Chance Study Dossier
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Protocol synopsys

Sponsor

European Foundation for the study of Chronic Liver Failure (EF-Clif)

Title

LIVER TRANSPLANTATION IN PATIENTS WITH CIRRHOSIS AND SEVERE ACUTE-ON-CHRONIC LIVER FAILURE (ACLF): INDICATIONS AND OUTCOMES (CHANCE)

Study centers

Multicenter and international. An updated list on the participating centers can be found at https://www.efclif.com/foundation/news-and-events/updated-list-of-participant-hospitals-in-the-chance-study

Primary objective

To compare 1-year graft and patient survival rates after liver transplantation (LT) in patients with ACLF-2 or 3 at the time of LT with patients with decompensated cirrhosis without ACLF-2 or 3 at the time of LT and transplant-free survival of patients with ACLF-2 or 3 not listed for LT

Secondary objectives

Secondary objectives are as follows:

To assess the proportion of patients with ACLF-2 or 3 referred to transplant team who are listed or not and reasons of this decision.
To evaluate the outcomes of patients listed with ACLF-2 or 3 on the waiting list compared with those of patients listed with decompensated cirrhosis without ACLF-2 or 3.
To define independent predictive factors of death/delisting on the waiting list for patients listed with ACLF-2 or 3 and develop a new prognostic model based on ACLF criteria to predict mortality on the waiting list and to improve the allocation of organs.
To compare the characteristics of accepted grafts for patients listed with ACLF-2 or 3 with those of patients listed with decompensated cirrhosis without ACLF-2 or 3 and their impact on post-LT outcomes.

To explore independent predictive factors of death after LT for patients transplanted with ACLF-2 or 3 to design futility criteria for LT.
To compare post-LT survival rates of patients with ACLF-2 or 3 at listing and patients without ACLF at listing who develop ACLF-2 or 3 on the waiting list.
To compare post-LT quality of life (QoL) for patients listed with ACLF-2 or 3 with those of patients listed with decompensated cirrhosis without ACLF-2 or 3.
To assess the resources utilization for patients listed with ACLF-2 or 3 (in intention-to-treat and per protocol) compared with patients listed with decompensated cirrhosis without ACLF-2 or 3.

Exploratory objectives

The exploratory objectives are as follows:

To assess the predictive ability of new biomarkers to predict the prognosis on the waiting list and after LT for patients with decompensated cirrhosis with or without ACLF-2 or 3.

To investigate the impact of LT on systemic disturbances (inflammation, leukocyte dysfunction, metabolic alterations) observed in ACLF.
To explore the mechanisms of liver and extrahepatic organ recovery after LT in patients with ACLF-2 or 3 and determinants of this recovery.

Study duration

Duration of enrolment period: 2 years

Post-LT follow-up: 1 year

Total duration: 3 years

Study design

Prospective non-interventional non-observational study

Study population and number of patients

Pre-screening group:

All patients with ACLF-2 or 3 referred to the transplant team (unlimited).

Group 1:

Patients listed for liver transplantation with ACLF-2 or 3 at the time of listing or developing ACLF 2-3 while on the waiting list (n=2,000).

Group 2:

Patients listed for liver transplantation with decompensated cirrhosis without ACLF-2 or 3 and poor liver function (MELD > 20) at the time of listing (n=500).

Group 3:

Patients having ACLF-2 or 3, are assessed for inclusion in the waiting list, but are finally not listed for liver transplantation (n=500).

Main eligibility criteria

Inclusion criteria

1.All patients with ACLF-2 or 3 referred to the transplant team (unlimited).

2.Subjects with diagnosis of liver cirrhosis (based on clinical, laboratory, endoscopic, and ultrasonographic features or on histology).

3.Subjects who have been hospitalized for acute decompensation of liver cirrhosis and referred to the transplant team:

Group 1: patients listed for liver transplantation with ACLF-2 or 3 at the time of listing or developing ACLF 2-3 while on the waiting list.
Group 2: patients listed for liver transplantation with decompensated cirrhosis without ACLF-2 or 3 and poor liver function (MELD>20) at the time of listing.
Group 3: patients having ACLF-2 or 3, are assessed for inclusion in the waiting list, but are finally not listed for liver transplantation.

4.Patients (or trusted person, family member or close relation if the patient is unable to express consent) who have been informed and signed their informed consent.

Exclusion criteria

A subject meeting any of the following exclusion criteria is NOT eligible for participation in the study.

1.Acute or subacute liver failure without underlying cirrhosis.

2.Patients with hepatocellular carcinoma outside Milan criteria or other active neoplasia.

3.Subjects listed for transplantation other than liver or liver-kidney transplant.

4.Subjects with previous liver transplantation.

5.Vulnerable population (person under temporary or permanent guardianship or deprived of liberty by a judicial decision).

6.Vulnerable population (person under temporary or permanent guardianship or deprived of liberty by a judicial decision).

7.Pregnant and/or breastfeeding woman.

8.Patients with relevant comorbidities that could impact the prognosis:

Subjects with very severe hepatopulmonary syndrome (with PaO2 < 50 mmHg on FiO2 21%) or moderate to severe portopulmonary hypertension (non-reversible mPAP ≥ 35 mmHg or PVR ≥ 500 dyn.s.cm-5).

Statistical methods

Group comparisons will be made using Student’s t-test, the Mann-Whitney test, the Chi-squared test, or Fisher’s exact test, as appropriate. In order to identify factors associated with the occurrence of death, univariate and multivariate regression analyses will be performed using the Fine and Gray competing risks proportional hazards regression model.

All tests will be two-tailed and a p value of less than 0.05 will be considered to be statistically significant.

Kick off requirements

Ethics committee
Collaboration Agreement
User setup at the eCRF
Received sampling material
(only in centers participating in sampling)
Training

Ready to start the recruitment!

Closing requirements

All visits and follow ups completed
All queries closed
All biobank information sent to BCN
All samples sent to BCN

You center will be considered closed

Electronic Case Report Form

Platform Overview

How to login

clifresearch.com/chance

User and password will be sent by the DMC to the investigators
In first log the password should be changed in order to maintain the coinfidenciality

All the people involved in the data entry process will receive the user and password The provided email address will be used for all communications. Please provide your most used email address if you don’t want to lose any important information about the study

We recommend you to use Google Chrome and or Mozilla Firefox
Please avoid the use of smart devices

Documents

Documentation tab

Repository of all the documents needed to run the study (downloadable pdfs)
List of all the documents that can be found in this section:

Protocol
Informed consents
Paper CRF
Biobank SOPs
QOL Scores printable version in local langages
eCRF userguide

Please notice that quality of life scores should be completed by the patient before uploading the information into the platform. You can find the available translations to the local languages in this section or directly from the specific form

DM and Support

chance_dm@efclif.com
use this email address for all the communications with the DMC in order to obtain a fast answer to any question you may have

Examples of communications with the Data Management Center (DMC):

Technical problem
Doubt about the eCRF
Doubt about biobank
Send information related to biobank
Send information related to CT-Scan

Main Menu of the eCRF Platform

How to add a new patient

Adding a new patient:

click the "add a new patient / screening failure" button

Please note that it is necessary to save the pre-screening form in order to obtain the patient code. This patient code is unique for the whole study and it is the responsibility of the investigator to know the relationship between this code and the medical record number

Once the patient code is available, it will appear in the main screen of patients
Main screen is ordered by patient code, being the last patient entered, the first of the list

There are basic variables selected to search the patient and filters (funnel-shaped icon next to each variable Filter ) to perform and advanced search

Short cuts of the platform

Please be sure of using the “next“ and “exit without save“ buttons in order to navigate through the platform. Back button of the browser does not ensure that patient’s data are properly saved

“Calendar icon” is the recommended route during the data entry process. It is a shortcut to the visit schedule

“Folder icon” is the recommended route during the data cleaning process. It is a shortcut to all the independent forms as well as all the queries

Visit Schedule

Group 1

Group 2

Group 3

Depending on the Patient’s Group, visit schedule appearance is different. Nevertheless, the visits can be grouped by categories

REGULAR VISITS:

NON REGULAR VISITS:

Color legends

There are different icons that identify the possible status of forms and visits. In case of forms:

Green check for complete forms
Pencil for incomplete forms
Empty for empty forms

Please notice that all forms will be monitored once they are with the green check. In case of visits:

Green for complete visits
Yellow for incomplete visits
Red for empty visits

Visit Contents

Common contents

Visit date form:

Crucial to complete the visits in the correct order

Saving this form will allow you to access the rest of the forms that have to be completed afterwards It is not possible to complet visits in a wrong order

Clinical events form:

Registers all the relevant information regarding the events pre and post liver transplantation. Example of events that will be registered: ascites, hepatic encephalopathy, bleeding, acute kidney injury, infections, acute alcoholic steatohepatitis, ACLF, hepatocellular carcinoma, neurological complications, myopathy, rejection, biliary complications, portal vein thrombosis, etc.

Each event is showed or not depending on the visit. This means that, once registered the liver transplant visit, all those events corresponding to the prior period, will not be showed in order not to create inconsistencies.
Some events (i.e. bleeding and infections) require more details.
Specific forms will show up to complete them.

Vital signs and hemodynamic parameters form:

Registers information depending on the site of the patient (not depending on the visit):

Emergency room
Regular ward
ICU. If the patient is in ICU, in this case “hemodynamic parameters section” should be completed

Laboratory form:

Registers data regarding hematology, coagulation, biochemistry, urine analysis, arterial /venous blood gas panel and immunosuppressives (these ones only after liver transplantation and only if patient takes these medications)

Values not available in this form should be completed as -99

Concomitant medication and procedures form:

3 sections:

Procedures underwent by the patient (limited to those that be relevant for the study and they are different depending on the moment of the study, being the most important periods pre and post liver transplantation)

Treatments taken by the patient (find uploaded the last version of WHO Drugs Dictionary with no limitation of treatments)
Treatments taken by the donor that could be relevant for the study

Scores form:

Glasgow coma score: required in all visits and values should be entered manually into the application
CLIF C OF Score, Child Pugh, Meld and Meld-Na: required before liver transplantation. These scores are automatically calculated with the values entered in prior forms

Apache II and Sofa Score: required pre and after liver transplantation but only if patient is in ICU. All these scores are automatically calculated with the values entered in prior forms except chronic health points in Apache II score, which shall be entered manually

Specific contents

Specific forms depending on the visit & Patient's group

Inclusion, Day 7, Month 3 (Only G3), Extra visit, Liver TX, Day 3 post liver TX, Day 7 post liver TX, Day 28 post liver TX, Month 3 post liver TX

Month 3 post liver TX, month 12 post liver TX

Frality Index, funcional & sarcopenia status

Inclusion, Day 28 post liver TX, Month 3 post liver TX, Month 6 post liver TX, month 12 post liver TX

Only in liver transplantation visit

Biobank form:

Only for those centers who accept to collect samples.
(Otherwise, it will be hidden).

In case a patient does not consent for biobanking or consenting partially, form will be shown accordingly

Frailty index, functional and sarcopenia status forms:

3 sections:

Frailty Index: automatically calculated
Karnofsky index
Nutrition (BMI)
Sarcopenia: It is not mandatory to upload a CT-Scan in all visits neither for all patients

If uploading a CT-Scan please make sure it is a “.DICOM” format and blinded without any personal data from the patient

Quality of life scores forms:

To be transcribed once the patient has completed the paper version in his/her own language

Donor’s and surgery data form:

Registers the variables regarding clinical information from the donor (i.e. comorbidities, lab parameters, demographics, graft) and main characteristics of the surgery. Please remember to include donor treatments in this section