Clinical trial NCT03056612: Predicting Acute-on-Chronic Liver Failure in Cirrhosis (PREDICT) Study
Official title: Predicting Acute-on-Chronic Liver Failure in Cirrhosis (PREDICT) Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Liver Cirrhosis With Acute Decompensation
Lead sponsor: European Foundation for Study of Chronic Liver Failure
Sponsor class: OTHER
First posted: 2017-02-17
Enrollment: 1314
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The population of patients would include ca. 1,200 cirrhotic patients over a twelve-months period. These patients will be admitted/referred to the study center because of acute decompensation of cirrhosis (ascites, overt encephalopathy, GI-hemorrhage, new onset of non-obstructive jaundice and/or bacterial infections), without ACLF (as defined according to the CANONIC study ) at hospitalization.

Brief summary: The aim of this study is to assess prospectively the critical period prior to the development of Acute-on-Chronic Liver Failure (ACLF) (1), to uncover mechanistic and pathophysiological processes associated with the development and clinical course of ACLF (2) and to identify the precipitating events of ACLF (3).

Detailed description: 1. This International-European, investigator-initiated, multicenter, prospective, observational study will be performed in centers that belong to the European Foundation for the Study of Chronic Liver failure (EF-CLIF)-European Association for Study of the Liver (EASL)-EASL-CLIF Consortium.
2. The population of patients would include ca. 1,200 cirrhotic patients over a twelve-months period. These patients will be admitted/referred to the study center because of acute decompensation (AD) of cirrhosis (ascites, overt encephalopathy, GI-hemorrhage, new onset of non-obstructive jaundice and/or bacterial infections), without ACLF (as defined according to the Canonic study ) at hospitalization.
3. After the enrolment visit, the patients will be stratified into two groups: Group 1 patients with high risk of ACLF development (CLIF-C AD score ≥ 50) and in Group 2 patients with low risk of ACLF (CLIF-C AD score \<50). The whole cohort will be followed for 3 months, while Group 1 will be followed more closely. Development of ACLF is an end-point and in this case a final visit 7-10 days after ACLF development is planned. Data on liver transplantation, mortality and causes of mortality 3 months, 6 months and 12 months will be collected in the whole cohort.
4. Prospective collection of biological material and performance of ancillary studies investigating predictors for development and pathogenesis of ACLF.

Specific goals of the study:

* To identify early clinical predictors, biomarkers, mechanisms and precipitating events during the critical period prior to and involved in the development and clinical course of ACLF (with special emphasis to medical trajectory and drug history) in patients admitted/referred to study center with acute decompensation of cirrhosis (ascites, GI-hemorrhage, overt encephalopathy, new onset of non-obstructive jaundice and/or bacterial infections) and the chronological relationship of the events with occurrence and dynamics of ACLF development.
* To develop a score predicting ACLF development (CLIF-PREDICT score) and assess 28-day, 90-day, 6-month and 1-year all-cause mortality in cirrhotic patients with acute AD, but without ACLF.
* To serve as a core (hub) study for prospective ancillary studies regarding diagnosis, prognosis and pathogenesis of AD and ACLF.

Main endpoints

* Assessment of the critical period prior to ACLF development

  * Characterization of mechanisms responsible for ACLF development
  * Predictors of clinical course dynamics of ACLF evolution and mortality.
  * Identification and role of precipitating events for ACLF development.
* To elaborate a CLIF-PREDICT score 2. Secondary endpoints
* Prospective core ancillary studies to investigate the pathogenesis of ACLF.

Eligibility criteria: Inclusion Criteria:

The patients admitted/referred to study center with AD of cirrhosis (ascites, overt encephalopathy, new onset of non-obstructive jaundice, GI-hemorrhage and/or bacterial infections), but without ACLF (as defined according to the CANONIC study) at study inclusion.

Exclusion Criteria:

1. Presence of ACLF at inclusion;
2. Pregnancy;
3. Age \<18 years;
4. Patients with acute or subacute liver failure without underlying cirrhosis;
5. Patients with cirrhosis who develop decompensation in the postoperative period following partial hepatectomy;
6. Evidence of current malignancy except for non-melanocytic skin cancer and hepatocellular carcinoma within Milan criteria;
7. Presence or history of severe extra-hepatic diseases (e.g., chronic renal failure requiring hemodialysis, severe heart disease (NYHA \> II); severe chronic pulmonary disease (GOLD \> III), severe neurological and psychiatric disorders);
8. HIV-positive patients
9. Previous liver or other transplantation
10. Admission/referral of more than 72 hours before inclusion
11. Patients who decline to participate or who cannot provide prior written informed consent and when there is documented evidence that the patient has no legal surrogate decision maker and it appears unlikely that the patient will regain consciousness or sufficient ability to provide delayed informed consent;
12. Physician´s denial (e.g. the investigator considers that the patient will not follow the protocol scheduled).

Primary outcomes:
measure: Number of patients developing ACLF within 12 weeks and severity of ACLF development
timeFrame: 12 weeks
Secondary outcomes:
measure: Score to PREDICT ACLF
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Medical University Graz
city: Innsbruck
country: Austria
facility: Medical University of Innsbruck
city: Vienna
country: Austria
facility: Medical University of Vienna
city: Antwerp
country: Belgium
facility: University Hospital Antwerp
city: Brussels
country: Belgium
facility: C.U.B Erasmo
city: Ghent
country: Belgium
facility: Ghent University Hospital
city: Leuven
country: Belgium
facility: University Hospital Leuven
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Hvidovre University Hospital
city: Bondy
country: France
facility: Hospital Jean Verdier
city: Paris
country: France
facility: Hopital Beaujon
city: Paris
country: France
facility: Hopital Paul Brousse
city: Aachen
country: Germany
facility: RTWH Aachen
city: Bonn
country: Germany
facility: University Hospital Bonn
city: Frankfurt am Main
country: Germany
facility: JW Goethe University Hospital
city: Halle
country: Germany
facility: University Hospital Halle-Wittenberg
city: Hannover
country: Germany
facility: Hannover Medical School
city: Jena
country: Germany
facility: University Hospital Jena
city: Leipzig
country: Germany
facility: University Hospital Leipzig
city: Munich
country: Germany
facility: University Hospital Munich LMU
city: Debrecen
country: Hungary
facility: University of Debrecen
city: Bologna
country: Italy
facility: University of Bologna
city: Brindisi
country: Italy
facility: Internal Medicine PO Ostuni
city: Padova
country: Italy
facility: University Clinic Padova
city: Rome
country: Italy
facility: Universita Sapienza
city: Torino
country: Italy
facility: A.O.U. Torino
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Vila Real
country: Portugal
facility: CHTMAD Vila Real
city: Kosice
country: Slovakia
facility: Pavol Jozef Sfarik University Kosice/Roosevelt Hospital Bystrica
city: Barcelona
country: Spain
facility: Hospital Clinic y Provencial de Barcelona
city: Barcelona
country: Spain
facility: Hospital de Sant Pau
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d´Hebron
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal
city: Sevilla
country: Spain
facility: Virgen del Rocio
city: Bern
country: Switzerland
facility: Inselspital
city: Geneva
country: Switzerland
facility: Hôpitaux Universitaires Geneve
city: St. Gallen
country: Switzerland
facility: Cantonal Hospital St. Gallen
city: Istanbul
country: Turkey
facility: Marsara University
city: Birmingham
country: United Kingdom
facility: Birmingham University Hospitals
city: London
country: United Kingdom
facility: Imperial College
city: London
country: United Kingdom
facility: King´s College
city: London
country: United Kingdom
facility: Royal Free Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals
city: Plymouth
country: United Kingdom
facility: Derriford Hospital, Plymouth Hospitals Trust
Study officials:
References:
citation: Trebicka J, Fernandez J, Papp M, Caraceni P, Laleman W, Gambino C, Giovo I, Uschner FE, Jansen C, Jimenez C, Mookerjee R, Gustot T, Albillos A, Banares R, Jarcuska P, Steib C, Reiberger T, Acevedo J, Gatti P, Shawcross DL, Zeuzem S, Zipprich A, Piano S, Berg T, Bruns T, Danielsen KV, Coenraad M, Merli M, Stauber R, Zoller H, Ramos JP, Sole C, Soriano G, de Gottardi A, Gronbaek H, Saliba F, Trautwein C, Kani HT, Francque S, Ryder S, Nahon P, Romero-Gomez M, Van Vlierberghe H, Francoz C, Manns M, Garcia-Lopez E, Tufoni M, Amoros A, Pavesi M, Sanchez C, Praktiknjo M, Curto A, Pitarch C, Putignano A, Moreno E, Bernal W, Aguilar F, Claria J, Ponzo P, Vitalis Z, Zaccherini G, Balogh B, Gerbes A, Vargas V, Alessandria C, Bernardi M, Gines P, Moreau R, Angeli P, Jalan R, Arroyo V; PREDICT STUDY group of the EASL-CLIF CONSORTIUM. PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis. J Hepatol. 2021 May;74(5):1097-1108. doi: 10.1016/j.jhep.2020.11.019. Epub 2020 Nov 20.
citation: Trebicka J, Fernandez J, Papp M, Caraceni P, Laleman W, Gambino C, Giovo I, Uschner FE, Jimenez C, Mookerjee R, Gustot T, Albillos A, Banares R, Janicko M, Steib C, Reiberger T, Acevedo J, Gatti P, Bernal W, Zeuzem S, Zipprich A, Piano S, Berg T, Bruns T, Bendtsen F, Coenraad M, Merli M, Stauber R, Zoller H, Ramos JP, Sole C, Soriano G, de Gottardi A, Gronbaek H, Saliba F, Trautwein C, Ozdogan OC, Francque S, Ryder S, Nahon P, Romero-Gomez M, Van Vlierberghe H, Francoz C, Manns M, Garcia E, Tufoni M, Amoros A, Pavesi M, Sanchez C, Curto A, Pitarch C, Putignano A, Moreno E, Shawcross D, Aguilar F, Claria J, Ponzo P, Jansen C, Vitalis Z, Zaccherini G, Balogh B, Vargas V, Montagnese S, Alessandria C, Bernardi M, Gines P, Jalan R, Moreau R, Angeli P, Arroyo V; PREDICT STUDY group of the EASL-CLIF Consortium. The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology. J Hepatol. 2020 Oct;73(4):842-854. doi: 10.1016/j.jhep.2020.06.013. Epub 2020 Jul 13.