource links provided by NLM:


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

Primary Outcome Measures:
  • AUC (T0-T120) of serum C-peptide, determined after a mixed meal tolerance test at month 12, compared to baseline. [ Time Frame: Baseline, month12 ]

Secondary Outcome Measures:
  • Serum concentrations of C-peptide [ Time Frame: month 3, month 6, month 9, month 15 ]
  • AUC (T0-T120) of serum C-peptide after a mixed meal tolerance test after treatment discontinuation [ Time Frame: month 15 ]
  • Diabetic monitoring (insulin use) [ Time Frame: baseline, Day 1, Day 5, month 1, month 3, month 6, month 9, month 12, month 15, month 18, month 21. ]
  • HbA1c and IDAA1c score [ Time Frame: baseline, month 3, month 6, month 9, month 12, month 15 ]
  • Number of hypoglycaemic episodes (< 0.5 g/L on capillary sample) over 15 days before each visit. [ Time Frame: baseline, Day 1, Day 5, month 1, month 3, month 6, month 9, month 12, month 15, month 18, month 21 ]
  • Number of clinically significant symptomatic episodes of hypoglycaemia between each visit. [ Time Frame: baseline, Day 1, Day 5, month 1, month 3, month 6, month 9, month 12, month 15, month 18, month 21 ]
  • Change in Tregs (expressed as percentage of CD4 and absolute numbers) at day 5 compared to baseline. [ Time Frame: Baseline, Day 5. ]
  • Change in trough level of Tregs (%CD4+ and absolute numbers) at month 1, month 3, month 6, month 9, month 12, compared to baseline; and then month 15 and 24 after treatment discontinuation. [ Time Frame: Baseline, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 24 ]
  • Change in Foxp3 gene methylation [ Time Frame: Day 1, Day 5, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15 ]
  • Cytokines and chemokines assays at day 5, month 1, month 3, month 6, month 9, and month 12 compared to baseline and then month 15 and month 24 after treatment discontinuation. [ Time Frame: Baseline, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 24 ]
  • Transcriptome analysis. [ Time Frame: Baseline, Month 6, Month 12 ]
    Transcriptome analysis on whole PBMCs will allow analysis of changes in inflammation-related signatures, as already described in Saadoun et al. NEJM, 2011.

  • Genotyping at baseline [ Time Frame: baseline ]
    Genotyping will be used to assess genetic variation (polymorphisms) associated with T1D, such as those linked to IL2RA, PTPN22, CTLA-4...

  • Treg phenotype and functionality in adults and adolescents only including pStat5 analysis [ Time Frame: Day 1, Day 5, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15 ]
  • Clinical examination. [ Time Frame: Baseline Day 1, Day 5, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24 ]
  • Height/weight and pubertal stage especially for children and adolescents. [ Time Frame: Baseline, Month 12, Month 24 ]
    Based on Tanner staging (Tanner J. M. 1986).

  • Routine laboratory tests [ Time Frame: Baseline Day 1, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24 ]
    Biochemistry, Liver function

  • Haematology [ Time Frame: Baseline Day 1, Day 5, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24 ]
  • Detection of IL-2 auto-antibodies [ Time Frame: Day1, Month 6, Month 12 ]
  • T cells repertory [ Time Frame: Day 1, Day 5, Month 6, Month 12 ]
  • Intestinal microbiota. [ Time Frame: Baseline, Month 6, Month 12 ]
  • Adverse event. [ Time Frame: Baseline, Day 1, 2, 3, 4, 5, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24 ]
    Throughout the study.


Estimated Enrollment: 138
Study Start Date: June 2015
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: rhIL-2
  • 0.5 MIU/m²/day of IL2 with a maximum of 1MIU/day in a volume of 1 ml for children and adolescents,
  • 1MIU/day for adults.

Subcutaneous injection every day (5 days) then:

  • Regimen A injection every two weeks between D15 and D351,
  • Regimen B injections every week between D15 and D351
Drug: rhIL-2
Subcutaneous injections of IL2 according to regimen A Subcutaneous injections of IL2 according to regimen B
Placebo Comparator: Placebo

Placebo with a identical formulation and regimen of injections i.e. Subcutaneous injection every day (5 days) then:

  • Regimen A injection every two weeks between D15 and D351
  • Regimen B injections every week between D15 and D351
Drug: Placebo
Subcutaneous injections of Placebo according to regimen A Subcutaneous injections of Placebo according to regimen B

  Show Detailed Description

  Eligibility

Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   12 Years to 35 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria

  • Age 12-35 years old.
  • Male or female both using effective methods of contraception during treatment if sexually active.
  • Specifically; Females (if sexually active) with childbearing potential must use contraceptive methods that are considered as highly-effective (pearl index < 1). The following methods are acceptable: Oral , injectable, or implanted hormonal contraceptives (with the exception of oral minipills ie low-dose gestagens which are not acceptable (lynestrenol and norestisteron), Intrauterine device, Intrauterine system (for example, progestin-releasing toit),
  • beta HCG negative at inclusion;
  • With type-1 diabetes:
  • Newly diagnosed (ADA criteria, see annexe 19.6) at most two months between insulin initiation and anticipated start of experimental treatment.
  • Positive for one or more of the autoantibodies typically associated with T1D (anti-islet, -insulin, -GAD, -IA2, -ZnT8)
  • With a detectable peak C-peptide concentration during a standardised MMTT at Visit MMTT (≥0.2pmol/ml);
  • patients with a stable blood glucose level and seric glycaemia between 60 mg/dL and 250 mg/dL verified at MMTT visit
  • Absence of clinically significant abnormal laboratory values (out of range and associated with clinical symptoms or signs) in haematology, biochemistry, thyroid, liver and kidney function;
  • Normal cardiac function: no documented history of heart disease and absence of family history of sudden death, normal ECG especially QTc duration within normal value (<480ms);
  • Free, informed and written consent, signed by the patient and investigator before any Study examination. If the patient is a minor by child and both parents or child and the legal representative in case only one parent is alive. (Journal officiel des communautés européennes (1.5.2001)
  • NB: patient with history of thyroidism on treatment at the inclusion and with normal thyroid hormone values (TSH+T4) can be included.

Exclusion criteria

  • Children under the age of 12 years old cannot be included
  • Patient who, before inclusion, have been treated with other anti-diabetic medication than Insulin for more than 3 months consecutively
  • Chronic adrenal insufficiency known or fasting ACTH ≥2.5 ULN normal at inclusion after control;
  • Anti TPO present at inclusion and abnormal TSH and T4
  • Anti-transglutaminase positive at inclusion
  • Hypersensitivity to the active substance or to any of the excipients
  • Any major health problem including: any major auto-immune/auto-inflammatory disease (other than type 1 diabetes) present at inclusion, any significant respiratory disease (such as moderate or severe COPD or asthma) requiring the chronic use of corticosteroids (whatever route of administration) and serious digestive malfunctions.
  • Patient with existing malignancy or history of malignancy
  • Major psychosocial instability with expected lack of compliance with insulin treatment, psychiatric pathology of patient or parents, or major problems of family dynamics;
  • Signs of active infection;
  • Any patient with obesity defined as BMI ≥ 35
  • Existence of a serious malfunction of a vital organ;
  • History of organ allograft;
  • Use of treatments not allowed in the Study (see Section 8.4.2);
  • Vaccination with alive attenuated virus within 4 weeks of the first injection of the induction period and during the whole maintenance period
  • Pregnant female (confirmed by laboratory testing) or lactating
  • Participation in another clinical trial in the previous 3 months;
  • Lack of affiliation to a social security scheme (as a beneficiary or assignee).
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02411253


Contacts
Contact: David Klatzmann, MD, Ph.D. +33.1.42.17.74.61 david.klatzmann@upmc.fr

Locations
Belgium
Pediatric Department, Centre Hospitalier Régional de la Citadelle Not yet recruiting
Liège, Province de Liège, Belgium, 4000
Contact: Ramona C NICOLESCU, Dr    0032 42 25 71 02    rcnicolescu@yahoo.com   
France
Centre d'Investigations Cliniques, CHU-HOPITAL HAUTEPIERRE Active, not recruiting
Strasbourg, Alsace, France, 67098
Centre d'Investigations Cliniques, HÔPITAL CIVIL Active, not recruiting
Strasbourg, Alsace, France, 67098
Service de pédiatrie 1CHU de HAUTEPIERRE Recruiting
Strasbourg, Alsace, France, 67098
Contact: Marie MANSILLA       marie.mansilla@chru-strasbourg.fr   
Structure d'Endocrinologie-Diabète-Nutrition et Addictologie HOPITAUX UNIVERSITAIRES NHC Recruiting
Strasbourg, Alsace, France, BP421 - 67091
Contact: Laurence KESSLER, Pr       laurence.kessler@chru-strasbourg.fr   
Endocrinologie et diabétologie pédiatrique, Hôpital des Enfants - CHU-Bordeaux Withdrawn
Bordeaux, Aquitaine, France, 33076 Bordeaux Cedex
Service d'endocrinologie, diabétologie, maladies métaboliques, et nutrition, CHU de Bordeaux, Hôpital Haut Levêque Recruiting
Pessac, Aquitaine, France, 33604
Contact: Vincent RIGALLEAU, Pr.    06 63 24 45 51    vincent.rigalleau@chu-bordeaux.fr   
Service d' Endocrinologie HOPITAL CAVALE BLANCHE Recruiting
Brest, Brittany, France, 29609
Contact: Emmanuel SONNET, Pr    02 98 34 71 19    emmanuel.sonnet@chu-brest.fr   
Service de Pédiatrie, HOPITAL MORVAN Recruiting
Brest, Brittany, France, 29609
Contact: Chantal METZ, MD    00 33 2 29 02 00 04    chantal.metz@chu-brest.fr   
Service de Pédiatrie CHRU DE NANTES Recruiting
Nantes, Brittany, France, 44093
Contact: Sabine BARON, Pr       sabine.baron@chu-nantes.fr   
Contact: celine ROBIN, CRC    02 40 08 78 04    celine.robin@chu-nantes.fr   
Service d' Endocrinologie Diabétologie CHRU DE RENNES Not yet recruiting
Rennes, Brittany, France, 35033
Contact: Marc De Kerdanet, Pr    00 33 2 99 26 71 36    marc.de.kerdanet@chu-rennes.fr   
Médecine pédiatrique, CHU Jean Minjoz Recruiting
Besançon, Franche-Compté, France, 59037
Contact: Anne-Marie Bertrand, Dr.    03 81 21 81 34    bertrand.anne-marie@wanadoo.fr   
Service Diabétologie -Endocrinologie, CHU Jean Minjoz Recruiting
Besançon, Franche-Comté, France, 59037
Contact: Sophie Borot, Dr.    06 89 16 22 46    sophie.borot@gmail.com   
Service MME, ENDOCRINOLOGIE, GHU CAREMEAU Recruiting
Nimes Cedex 9, Gard, France, 30029
Contact: Valeria COSMA, Pr       valeria.COSMA@chu-nimes.fr   
CIC Paris-Est (Adultes), Hôpitaux Universitaires Pitié-Salpêtrière, Charles Foix Active, not recruiting
Paris, Ile de france, France, 75013
CIC pédiatrique Hôpital Necker Enfants Malades Active, not recruiting
Paris, Ile De france, France, 75015
Endocrinologie gynécologie diabétologie pédiatriques, Hôpital Universitaire Necker Enfants Malades. Recruiting
Paris, Ile De France, France, 75015
Contact: Michel Polak, Pr    +33 (0)1 44 49 48 02    michel.polak@nck.aphp.fr   
CIC Pédiatrique, Hôpital d'enfants Robert Debré Active, not recruiting
Paris, Ile de France, France, 75019
Institut E3M, Hôpital Pitié-Salpêtrière Recruiting
Paris, Ile-de France, France, 75013
Contact: Agnés Hartemann, Pr.    01 42 17 81 18 ext 80 70    agnes.hartemann@psl.aphp.fr   
Service d'Endocrinologie Pédiatrique, Hôpital d'enfants Robert Debré Recruiting
Paris, Ile-de France, France, 75019
Contact: Jean-Claude CAREL, Pr    01 40 03 53 03    jean-claude.carel@inserm.fr   
Service de Diabétologie Endocrinologie Hôpital LARIBOISIERE Not yet recruiting
Paris, Ile-de-France, France, 75010
Contact: Jean-François Gautier, Pr       jean-francois.gautier@aphp.fr   
Service Pédiatrie - Pôle femmes enfants, CHU de Nîmes, Hôpital Universitaire Carémeau Recruiting
Nïmes, Languedoc-Roussillon, France, 30029 Cédex 9
Contact: Tu Anh TRAN, Pr.    04 66 68 32 84 ext 32 85    tu.anh.tran@chu-nimes.fr   
Service Pédiatrie - Gastro-entérologie, Hépatologie, Nutrition, Diabétologie, Hôpital des Enfants Pôle Enfants Not yet recruiting
Toulouse, Midi Pyrénnées, France, 31059 Toulouse cedex 9
Contact: Claire LE TALLEC, Dr    05 34 55 85 64    letallec.c@chu-toulouse.fr   
CHRU de Lille, Hôpital Claude Huriez Service d'endocrinologie Recruiting
Lille, Nord-Pas-de-Calais, France, 59037
Contact: Pierre FONTAINE    03 20 44 45 13    pierre.fontaine@chru-lille.fr   
Service d'endocrinologie-diabétologie gynécologie pédiatriques, CHRU de Lille, Hôpital Jeanne de Flandre, Recruiting
Lille, Nord-Pas-de-Calais, France, 59037
Contact: Jacques WEILL, Pr.    03 20 44 46 95    Jacques.WEILL@CHRU-LILLE.FR   
Service d' Endocrinologie, maladies métaboliques HOPITAL NORD Not yet recruiting
Marseille, Paca, France, 13015
Contact: Anne DUTOUR, Pr       AnneEveSophie.MEYER@ap-hm.fr   
Service de Nutrition - Maladies Métaboliques - Endocrinologie HOPITAL DE LA CONCEPTION Not yet recruiting
Marseille, Paca, France, 13385
Contact: René VALERO, Pr       rene.valero@ap-hm.fr   
Contact: Catherine ZEVACO, Pr       Catherine.ZEVACO@ap-hm.fr   
Hopital G&R Laënnec , Endocrinologie, Maladies Métaboliques et Nutrition Recruiting
Saint Herblain, Pays de la Loire, France, 44093 NANTES Cedex 1
Contact: Lucy Chaillous, Pr       lucy.chaillous@chu-nantes.fr   
Unité d'Endocrinologie et Diabétologie Pédiatriques, CHU de Marseille, Hôpital La Timone Enfants Recruiting
Marseille, Provence-Alpes-Côte-d'Azur, France, 13385 Marseille Cedex 5
Contact: Rachel Reynaud, Pr.    04 91 38 80 40 ext 67 30    Rachel.REYNAUD@ap-hm.fr   
Endocrinologie-Diabétologie-Maladies de la nutrition, Centre Hospitalier Lyon-Sud Recruiting
Lyon, Rhones-Alpes, France, 69495
Contact: Charles THIVOLET, Pr.    04 78 86 14 87    charles.thivolet@chu-lyon.fr   
Service d'Endocrinologie pédiatrique - HFME Not yet recruiting
Lyon-bron, France, 69677
Contact: Delphine Bernoux, Pr    00 33 4 72 35 79 99    delphine.bernoux@chu-lyon.fr   
Germany
Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg Not yet recruiting
Freiburg, Baden-Württemberg, Germany, 79106
Contact: Jochen SEUFERT, Pr    Tel. +49 761 270 34200    jochen.seufert@uniklinik-freiburg.de   
Division of Endocrinology, Diabetology and Metabolic Diseases, University Hospital of Freiburg, Department for children and adolescents Not yet recruiting
Freiburg, Baden-Württemberg, Germany, 79106
Contact: Karl O SCHWAB, Pr    +49 761 270 44140    karl.otfried.schwab@uniklinik-freiburg.de   
Institute of Diabetes Research, Helmholtz Zentrum München Recruiting
München, Bayern, Germany, D 80804
Contact: Annette G ZIEGLER, Pr    00 49 089 3187 2896    anette-g.ziegler@helmholtz-muenchen.de   
Institute of Diabetes Research, Helmholtz Zentrum München Not yet recruiting
München, Bayern, Germany, D 80804
Contact: Katharina Warncke, Pr    00 49 089 3187 2896    Katharina.Warncke@lrz.tu-muenchen.de   
Netherlands
Center for Pediatric and Adolescent Diabetes Care and Research Not yet recruiting
Rotterdam, Randstad Holland, Netherlands, 3011 TG Rotterdam
Contact: Henk-Jan AANSTOOT, Dr.    +31-10-280-7277 ext 9872    h.j.aanstoot@diabeter.nl   
Sweden
Dept. of Clinical Sciences Lund University, Skåne University Hospital. Not yet recruiting
Malmö, Öresund Region, Sweden, 205 02 Malmö
Contact: Corrado M. CILIO, Pr.    +46-70 43 30338 ext +46-40-391127    corrado.cilio@med.lu.se   
Switzerland
Endocrinology and Diabetes department, University Hospital of Basel Not yet recruiting
Basel, Bâle-Ville, Switzerland, 4031 Basel
Contact: Marc Donath, Pr.       mdonath@uhbs.ch   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Iltoo Pharma
Investigators
Study Director: David Klatzmann, MD, Ph.D. Assistance Publique - Hôpitaux de Paris
  More Information

Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT02411253     History of Changes
Other Study ID Numbers: P121001
First Submitted: March 23, 2015
First Posted: April 8, 2015
Last Update Posted: November 9, 2016
Last Verified: September 2016

Keywords provided by Assistance Publique - Hôpitaux de Paris:
IL2
Interleukin 2
IL-2
Auto-immune disease
Insulin
Diabetes
Regulatory T cells
Treg
Immunoregulation
Immune tolerance
Immunotherapy

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases