October 24, 2022 The 4th DECISION General Assembly brings together members of the consortium to review project progress and design the COMBAT trial protocol As the DECISION project reaches a critical point, members of the consortium meet in Madrid, Spain, to discuss progress and results from multiomics analyses performed in a large cohort of patients with acute decompensation of cirrhosis and acute-on-chronic liver failure to decide what are the next actions towards testing the best combinatorial therapy possible for these patients

BARCELONA—The 4th DECISION General Assembly meeting took place in Madrid, Spain, from 19 to 21 October 2022. This meeting brought together partners from 21 institutions and industry in 10 countries to review progress and discuss further about most recent results leading to biomarker candidates that can better predict prognosis of acute decompensation of cirrhosis. With the aim to develop novel therapeutic approaches to treat cirrhotic patients that develop acute-on-chronic liver failure (ACLF), the COMBAT trial within DECISION will evaluate safety of most promising drug combinations identified through data-driven approaches and validated in pre-clinical studies using animal models of liver disease.

Day 1 kicked off to a good start with a workshop on scientific paper writing. Twenty-six participants worked on the drafting of seven papers. Later in the afternoon, the Coordinator of DECISION Pierre-Emmanuel Rautou, Inserm–Université Paris Diderot, France and Principal Investigator at EF CLIF, Spain, chaired the opening meeting. The keynote lecture by Agustín Albillos, Hospital Universitario Ramón y Cajal, Spain, on the effects of low molecular weigth heparin on cirrhosis marked the start of the 4th DECISION General Assembly.

On day 2, scientific articles in preparation and discussed on the previous day, were presented by the researchers involved in work packages 1–3 to all members of the consortium. Richard Moreau, Inserm–Université Paris Diderot, France, and Honorary Director of the Grifols Chair and Principal Investigator at EF CLIF, Spain, presented the correlations of clinical blood counts and RNA-sequencing-inferred blood counts and showed differences across clusters revealed by gene set enrichment analysis using blood transcription modules. He concluded his presentation summarizing ongoing tasks and those to be addressed in the following months including the development of a gene score predicting outcome at presentation of acute decompensation of cirrhosis. To achieve this, machine learning algorhithms will be employed. Next, Santha Valainathan, Inserm–Université Paris Diderot, France, presented plasma large extracellular vesicles profiling results in patients with stable and unstable decompensation of cirrhosis and pre-ACLF from the PREDICT and MICRO-SPY cohorts. To validate the results obtained by computational methods, PREDICT and ACLARA cohorts were considered for comparison. Valainathan concluded that heat-denatured extracellular vessicles profiles provide added value to predict mortality in patients with acute decompensation of cirrhosis. Sara Palomino, Navarrabiomed, Spain, presented the progress made on systems medicine computer models for stratification of patients with complex diseases applied to ACLF. She showed data-driven methods as a reliable approach to identify patient phenotypes at the early stage of disease prospectively within the CANONIC, PREDICT and ACLARA cohorts. Next, Cristina López-Vicario, Fundació Clínic per a la Recerca Biomèdica, Spain, presented the results from extensive characterization of new biomarkers using omics approaches. Frank Uschner, University Clinic Münster, Germany, presented new animal models for ACLF and for non-acoholic steatohepatitis (NASH) exposing rats to different dietary regimes or inducing agents.

In the afternoon, work package leaders presented an update on completed and ongoing actions, deliverables and milestones. For and on behalf of partners in work package 5, Paolo Caraceni, University of Padua, Italy, presented the COMBAT trial protocol, a proof-of-concept/phase IIa prospective, randomized controlled clinical trial. The COMBAT trial will measure prognostic biomarkers of acute decompensation of cirrhosis based on the data generated from workpackages 1–3. The optimal combinatorial drug treatment is based on already existing therapies for patients with acute decompensation of cirrhosis and was agreed upon by members of the Steering Committee. Time for submissions, adherence for good clinical practice, need to respect the timeline of the project and financial constraints should be considered for the success of the trial as noted by Caraceni. Jonel Trebicka, University Clinic Münster, Germany, and Principal Investigator at EF CLIF, Spain, presented and discussed results from work package 4 including the selection and validation of combinatorial therapies using rat models of liver disease (namely, cholestasis, alcohol-related liver disease, NASH, and ACLF). Next, Ameli Schwalber, Concentris GbmH, Germany, and Marko Korenjak, President of the European Liver Patients' Association (ELPA), Belgium, summarized the actions undertanken in the last few monts and presented future planned activities within work package 7 on communication, dissemination and exploitation of results from DECISION. They announced the next laymen event to be hosted by Concentris and ELPA on 6 March 2023 online.

On day 3, David Gomez-Cabrero, Navarrabiomed, Spain, for and on behalf of partners within work package 3 presented his insights on patient stratification with regard to the development of prognostics and response tests to new combinatorial therapies for acute decompensation of cirrhosis using systems approaches. During this session, Palomino provided more details on the stratification of patients and proved the robustness of the methods used to cluster patients while reducing complexity due to patient heterogeneity. Estefania Hergo Iglesias, Navarrabiomed, Spain, presented work in progress regarding the implementation of systems biology to patient data in the PREDICT cohort. In developing a prognostic model, she discussed identification of features based on multiomics integration and transcriptomics alone—the features identified will help to predict progression of the disease and survival in patients with ACLF. Huergo Iglesias also presented the results from three drug combinations based on the patient data available. She presented preliminary results on the validation of the prognostic model using patient data from the CANONIC, PREDICT and ACLARA cohorts. Last but not least, Narsis Kiani, YouHealth, Sweden, presented results from the analysis performed on three drug combinations based on ongoing animal model experiments. She presented machine learning approaches to survival of patients with acute decompensation and ACLF.

After a short break, Itziar de Lecuona, University of Barcelona, Spain, provided an overview of deliverables within work package 6. She highlighted the added value of the Code of Conduct and Research Integrity Policy for Scientific Publications —a reference document including the guides to best practice in clinical research from partner institutions in the consortium and recommendations for researchers within DECISION. More recently, the Checklist for Participants to Ensure Informed Consent and Other Mechanisms for Those Unable to Give a Written Consent was created. This document, based on the Declaration of Helsinki and practical guidelines that should be considered when conducting biomedical research issued by the World health Organization (WHO) and the United Nations Educational, Scientific and Cultural Organization (UNESCO), aims to facilitate the identification, compliance, and verification of the key aspects related to research involving human subjects, the uses of human biological samples, and/or personal data. Early in October, the Bioethics and Law Observatory at University of Barcelona created a brochure based on the Guidelines for Reviewing Health Research and Innovation Projects that Use Emergent Technologies and Personal Data. She shared her insights on the recently launched Data Protection Impact Assessment Platform for Health Research and Innovation. With regard to the COMBAT trial, ethics and regulatory issues should be considered in order to use this new clinical trial system. Next, Isabelle Durand-Zaleski, Assistance Publique–Hôpitaux de Paris, France, presented progress on the health economic analysis within work package 6. Finalization of the protocol, electronic case report form and regulatory aurhorization for the COMBAT trial are items to addressed next, explained Durand-Zaleski.

During the closing session, Hemann Mucke, HM Pharma Consultancy, Austria, on behalf of all members of the Scientific and Ethical Advisory Board shared his insights and conclusions from this three-day general assembly meeting. With regard to bioinformatics and pre-clinical experiments, in his view, there is no flaw in the project rationale and the methods used appear to be the best available methods. Centralizing regulatory responsibility is essencial in this project, though, and next steps should consider to apply for scientific advice from the European Medicines Agency (EMA) after finalizing the clinical trial protocol. Dominique Valla, Université Paris-Diderot, France, member of the Scientific and Ethical Advisory Board in DECISION acknowledged the effort by partners with regard to the preparation of the scientific articles presented and made specific recommendations on the power, relevance and impact of the COMBAT trial. "You should be not only proud, but also confident in succedding in this project", he concluded.

The meeting ended with a general discussion chaired by Rautou who closed the session thanking all partners for their efforts and great work.

This study received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 847949.

About DECISION

Decompensated cirrhosis is an advanced form of cirrhosis of the liver associated with development of ascites, hepatic encephalopathy, gastrointestinal hemorrhage, and progression to acute-on-chronic liver failure (ACLF). Despite multiple treatments, mortality in patients with decompensated cirrhosis remains high. The EU-funded DECISION project aims to understand the pathophysiology of decompensated cirrhosis leading to ACLF and to decrease patient mortality. This project will integrate results of high-throughput multiomic profiling with comprehensive clinical data from 2200 fully characterized patients with available standardized biological samples. DECISION will help to identify novel combinatorial therapies to prevent high mortality for patients with decompensated cirrhosis. Combinatorial therapies will be optimized in novel animal models and the best combinations will be tested in patients at high-risk of progressing to ACLF in a phase II clinical trial.