November 07, 2022 CHANCE investigators meet on the occasion of The Liver Meeting 2022 in Washington D.C, USA The 3rd CHANCE Investigator Meeting took place on 4 November 2022 in Washington D.C, USA

BARCELONA—The 3rd CHANCE Investigator Meeting took place in Washington D.C., USA, on the occasion of the 73rd Annual Meeting of the American Association for the Study of Liver Diseases (ASSLD). The CHANCE investigator meeting brought together 46 investigators and professionals from 10 countries (Argentina, Canada, France, Germany, India, Italy, Spain, The Netherlands, UK, and USA), 34 people attended in person and 12 joined online, to review and discuss project progress, share experiences and address challenges of patient recruitment.

The meeting focused on the status of recruitment in North America and provided a great opportunity to introduce newly appointed regional coordinators, Constantine Karvellas, University of Alberta, Canada, and Ruben Hernaez, Michael E. DeBakey Veterans Affairs Medical Center, TX, USA.

Rajiv Jalan, Scientific Director of the European Foundation for the Study of Chronic Liver Failure (EF CLIF) who serves as Scientific Coordinator of the CHANCE study, welcomed attendees and officially introduced Karvellas and Hernaez in their new appointment as regional coordinators for North America replacing Vinay Sundaram at Cedars-Sinai Medical Center, CA, USA, who recently passed away. Jalan called attendees to provide their feedback and how we can do better in terms of recruitment and data quality. "Despite COVID-19 and the lack of face-to-face interaction the program has actually gone fantastically well and we are now at a very interesting stage, nearly at 500 patient recruitment", Jalan explained.

In paying tribute to Vinay Sundaram, Hernandez summarized his career and highlighted his many contributions to the field which include the first publication comparing mortality in the waitlist or removal based on the model for end-stage liver disease (MELD) score vs acute-on-chronic liver failure (ACLF) criteria with data from the United Network for Organ Sharing (UNOS) and the American College of Gastroenterology clinical guidelines on hereditary hemochromatosis. Sundaram understood the burden of ACLF and did a lot of work on liver transplantation. Hernaez presented the Multi-Organ Dysfunction and Evaluation for Liver Transplantation (MODEL) Consortium which includes 15 centers across the US and Canada, a consortium that Sundaram helped establish. In Hernaez's words, Sundaram was a sponsor rather than a mentor – he was a committed professional who shared knowledge, advocated for and enabled advancement of his colleagues and peers, he was a medical practitioner that cared for his patients and champion who engaged with the broader hepatology community. To close this session, Jalan prompted attendees to Dr. Vinay Sundaram Legacy Fund by the AASLD Foundation for donations.

Next, Jalan reviewed the questions that are relevant in the context of liver transplantation for severe ACLF. One of the key limitations of using MELD-Na is that the score underestimates the risk of death of patients with ACLF. Indeed, one of the observations by Sundaram and Jalan and others indicates that MELD-Na less than 25 in ACLF grade 2 or 3 represents a high risk of death in the waitlist for these patients. Jalan pointed out that relevant questions remain unanswered, and the benefits of liver transplantation for ACLF 3 patients need to be further addressed. Many lines of investigation have shed light on independent risk factors for high mortality after liver transplant in severe ACLF (i.e., severe comorbidities, acute respiratory distress syndrome, high vasopressor, severe lactatemia, uncontrolled/fungal/multidrug resistant infection, time on waitlist, and transplantation using marginal organs). However, these are not contraindications for liver transplantation themselves and rather a combination of these may be necessary to consider not to transplant these patients. Available retrospective data provide evidence that liver transplantation in selected patients with ACLF 3 results in increased survival in these patients. Thus, the CHANCE study was designed to address the lack of intent-to-treat results from the time of waitlisting, detailed information about waitlist outcomes, best organ allocation system for this population, objective limits to define futility, best time to do liver transplant, characteristics of donor organs to ensure good post-liver transplant outcomes, long-term post-liver transplant survival rate and impact on patients' quality of life, resource utilization of performing liver transplant, and potential differences across regions where clinical practice and management of these patients may differ widely. The CHANCE study is an ambitious collaborative project that counts with the support of the International Liver Transplantation Society (ILTS) and the European Liver and Intestine Transplant Association (ELITA) project. "For this project to be successful, physicians are not enough", Jalan explained. "We need to bring in surgeons, intensivists, and hepatologists", he added. Jalan showed how the CHANCE study is organized and briefly introduced the structure that supports the study which involves 93 centers distributed in five regions across the globe. The CHANCE study aims to recruit 2000 patients to compare 1-year and patient survival rates after liver transplant in patients with ACLF 2 or 3 at the time of liver transplantation with patients with decompensated cirrhosis without ACLF, and survival of patients with ACLF 2 or 3 that do not receive a liver transplant. Jalan explained how the study also offers the opportunity for researchers in CHANCE to pursue further many of the unanswered questions, and propose and conduct ancillary studies.

Cristina Sanchez-Garrido, Head of the Data Management Center at EF CLIF, presented preliminary results with nearly 500 patients. Sanchez-Garrido explained that the sample size is currently balanced as per requirement of the study protocol with a total of 454 patients recruited at the end of October 2022. She presented the world distribution of the 46 centers that are open and actively recruiting and figures on patient recruitment by region and country. As example of good patient recruitment performance, Sanchez-Garrido presented the status of Latin America with centers that started recruiting patients as early as July 2021. Preliminary data was based on patients with at least one follow-up visit showing already very promising results: 60.9% of patients in group 3 (ACLF 2 or 3 referred for liver transplantation but not listed as they develop contraindications to liver transplant) died whereas only 20.1% of patients in group 1 (ACLF 2 or 3 listed for liver transplantation) died before receiving a liver transplant. Sanchez-Garrido pointed out that although one of the original concerns in the design of the study was the existence of potential differences among centers and regions, data shows that there is no apparent bias among continents that could impact the results obtained so far.

Next, Karvellas reviewed the status of recruitment in North America. Centers in North America, both in USA and Canada, are closely to finalize agreements and starting to recruit their first patients. Karvellas compared the percentage of death before liver transplant in North America, which overall appears similar in other regions. "With organ donation rates across the world being significantly different, it is interesting to see fairly similar results from different parts of the world", he added.

Cedars-Sinai Medical Center, CA, USA was approved to recruit about one year ago and has been the top recruiting center in North America since the start of the study. Alexander Kuo, investigator at Cedars-Sinai Medical Center, shared his insights about the success of patient recruitment in his center. He acknowledged the commitment and efforts of Sundaram that made it all possible. "We want to carry on his legacy, his work. I think the best way to honor him is by pushing forward with all his projects, including this one which is very dear to his heart", he declared. Kuo also highlighted the importance of having a dedicated inpatient nurse practitioner in their liver service who champions in identifying ACLF patients. He recognized that this strategy has been key to successfully recruit patients in group 1. Also, patients in group 1 were very eager to participate in the study while group 3 has been more challenging as these patients may either pass or want a second opinion from other centers. In order to recruit more patients in group 2, the center will integrate their outpatient liver transplant coordinators and Kuo expects this group to start picking up soon.

Next, Jalan invited Hernaez and Karvellas to take the floor at the start of an open discussion session that aimed at sharing ideas on how to improve participation and patient recruitment, and streamline study-related processes.

At last, Paolo Angeli, Chair of the EASL-CLIF Consortium Steering Committee at EF CLIF, and Anna Bosch, General Manager of EF CLIF, thanked everyone for their efforts and good work. Angeli concluded that "we already got a result". He referred to the cover of the Journal of Hepatology reporting the percentage of patients transplanted with ACLF being quite heterogeneous within Europe. "Now this (percentage) is more homogeneous within a larger geographical area. This is the first result, indeed", he added.

The CHANCE study is promoted by EF CLIF.

About the CHANCE study

CHANCE is a multicenter, global, observational study designed to assess the benefit of liver transplantation in patients with acute-on-chronic liver failure (ACLF) grade 2 or grade 3. This study counts with the support of the International Liver Transplantation Society (ILTS) and the European Liver and Intestine Transplant Association (ELITA) to recruit 2000 patients in 80 centers in 27 countries around the world. The primary objective of the CHANCE study is to compare 1-year graft and patient survival rates after liver transplantation in patients with ACLF grade 2 or grade 3 at the time of liver transplantation with patients with decompensation of cirrhosis without ACLF-2 or 3 and transplant-free survival of patients with ACLF-2 or 3 not listed for liver transplantation. The international nature of this study will allow for deep assessments of the potential impact of different precipitating factors of ACLF (e.g., alcohol vs. Hepatitis B virus flare), different types of liver transplantation (deceased donor vs. living donor liver transplantation) and different regional and national allocation systems on transplant outcomes. Beside these clinical objectives, the CHANCE study aims to build a repository of biological samples to explore new biomarkers to predict prognosis on the waiting list and after liver transplantation, and mechanisms of liver and extrahepatic organ recovery. Identifier: NCT04613921