To achieve a better understanding of acute decompensation of cirrhosis and to identify novel combinatorial therapies, DECISION builds on 3 large available prospective cohorts of patients with acute decompensation of cirrhosis, namely CANONIC (from Europe), PREDICT (from Europe) and ACLARA (from South America). From the beginning of DECISION, many advances have been made on the characterization and the analysis of these cohorts.
First, specialty laboratories of DECISION performed epigenomics, whole-blood transcriptomics, serum microRNA profiling, serum metabolomics analysis, plasma inflammatory protein (cytokines) and lipid (eicosanoids) mediators characterization and plasma extracellular vesicle concentration measurement in samples from 1355 patients from the PREDICT and ACLARA studies, using state-of-the-art high-throughput technologies. These results have been merged with those of the CANONIC cohort, obtained outside DECISION. On top of that, single cell transcriptomics of blood cells, untargeted proteomic analysis of plasma extracellular vesicles and circulating miRNA next generation sequencing has been performed on blood samples from selected patients with acute decompensation of cirrhosis (n=23 to 65) to broaden our view of changes occurring in those patients.
In parallel, detailed clinical data of the patients included in CANONIC, PREDICT and ACLARA including medical history, clinical presentation, drugs taken and outcome, have been harmonized and merged into a unique database. Omics data have been integrated with these clinical data in this unique database. Systems approaches have been used to better understand patient heterogeneity in acute decompensation of cirrhosis: we already published results of approaches using only clinical data and identified three clusters of patients with different presentation and outcomes; we also made available the tools we developed. We are on the one side analyzing in depth the added value of omics data on top of clinical data, and on the other side deciphering what each omic approach brings to our understanding on the pathophysiology of acute decompensation of cirrhosis. .
At the same time, DECISION’s teams started the analysis of the merged harmonized clinical databases to identify new combinatorial therapies. Using safety-efficacy approach, machine learning approach and comparison of expected vs. observed survival, we identified three combinations of drugs. These three combinations of drugs have been tested in the new rat models of decompensation of cirrhosis leading to ACLF we identified in DECISION. Based on those analyses as well as on practical considerations, we chose one of these three combinations, i.e. human albumin combined with enoxaparin.
We then designed the phase II randomized COMBAT trial that tests this combination of drugs. The first patients have been included. We also built an observational trial, called PROSPECT, allowing us to test the value of the prognostic tests we developed. .
In order to disseminate of our findings to the widest possible audience, DECISION’s teams -with the help of the European Association for the Study of the Liver (EASL) and the European Liver Patients Association (ELPA)- conducted many dissemination actions towards scientists and physicians (e.g. organization of conferences, newsletters), patients (meetings with patients) and general audience (e.g. press releases, website, publication in journals for laymen).
