> PREDICT

PI: Jonel Trebicka (University of Bonn, Germany)
Promoter: EF-CLIF

The PREDICT Study was designed to prospectively observe patients with cirrhosis and Acute Decompensation (AD) at risk of developing ACLF within three months, and to discover new clinical and laboratory predictors of ACLF development, patho-physiological mechanism (using prospective ancillary studies) and potential treatment to prevent ACLF.

The recruitment for the PREDICT Study was closed on the 31 of July 2018 and the last patient and last visit was on the 30 of October 2018. Finally, 47 centres included at least one patient. In total were recruited 1314 patients of which 732 patients had at inclusion CLIF-C AD score > 50 (Group 1), 374 patients a CLIC-C AD score ≤ 50 (Group 2) and 208 patients were recruited with ACLF at inclusion. These data numbers may change during the cleaning of the patients.

Currently, the Data Management Centre, together with the centres, are working constantly, in the cleaning of the patients and so far there are 896 patients clean, with 3802 recorded visits and sampling of biological material. In the PREDICT bio-bank there are located currently, more than 120.000 aliquots of different material. So far, the rate of development of ACLF in the patients of Group 1 and Group 2 is respectively 25% and 10%, with a median of 18.3%.

The mean time of ACLF-development was 14 days after inclusion. Moreover, at 90 days ca. 6% of the patients were transplanted and 17% of the patients died. These data are changing slightly with the increasing number of patients cleaned.

Overall, PREDICT study has been another example of successful collaboration within the European Academic centres and underlines the importance of the disease. We believe that this study will uncover major parts of currently unknown pathogenesis of development of ACLF and deliver important insight in potential therapeutic approaches of this disease.

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> INFECIR 2 STUDY

PI: Javier Fernández (Hospital Clínic, Barcelona, Spain)
Funder/Promoter: Fundació Clínic

Study focused on the effects of albumin administration in the prevention of hepato-renal syndrome and death in patients with cirrhosis, bacterial infections other than spontaneous bacterial peritonitis and high risk of hospital mortality.

This was a phase IV, open-label, multicentre European RCT aimed at evaluating if albumin administration impacts survival in patients with advanced cirrhosis and non-SBP infections. From April 2014 to December 2016, 776 patients were screened and 119 patients (15.3%) were included in the study. Hospital Clinic of Barcelona (n=33), University of Padova (n=9), Sapienza University in Rome (n=9), University Hospital in Bonn (n=9), San Giovanni Battista Hospital, Turin (n=7) and Erasme Hospital, Brussels and Aarhus University Hospital (n=6 each) were the centres with the highest inclusion rates. The study was stopped in December 2016 due to low recruitment rate and lower than expected hospital mortality.

A preliminary analysis of the results was presented in the EASL meeting in Paris in April 2018 (poster presentation). A detailed analysis was performed in the following months that derived in a full manuscript that has been sent for publication. The main results reported in the manuscript are the following: multicentre, open-label trial in which 118 patients with advanced cirrhosis (defined as serum creatinine ≥1.2 mg/dL, serum sodium ≤130 mEq/L, and/or serum bilirubin ≥4 mg/dL) and infections unrelated to SBP were randomly assigned to receive antibiotics plus albumin (n = 61) or antibiotics alone (n = 57). The primary outcome was in-hospital mortality; the secondary outcomes were the albumin’s effects on clinical course.

Results: There were no significant baseline between-group differences in standard laboratory tests, serum biomarkers of systemic inflammation and circulatory dysfunction and liver severity scores. However, the combined prevalence of ACLF and kidney dysfunction was significantly higher in the albumin-plus-antibiotics group (44.3% vs. 24.6% in the antibiotics-alone group; p=0.02), indicating greater baseline overall severity. The primary outcome occurred at the same rate in the two groups (13.1% vs. 10.5%; P=0.66). Circulatory and renal functions only improved in the albumin-plus-antibiotics group.

The resolution rate of baseline ACLF was higher in the albumin-plus-antibiotics group (82.3% vs. 33.3%; P=0.03), an effect associated with decreased inflammation. The prevalence of nosocomial infections was lower in the albumin-plus-antibiotics group (6.6% vs. 24.6%; P=0.007). Conclusions: In this trial involving patients with advanced cirrhosis and infections unrelated to SBP, in-hospital mortality was not different between patients who received albumin plus antibiotics and those who received antibiotics only.

However, patients assigned to albumin were sicker at baseline and, during follow-up, had decreased inflammation, higher rate of ACLF resolution, and less nosocomial infections.

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> SCOTCH

PI: Alexander Wilmer (University Hospital, UZ Leuven, Belgium)
Sponsor: University Hospitals Leuven

Study designed to assess the clinical impact and safety of low dose steroids in the treatment of hypotensive Cirrhotic Patients with suspicion of sepsis (Supplemental Corticosteroids in Cirrhotic Hypotensive Patients with Suspicion of Sepsis. The SCOTCH – trial).

This is a phase IV, double-blind, randomized, placebo- controlled, multicentre trial, in cirrhotic patients with septic shock aimed to assess if stress dose steroids treatment improves 28-day mortality in cirrhotic patients with septic shock (n=356).

Ten centres are currently active to recruit: Spain (n=4), Belgium (n=2), United Kingdom (n=2) and Italy and Czech Republic (n=1, each). However, only 4 centres have recruited patients: Barcelona, Leuven, Plymouth and Prague. Until now, 264 patients have been screened and 69 patients (26%) have been included. We estimate that the inclusion will finish at the end of 2022. An interim analysis has been scheduled after the inclusion of the first 100 patients.

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> THE APACHE TRIAL

PI: Javier Fernández (Hospital Clínic, Barcelona, Spain) and Fin Stolze Larsen (Rigshospitalet, Copenhagen, Denmark).
Sponsor: Instituto Grifols, S.A.

The APACHE TRIAL is aimed to study the effects of plasma exchange on short-term survival in patients with ACLF and high risk of mortality (Effects of Plasma Exchange with Human Serum Albumin 5% on Short-term Survival in Patients with Acute-On-Chronic Liver failure at High Risk of Hospital Mortality).

This is a phase III, multicentre, randomized, open-label trial in 380 patients with ACLF-1b, ACLF grade 2 or ACLF-3a aimed to determine whether plasma exchange with 5% albumin (from 4 to 9 plasma exchange sessions) improves 90-day survival in comparison with standard medical therapy..

The study will be performed in around 35 centres from Europe and USA. The submission process started in September 2018 and is still pending in the majority of the centres. The approval has been obtained in Spain, Belgium and in 3 centres from USA. We estimate to start the study enrolment within the second/third quarter of 2019. The estimated duration of the study is 36-48 months.

> ALADDIN STUDY

PI: Joan Clària (Hospital Clínic, Barcelona, Spain), Richard Moreau (Hôpital Beaujon, Clichy, France), and Ramon Bataller (University of Pittsburgh, USA).
Sponsor: Instituto Grifols, S.A.

The ALADDIN STUDY is a complementary study to the APACHE, aimed to assess the mechanisms of systemic inflammation and ACLF in patients with and without ACLF.

This translational research project is coupled to the APACHE Study. It will be performed in blood and plasma samples and monocytes and neutrophils obtained from patients with ACLF included in the APACHE Study (n=150) and from an additional group of 100 patients with acute decompensated cirrhosis but without ACLF that will serve as control group. Patients of the control group will be enrolled in the Hospital Clinic in Barcelona.

The ALADDIN Study will be performed in selected European Centres participating in the APACHE Study. In the last quarter of 2018 the promoter initiated the submission process (CA and EC).

> THE PRECIOSA STUDY

PI: Javier Fernández (Hospital Clínic, Barcelona, Spain) and Paolo Angeli (Padova, Italy).
Sponsor: Instituto Grifols, S.A.

The PRECIOSA STUDY is focused on exploring the effects on survival of long-term albumin administration in patients with decompensated cirrhosis.

This is a phase IV, European and American, multicentre, randomized open-label trial in 410 patients with decompensated liver cirrhosis with ascites aimed to determine whether long-term albumin administration (1.5 g/kg body weight every 10 days for 12 months) improves 1-year transplant-free survival in comparison with standard medical therapy.

The study will be performed in about 45 centres from Europe and USA. The submission process is still ongoing in some centres from Europe. The initiation visit has been performed in 22 centres, 12 from USA and 10 from Europe. Until date, 6 patients have been recruited (all in USA). After an investigation meeting held in Atlanta substantial amendments were done in the initial protocol to improve the recruitment rate. Protocol version number 4 has been submitted for approval to the CA and EC in USA and Europe. In March 29, a new investigator meeting will be held, this time in Madrid (for the European centres).

NEW STUDIES

> MICROB-PREDICT

MICROBiome-based biomarkers to PREDICT decompensation of liver cirrhosis and treatment response.

SC1-BHC-03-2018
Exploiting research outcomes and application potential of the human microbiome for personalized prediction and prevention of disease.

PI: Jonel Trebicka
(University of Frankfurt, Germany)
Promoter: European Community H2020

EFCLIF presented, as Coordinator, the project entitled “MICROBiome-based biomarkers to PREDICT decompensation of liver cirrhosis and treatment response (MICROB-PREDICT)”. This project was accepted for funding and the project will start on the 1. of January 2019.

Briefly, decompensation of liver cirrhosis and progression towards acute-on-chronic liver failure (ACLF) causes 1.2 million deaths per year. Microbiome is causally involved in cirrhosis progression and is often the first barrier for drugs, on their way into the patient. Thereby, microbiome metabolizes the drugs, shapes their effects and, possibly, determines the host response to drugs. A better understanding of the underlying processes is necessary for more personalized risk stratification, and consequently, is crucial to have more informed, clinical decision-making, with regard to patient health care and treatment.

The aims of MICROB-PREDICT are 1) to better understand the role of microbiome and the gut-liver-axis interactome with respect to microbiome functionalities, 2) to identify microbiome-based biomarkers and signatures for personalized prediction of decompensation and ACLF, and response to treatment, 3) to design three new tests as easy-to-use tools and point-of-care, smartphone-connected nanobiosensors, and 4) to validate them in a randomized controlled trial.

To achieve these aims, MICROB-PREDICT has a structured program in 11 workpackages, which will assemble existing data and samples from major microbiome initiatives in hepatology (12 international studies, >10,000 patients), and enrich them with holistic and in-depth analysis, using cutting-edge multi-omics technologies of host and microbiome from different body sites in samples of >1,000 patients, collected in a longitudinal manner with sequential visits and controlling for confounders.

MICROB-PREDICT results will foster more accurate personalized risk stratification and personalized treatment of decompensated cirrhosis and ACLF. Involvement of world-leading microbiome specialists, technology leaders and clinical experts makes this a program of scientific excellence; patient organizations (ELPA) and the European Association for the study of the Liver (EASL) will channel our results into a powerful dissemination, communication, training and exploitation program.

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NEW STUDIES

> DECISION

Decompensated cirrhosis: identification of new combinatorial therapies based on system approaches.

SC1-BHC-02-2019
Systems approaches for the discovery of combinatorial therapies for complex disorders.

PI: Pierre-Emmanuel Rautou (INSERM and Hepatology Department at Beaujon Hospital, Clichy, France)
Promoter: European Community H2020

The EF-CLIF has prepared and submitted a new proposal for this topic entitled DECompensated cirrhosIS: IdentificatION of new combinatorial therapies based on system approaches (DECISION)”. The Principal Investigator of the proposal will be Pierre-Emmanuel Rautou, from the INSERM, and in case of funding, the Consortium will be established among partners from several Research Institutions and SMEs across Europe, with an estimated budget of 6 M €. It is a two-stage call and the proposal already succeeded on the first stage. The deadline for the second stage will be April 9, 2019..

The objective of the DECISION project is to enhance our systems level understanding of the pathophysiology of decompensation of cirrhosis by multi-omic profiling of large and clinically well characterized cohorts of patients, with available standardized biobank samples.

The gained understanding will allow the development of biomarkers and combinatorial therapies tailored to the needs of individual patients or stratified patient groups, with the objective to decrease their risk of death at 28 days.

The DECISION project gathers the expertise from 22 different European partners (hospitals, research foundations and institutes, patient and physician associations, and small-and-medium-sized enterprises, SMEs) to accomplish the following specific aims:

  • 1. To analyse and better explain at systems level the pathophysiology of decompensation of cirrhosis, combining genomics, epigenomics, microRNA, transcriptomics, metabolomics and inflammatory mediators with patients’ clinical features and response to treatments, (WP1 and 2).
  • 2. To explore the exact contribution of treatments to the outcome of decompensation of cirrhosis, and thereby to provide important foundations for the development of future combinatorial therapies of available treatments (WP1 and 2).
  • 3. To develop novel companion biomarkers, identifying the patient population responding to the combinatorial therapies (WP2 and 3).
  • 4. To first refine existing animal models of decompensation of cirrhosis leading to ACLF, using transcriptomics and metabolomics approaches, and then to validate the combinatorial therapies identified by WP1 and 2 in those pre-clinical models (WP3).
  • 5. To test the new combinatorial therapies and biomarkers in a phase II clinical trial, built in the DECISION project to assess its efficacy and take-up in the clinical setting (WP4).
  • 6. To determine the cost-effectiveness of these new strategies, with the ultimate aim of decreasing the social and healthcare burden of decompensation of cirrhosis (WP5).

All of this conducted in respect of ethical and legal guidelines, animal welfare and patients’ rights (WP5).