PREDICT STUDY

PI: Jonel Trebicka
(University of Bonn, Germany).

Promoter: EF Clif

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, 1,308 patients were recruited, 1,071 of which were admitted for the treatment of an episode of mere-AD and 227 were recruited with ACLF at inclusion. After the cleaning of the database, the first two papers have been prepared in 2019.

The first paper describes the trajectory of acute decompensation of liver cirrhosis and distinguishes three different phenotypes. Three groups of patients were identified: Pre-ACLF patients (n=218), who developed ACLF and had 3-month and 1-year mortality rates of 53.7% and 67.4%, respectively. Unstable decompensated cirrhosis (UDC) patients (n = 233) required ≥1 readmission not developing ACLF and had 21.0% and 35.6% mortality rates. Stable decompensated cirrhosis (SDC) patients (n = 620) who were neither readmitted, nor developed ACLF and showed a 1-year mortality of only 9.5%. The three groups differed significantly in the grade and course of systemic inflammation (high-grade at enrollment with aggravation during follow-up in pre-ACLF; low-grade at enrollment with subsequent steady-course in UDC; and low-grade at enrollment with subsequent improvement in the SDC) and prevalence of surrogates of severe portal hypertension throughout the study (high in UDC versus low in pre-ACLF and SDC). Mere AD is a heterogeneous condition with three different clinical trajectories and two major pathophysiological mechanisms: systemic inflammation and portal hypertension.

The second study describes the role of precipitating events (PE) in the development of ACLF. A clinical event that precipitates the development of ACLF needs to have two properties. On the one hand, ACLF development should be in close chronological relationship with the PE, meaning that the diagnosis of the PE should be done before or at the time of ACLF onset, and ACLF onset should occur during the duration of the PE-effect. On the other hand, the PE should be characterized by a sufficient severity to induce organ dysfunction and/or failure. The most important PE seems to be bacterial infections (BI). BI were considered a potential PE for ACLF if they were diagnosed prior ACLF onset but resolved within the 48 hours timeframe before diagnosis of the syndrome or were detected at ACLF onset. BI occurring between day 1 and day 10 after the diagnosis of ACLF were considered as complications of ACLF and BI that resolved more than 48 hours before the onset of ACLF were considered unrelated to ACLF. Similarly, the criteria for acute alcoholic liver injury, gastrointestinal bleeding and other PEs were defined. The analysis is still work in progress.

Overall, PREDICT Study was another example of successful collaboration within the European Academic centers and underlines the importance of the disease. It is believed 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.

Predict Study Logo

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.

The results of the study have been recently published in two manuscripts: 1) Fernández J, Angeli P, Trebicka J, et al. Efficacy of albumin treatment for patients with cirrhosis and infections unrelated to spontaneous bacterial peritonitis. Clin Gastroenterol Hepatol 2019 Aug 5. pii: S1542-3565 (19)30844-4; 2) Fernández J, Clària J, Amorós A, et al. Effects of albumin treatment on systemic and portal hemo- dynamics and systemic inflammation in patients with decompensated cirrhosis. Gastroenterology 2019 Jul;157(1):149-162.

Infecir 2 Study Logo

SCOTCH TRIAL

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, multicentres trial, in cirrhotic patients with septic shock aimed to assessing 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 four centres have recruited patients: Barcelona, Leuven, Plymouth and Prague. Until now, 316 patients have been screened and 86 (27%) 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.

Scotch Logo

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 at studying 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 at determining whether plasma exchange with 5% albumin (from 4 to 9 plasma exchange sessions) improves 90-day survival in comparison with standard medical therapy.

The first centre was activated in April 2019, and the first patient was included in June 2019. Twenty seven centres were active to recruit at the end of 2019, 18 in Europe and 9 in USA. Twelve more (nine in Europe and three in USA) will be activated in the next few months. Until now, 18 patients have been screened and 17 patients have been included. The estimated duration of the study is 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 Trial, aimed at assessing the mechanisms of systemic inflammation and ACLF in patients with and without ACLF.

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

The ALADDIN Study is performed in selected European Centres participating in the APACHE Trial. The submission process (CA and EC) has been completed and until date, two centres have been activated (Frankfurt and Hospital Clinic in Barcelona). Eight additional hospitals will be activated in the next few months.

PRECIOSA TRIAL

PI: Javier Fernández
(Hospital Clínic, Barcelona, Spain) and Paolo Angeli (Padova, Italy).

Sponsor: Instituto Grifols, S.A.

The PRECIOSA Trial 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 at determining 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 first centre was activated in April 18, and the first patient was included in July 2018.

Forty three centres were active to recruit at the end of 2019, 31 in Europe and 12 in USA. Two additional North American centres will be activated in the next months. Until now, 58 patients have been screened and 43 patients have been included. The estimated duration of the study is 48-72 months. A new amendment to the protocol (version number 5) containing changes aimed at improving the recruitment rate and the selection of patients with poor prognosis, will be submitted shortly for approval to the CA and EC in USA and Europe.

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 Commission H2020

As coordinator, the EF Clif presented the project entitled “MICROBiome-based biomarkers to PREDICT decompensation of liver cirrhosis and treatment response (MICROB-PREDICT)”. Briefly, microbiome is causally involved in cirrhosis progression and it 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, it 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 nano-biosensors, 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.

This project was accepted for funding and the project started successfully on January 1st 2019. The involvement of world-leading microbiome and omics specialists, technology leaders and clinical experts makes this a program of scientific excellence. Indeed, in 2019 a challenge was announced in the kick-off meeting in Barcelona. Within WP2 and WP3, dealing with multi-omics could finish several deliverables already one year before the planed timeline and promising for the future work.

The resonance of the kick-off meeting in the media was expansive, thanks to the press releases, the press conference and further, with the presentation of the project in the community hub in the EASL. This was ensured by the involvement of patient organizations (ELPA) and the European Association for the study of the Liver (EASL) and also in the future EF Clif will channel our results into a powerful dissemination, communication, training and exploitation program.

Microb Predict Logo

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 Commission H2020

Cirrhosis mortality is mainly associated with cirrhosis decompensation (development of ascites, hepatic encephalopathy, gastrointestinal haemorrhage and progression to Acute on Chronic Liver Failure (ACLF). Despite multiple treatments, mortality in patients with decompensation of cirrhosis remains high. The EU-funded DECISION project aims to understand the pathophysiology of decompensation of cirrhosis leading to ACLF or death, and to decrease patient mortality.

The project will study the pathophysiology of decompensation of cirrhosis by integrating results of high-throughput multi-omic profiling with comprehensive clinical data from 2,200 fully characterised patients with available standardised biological samples.

DECISION will help to identify novel combinatorial therapies to prevent high mortality for patients with decompensation of cirrhosis. Finally, researchers will optimise these therapies in new animal models and then test the best combination in high-risk patients in a Phase II clinical trial. The DECISION project will gather the expertise from 22 different European partners (hospitals, research foundations and institutes, patient and physician associations, and small and medium-sized enterprises, SMEs) and will officially start on April 1st, 2020.

Decision Logo