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Translational approaches to disease modifying therapy of type 1 diabetes: an innovative approach towards understanding and arresting type 1 diabetes – Sofia ref.: 115797

Periodic Reporting for period 5 - INNODIA (Translational approaches to disease modifying therapy of type 1 diabetes: an innovative approach towards understanding and arresting type 1 diabetes – Sofia ref.: 115797)

Reporting period: 2019-11-01 to 2020-10-31

The overall objective of INNODIA is to advance in a decisive way how we predict, stage, evaluate and prevent type 1 diabetes (T1D). We are achieving this by creating novel tools, such as biomarkers, disease models and clinical trial paradigms. These tools allow us to understand at the cellular and molecular level distinctive paths of ontogeny and progression in this heterogeneous disease, thus impacting on the future management of T1D patients and at risk individuals.
Year 5 was crucial for INNODIA, with several key milestones reached; the major one being the start of the clinical trial, MELD-ATG, evaluating efficacy and safety of different doses of anti-thymocyte globulin (ATG) in new onset T1D individuals. Despite the COVID pandemic and lock-downs in many countries, our work progressed, with the first multi-omic biomarker analysis being finalized, recruitment of people with newly diagnosed T1D ongoing and the first clinical trial started. Publications of basic research continued and interaction was even more intense than in previous years, albeit in a virtual way. Perhaps the most important reflection of the success of the project is the continuing extension of our consortium, with 6 new partners joining and the network of clinical satellites in many European countries extending. Also the many interactions with external entities, including regulators (EMA), is a reflection of our success.

After major efforts at the start of INNODIA focusing on standardization of sampling protocols and ethical approvals, all clinical partners (WP 1) are now recruiting at full speed, resulting in an exponential increase of recruitment to a total of 4021 participants. Our clinical network is expanding, with new partners joined INNODIA and satellites of established INNODIA partners now present in 6 countries. All clinical centers are accredited and have been trained for use of the INNODIA eCRF.

As a cornerstone for the working of INNODIA, we have conceived the modular interrogation platforms for analysis of cellular and molecular features of T1D for beta-cell and immune cells, proteomes, lipidomes and metabolomes (WP2). Six Immune Hubs or Sub-Hubs are installed and active. We completed successfully an integrated multi-omics natural history study on samples of newly diagnosed (ND) participants. Work has been initiated on the ‘First 100 unaffected family members’. In addition, first distribution of samples for analysis of specific biomarkers (discovery research, collaboration WP3) has happened. Also, WP4 has elaborated approaches for GDPR-compliant analysis of the results of WP2 analyses embedded with clinical WP1 parameters in the INNODIA database by partners.

WP3 aims to gain better insight in the way beta-cells are destroyed in T1D. Development of novel biomarkers in particular is being pursued. Our collaborative research, focusing on the interplay between beta-cell and immune system has progressed in period 5. Despite being forced to homework for many researchers due to COVID, many virtual interactions took place, leading to fortification of existing collaborations and an amazing number of new INNODIA WP3 publications, mostly the result of collaborations between 2 or more INNODIA partners. We used the virtual annual meeting of EASD 2020 as the launching platform for many INNODIA presentations, with 14 oral and poster presentations by INNODIA researchers. Of importance, novel biomarkers issuing from WP3 work have now been incorporated in the multi-omics analysis performed on the ‘first ND 100’ described under WP2.

WP4 is devoted to the establishment of an integrative systems biology platform and in silico modelling for T1D. A crucial role for WP4 in period 5 has been the work in the biomarker identification effort on ‘the first 100’, preparing INNODIA for the first integrative analysis effort of clinical with multi-omics data and adaptation of the whole system for clinical trials. In this regard, WP4 has been instrumental in expanding the eCRF system to comply with regulatory requirements to be used in intervention clinical trials,

As INNODIA moved to the next level (clinical trial initiation and execution), the role of WP5 grows. We have progressed more rapidly than foreseen and are already running the first trial. To streamline our efforts, we have taken several steps: 1) Accreditation of clinical centers. All centers have been accredited in 2017/2018 and are being followed up for quality in recruitment. New centers were accredited in 2020, and re-accreditation is ongoing; 2) Establishment of a Masterprotocol on the backbone of which clinical trials run and that allows adaptive and novel trial design. This has been finalized and obtained positive advice in February 2020; 3) Establishment of a Clinical Trial Prioritization Committee (ICTPC) that handles prioritization of offered trials to INNODIA; 4) Establishment of the Clinical Coordination Centre to oversee the activities related to the clinical trials running in INNODIA. In 2020, the first INNODIA trial MELD-ATG (KU Leuven as sponsor, UCAM as coordinator and Sanofi providing study drug) has been initiated in September 2020 with first participant recruited on 15 December 2020.

WP6 groups all the work of managing and running INNODIA. As INNODIA grows in partners, in recruitment and in scientific output, we are stepping up the management of INNODIA. Next to overall project management, specific attention has been dedicated in 2020 to communication on the aspects related to the COVID-19 pandemic and increasing visibility of INNODIA network. Moreover, expansion (in budget, partners and projects), longterm sustainability and dealing with Brexit were prioritized. We stepped up communication to partners and increased the use of external communication channels to promote our work.
All activities have progressed well, with all deliverables reached. COVID affected our work, but through alternative strategies, the network is growing and delivering. We are now ready for important next steps: The completion of the ‘first 100’ integrated systems biology analysis and further dissemination and exploitation of the results, metabolic and multi-omic data gathered in our natural history study and present in our central INNODIA data warehouse; the progression of our first clinical trial (MELD-ATG) on the backbone of our innovative Masterprotocol and the realization of our view for the future. This will include exploring of new collaboration opportunities outside of the consortium, seeking for strategic partnership for future expansion of the network with new partners, all in close harmony with our PAC, representing people living with T1D and their families.
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