Servizio Comunitario di Informazione in materia di Ricerca e Sviluppo - CORDIS

Periodic Report Summary 2 - 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 will be a double-blind, randomised, placebo-controlled, stratified on age, parallel-group, multicentre European phase-IIb clinical trial.

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:
At the end of Period 2, we have identified and selected additional vendors:
-An audit Clinical Research Organization (APROVA) to perform the audit of the vendors and to check that adequate procedures have been set up across the study to ensure good quality and respect of ICH during the progress of the study.
-A Pharmacovigilance Clinical Research Organization (Symbec-Orion) to ensure international regulatory-bound declarations on safety.
-A flying nurse company (UPARC) to ensure safe clinical treatment administration at patient’s home.

A central laboratory (Eurofins Medinet) was entrusted additional activity of shipment to the centres of the pharmacy material.
We have obtained regulatory authorizations from Belgium, France, Netherlands and Germany to conduct DIABIL-2 trial. Partner 4 UHB is in charge of the submission to the Swiss Competent Authority and Swiss Ethic Committee. The documentation is now ready for submission.
We launched and achieved a Paediatric Investigational Plan procedure in parallel of the CTA submissions to define how children and adolescents should be recruited within DIABIL-2 and how these populations should be assessed within the overall clinical development.

Drug formulation and manufacturing activities continued actively. Three cGMP clinical batches were manufactured, labelled, packaged according to study characteristics, and distributed to centers that have been initiated.
Central Laboratory validated the dosing method for C-peptide. Central Laboratory prepared the sampling kits and organized sample and pharmacy material transport logistics.
The identification of the clinical trial centres continued and 25 sites in total (17 sites in France and 8 sites in other countries) have been finally selected to achieve the study within timelines.

Tasks described in WP3 began in June 2015.
-The first meeting of the DSMB took place on March 2015 before the beginning of the inclusion.
-Three French centres are allowed to recruit patients since the opening visit took place.
-12 patients have already been recruited in 3 French hospitals
-There were 5 monitoring visits following these inclusions.
-The two centralized laboratories began to receive sample from the investigator sites.

APHP has coordinated WP4 very actively during period 2 in order to standardize the procedures to process, analyse or store samples in all the centres involved in the study. APHP made personal contacts with the local immunologists in each centre to evaluate the local feasibility of the experiments. Analysis related to principal lymphocyte subsets and to Tregs are performed in situ by the centres. For genotyping, transcriptome, immunophenotyping analysis and TCR deep sequencing, biobanks are being collected and stored for centralized analysis.
An intensive preparatory work was dedicated to organize the logistics and define the specific needs including material necessary to sample patients, reagents and consumables needed for cytometry analysis and biobanking, with the aim to facilitate the work of the local labs (ex. color codes for each steps/tubes). APHP produced detailed standard operating procedures (SOPs) accordingly, ordered and provided the materials requested to each centre to ensure the harmonization of the experimental processes.
Because of the delay in the launch of DIABIL-2 trial, the ancillary analysis initially planned from month 13 to 48 in WP4 will be re-scheduled appropriately according to the request for an extension of 30 months of the Grant Agreement which will be submitted shortly to the EU Commission.
In-person pre-study visits have been organized to review the WP4 procedures with the immunology lab staff in each centre. APHP also contributed to bring technical support in cytometry.

At the end of period 2 WP5 has disseminated DIABIL-2 project to several scientific congresses.

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.

We will also analyse in depth the effects of IL-2 administration on the immune system, such as to discover biomarkers that could be correlated with clinical outcomes to provide a safe, specific and personalized treatment for type 1 diabetes.

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