Work Packages

Lead: FCRB

The challenging goal of this WP is to characterise by state-of-the-art high-throughput technologies the genomic, epigenomic, transcriptomic, microRNA and metabolomic landscapes together with circulating inflammatory mediators and extracellular vesicles profiles associated with outcome of decompensation of cirrhosis by re-analysing standardized biobank samples from 2,200 patients (40% men; 60% women). The main objectives of this WP are:

• To set the legal and ethical terms for the efficient transfer of biological materials to each of the DECISION partners involved in sample processing
• To discover genetic and epigenetic (methylation) signatures associated with outcome of decompensation of cirrhosis as well as response to treatment
• To phenotype blood immune cells by whole-blood transcriptomics, interpreted in light of single-cell transcriptomics in a subgroup of patients, in relation with outcome of decompensation of cirrhosis as well as response to treatment
• To investigate serum microRNA profiles associated with outcome of decompensation of cirrhosis as well as response to treatment
• To investigate serum metabolites associated with outcome of decompensation of cirrhosis as well as response to treatment
• To analyse plasma protein and lipid inflammatory (cytokines and eicosanoids) signatures associated with outcome of decompensation of cirrhosis as well as response to treatment
• To capture plasma extracellular vesicle diversity, as markers of tissue damage and cell injury, associated with outcome of decompensation of cirrhosis as well as response to treatment

Lead: EF CLIF

The DECISION project will integrate detailed clinical data from 2,200 patients with more than 8,600 time points, from 3 prospective cohorts (CANONIC, PREDICT and ACLARA), with results of multi-omics analysis of available biobank samples performed in WP1. Data management, integration and analysis are therefore tasks of strategic importance. WP2 will provide a professional data management hub with the following specific objectives:

• To harmonize and merge available clinical data-sets from three large international prospective cohorts (CANONIC, PREDICT and ACLARA) to be analysed by WP3
• To combine this clinical dataset with the results of multi-omics analysis performed in WP1 in a joint data
• To prepare and make the integrated secured central database available for systems approaches described in WP3

Lead: NBM-FSM

Heterogeneity in disease and drug response poses a major challenge in personalized medicine. It is necessary in order to decipher the optimal combinatorial therapy, to better understand the disease at a systems level. Therefore, in WP3 we will first combine all existing and newly acquired data (WP1-2) into a Systems Medicine framework. Second, we will use this framework during selection of optimal prognostic and response tests and new combinatorial therapies. WP3 consists of four objectives:

• Identify the omic-derived information that extends clinical information and, as a result, develop a system-based description of decompensation of cirrhosis leading to ACLF and death, through multi-omics data integration analysis
• Understand patient heterogeneity
• Identify candidate prognostic tests and tests for response to combinatorial therapy
• Identify candidate optimal combinatorial therapies for patients with decompensation of cirrhosis to prevent mortality

Lead: GUF

The main objective of WP4 is to test the identified combinatorial therapies (WP3) pre-clinically in different models of decompensation of cirrhosis, prior to use in the clinical trial (WP5). Different rat models of acute decompensation of cirrhosis leading to ACLF have been proposed by the scientific community, but none of those models fully recapitulates the heterogeneity of the human disease. The second key objective of WP4 is, therefore, to refine existing animal (rat) models of decompensation of cirrhosis leading to ACLF. Moreover, two biomarkers will be developed: one predicting the treatment outcome of patients with acute decompensation of cirrhosis (prognostic test) and one serving as companion biomarkers to monitor treatment response for better stratification of treatment (test for response to combinatorial therapy). To achieve this, WP4 will pursue the following specific objectives:

• To refine available and develop new models of acute decompensation of cirrhosis leading to ACLF, stratifying for gender and age
• To validate in pre-clinical studies the combinatorial therapies identified in silico
• To design one assay serving as biomarker of outcome of patients with acute decompensation of cirrhosis (prognostic test) and one serving as companion biomarkers to select patients responding to identified combinatorial therapy (test for response to combinatorial therapy)

Lead: UNIBO

WP5 will conduct a clinical study in patients hospitalized for AD of cirrhosis in order to evaluate a novel combinatorial therapy as well as novel tests developed for predicting which patients with decompensated cirrhosis have a poor prognosis (prognostic test) and which patients are more likely to benefit from the selected combinatorial therapy (test for response).

To achieve this, WP5 will pursue the following specific objectives:

• To conduct a proof-of-concept, phase II, multi-centre, open-label, randomized clinical trial (COMBAT trial) aiming to determine efficacy and safety of the combinatorial therapy selected according to the results of WP 1-4, having the highest chance of improving clinical outcome
• To evaluate the novel tests developed in WP 1-4 by using the biological samples collected from patients enrolled in the COMBAT trial and in a parallel observational prospective study

Lead: UB

DECISION is a multidisciplinary consortium including stakeholders of patients, academia, and industry and includes a broad and complex spectrum of methods and tasks. Therefore, several important ethical, legal, and socio-economic issues arise in this project, which will be addressed by this work package and can be summarized in the following main objectives of this WP:

• To develop and implement ethical and legal issues linked to the collection, analysis, transfer, and use of human and animal data and samples
• To develop and implement ethical and societal issues related to patients with decompensated cirrhosis
• To determine the cost-effectiveness of these new strategies based on the WP5 clinical trial and disease modelling with the ultimate aim of decreasing the social and healthcare burden of decompensation of cirrhosis

Lead: concentris

The objective of WP7 is the development of a communication strategy and dissemination plan aimed at potential stakeholders of the EU member states, namely patients, health care professionals, pharma and biotech companies, healthcare insurers, international professional networks, and the general public. The strategy will include the following specific aims:

• To make DECISION known to all stakeholders
• To disseminate the results to the scientific and medical community, healthcare, pharmaceutical and policy sectors, and the general public and foster interaction and exchange with patient organizations
• To exploit and valorise the intellectual property rights (IPR) generated within WP1-5 and safeguard the sustainability of DECISION
• To incorporate new knowledge on tests and combinatorial therapies into (inter)national clinical guidelines and inform patient communities of the benefits for the patients
• To prepare the next generation of scientists in the field of liver research

Lead beneficiary: EF CLIF

Effective project management is a central element of successful research. This is because large research projects entail a lot of administrative work. The following objectives will be actively pursued by WP8:

• To make DECISION achieve its objectives and to deliver in time, budget and quality its milestones and deliverables
• To help the consortium abide by the regulations and contractual obligations according to the grant agreement, its annexes and the consortium agreement
• To look after the project`s finances and to report them properly to the EC
• To establish a communication infrastructure which enables the partners to communicate efficiently and to stay connected for the run-time of the project
• To preserve the rights of the partners regarding intellectual property and to act as a mediator in case of disputes

Lead: EF CLIF

The objective of WP9 is to ensure compliance with all ethics requirements for research and clinical trials of the European Union.