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Ultra-low dose of IL-2 for the treatment of recently diagnosed type 1 diabetes

Periodic Report Summary 4 - DIABIL-2 (Ultra-low dose of IL-2 for the treatment of recently diagnosed type 1 diabetes)

Project Context and Objectives:
DIABIL-2 project aims at testing the efficacy of ultra-low dose Interleukin 2 for preventing or delaying Type 1 Diabetes disease progression in newly diagnosed patients. It is a double-blind, randomised, placebo-controlled, stratified on age, parallel-group, multicentre European phase-IIb clinical trial. DIABIL-2 is organized in 5 work packages.
Management and coordination of the consortium (WP1)
Its general objective is to ensure an effective and efficient coordination among DIABIL-2 consortium, its independent Advisory Board and with the European Commission.
Clinical trial implementation (WP2)
Its general objectives are to develop all ICH6 Essential Documents, to get approval from regulatory bodies and Institutional Review Boards (IRBs), and to organize Clinical Trial Treatment Units (CTTUs) preparation, clinical data collection, sample collection, banking and assays, in a Good Clinical Practice (GCP) and Good Clinical Laboratory Practice (GCLP) compliant phase-II Randomized Clinical Trial.
Clinical trial conduct (WP3)
Its general objective is to carry out the clinical trial in compliance with GCPs/ GCLPs rules, in order to demonstrate the efficacy and safety of ultra-low-dose IL-2 in patients with recently diagnosed Type-1 Diabetes (T1D).
Deep phenotyping (WP4)
Its general objectives is to gain insights into the molecular and cellular impact of ultra-low-dose IL-2 treatment (versus a placebo control) in newly diagnosed T1D patients, such as to discover biomarkers of safety and efficacy.
Dissemination and exploitation plans (WP5)
Its general objective is to organize a well targeted dissemination effort and early liaison with key stakeholders, including patients’ organisations and the pharmaceutical industry, in order to achieve full exploitation of our approach.

Project Results:
Period 1 : It was dedicated to prepare and finalise the main study documentation. CRO for regulatory submission, pharmacovigilance and monitoring were selected. Clinical centres in France, Germany, Netherlands, Belgium, Sweden and Switzerland were selected. IL2 drug substance was produced and validated for EU release.
Period 2 : In WP2, additional vendors were selected and a central laboratory was entrusted additional activity of shipment to the centres of the pharmacy material. Regulatory authorization from Belgium, France, Netherlands and Germany were obtained. A Paediatric Investigational Plan (PIP) procedure was initiated and achieved with the Paediatric Committee of the European Medicinal Agency to define how children and adolescents should be recruited and assessed within the overall clinical development. Methodology for recruitment of children within DIABIL-2 was defined as well as for further clinical studies up to market approval. WP3 began in June 2015 with 1st DSMB meeting, first centres allowed to recruit patients, 12 patients recruited in France and 5 monitoring visits. Period 2 for WP4 was dedicated to the organisation of samples collection, logistics and implementation of a standardized procedure to perform staining of Tregs by flow cytometry on fresh whole blood on-site. Partner APHP has coordinated the procedure that is now fully implemented in 15 immunology labs involved in the trial.
Period 3 : Regulatory authorizations have been obtained in Germany, Sweden, France and Netherlands for the recruitment of 6 to 11 years old patients. Approval was also obtained for 12-35 years old patients in Switzerland4 new sites in Germany, Sweden and Netherlands and 21 new sites in France have been initiated. In WP3, substantial amendments have been authorized by all the competent authorities; 25 centres have been activated during period 3 (23 in France; 1 in Germany; 1 in The Netherlands); 52 patients have been included and treated; 2 DSMB meeting have been held.
In WP4, a thorough work has been carried out to establish standardized experimental procedures for samples processing required to produce quality-controlled data for deep phenotyping. Bioinformatic workflows for single- and multi-scale omics data analysis have been established. Partner LUMC joined DIABIL-2 consortium, in charge of performing complementary immune analyses, notably the measurement of antigen specific responses.
Period 4
At the end of Period 4, the followings achievements can be noted:
For WP2:
• regulatory authorizations have been obtained for the recruitment of 6 to 11 years old patients
• 3 new Belgium centers have been added to the study protocol and a major amendment changing from 3 to 2 ages strata. The necessary regulatory documentation was updated and submitted
• new IMP documentation, IB and IMPD, were updated for submission to the authorities.
• Transport logistics of biological samples taken from patients continued through our Central Laboratory.
• 4 new sites in Belgium, France and Switzerland have been activated after full documentation has been set up and contract has been signed
• the flying nurse services has been set up in Belgium
For WP3:
• between April 2017 and September 2018, 49 patients have been included
• 3 DSMB meetings have been held
• 17 Steering Committee (SC) meetings have been held
• the two centralized laboratories received and analyses sample from the investigator sites
For WP4:
• the methodologies for deep phenotyping, TCR repertoire and transcriptome data production and analysis have been successfully set-up and implemented in WP4
• two articles have been published on the implementation of deep immunophenotyping: (Pitoiset F et al. A standardized flow cytometry procedure for the monitoring of regulatory T cells in clinical trials. Cytometry B Clin Cytom. 2018 Jan 6; Pitoiset F et al. Deep phenotyping of immune cell populations by optimized and standardized flow cytometry analyses. Cytometry A. 2018 Aug;93(8):793-802.
Potential Impact:
DIABIL-2 clinical trial is designed to demonstrate efficacy of low dose IL-2 as a treatment aimed at stopping autoimmune pancreatic beta cell destruction in patients with recently diagnosed T1D. Its success would be a major breakthrough for the treatment of T1D. If so, insulin intake in adult and children T1D patients will be drastically reduced and even stopped leading ultimately to decreased risk of long-term complications generally associated with incorrect metabolic control. This would open the door to late clinical development in the aim of obtaining market approval in this indication.
Such results should lead to major changes in T1D management. Beyond medical considerations, this will have significant social impact. Quality of life of children (and their parents), for whom the disease is often more sudden and aggressive, will be alleviated.
The in depth analysis of the effects of IL-2 administration on the immune system, should help to discover biomarkers that could be correlated with clinical outcomes to provide a safe, specific and personalized treatment for type 1 diabetes. Beyond, it should also provide some insights on the immune imbalance of T1D patients.
List of Websites:

Project information

Grant agreement ID: 305380


Closed project

  • Start date

    1 October 2012

  • End date

    31 March 2019

Funded under:


  • Overall budget:

    € 7 603 061,98

  • EU contribution

    € 5 900 000

Coordinated by: