Decompensated Liver Cirrhosis Research Network (UK-CLIF): Building consensus for hepatology trials in the UK

Liver cirrhosis, clinical trials, alcohol ALL Metrics - Views Downloads How to cite this article Crisp H, Tavabie O, Enever Y et al. Decompensated Liver Cirrhosis Research Network (UK-CLIF): Building consensus for hepatology trials in the UK [version 1; peer review: 3 approved]. NIHR Open Res 2024, 4:69 (https://doi.org/10.3310/nihropenres.13669.1) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente Select a format first ▬ ✚ Research Article [version 1; peer review: 3 approved] Helen Crisp1, Oliver Tavabie2, Yvanne Enever3, [...] Richard Allen https://orcid.org/0000-0003-0998-8249 4, Milton Silverman4, Juan Acevedo5, Abhishek Chauhan6, Brian Hogan7, Vishal Patel8, Rajeshwar Mookerjee1,7, Gavin Wright9, Richard Aspinall https://orcid.org/0000-0002-5208-8185 10, Stuart McPherson11, Andrew Cook12, Rajiv Jalan1,7, Gautam Mehta https://orcid.org/0000-0002-5696-359X 1,7Helen Crisp1, Oliver Tavabie2, [...] Yvanne Enever3, Richard Allen https://orcid.org/0000-0003-0998-8249 4, Milton Silverman4, Juan Acevedo5, Abhishek Chauhan6, Brian Hogan7, Vishal Patel8, Rajeshwar Mookerjee1,7, Gavin Wright9, Richard Aspinall https://orcid.org/0000-0002-5208-8185 10, Stuart McPherson11, Andrew Cook12, Rajiv Jalan1,7, Gautam Mehta https://orcid.org/0000-0002-5696-359X 1,7 PUBLISHED 06 Nov 2024 Author details Author details 1 UCL Institute for Liver and Digestive Health, London, UK 2 Leeds Teaching Hospitals NHS Trust, Leeds, UK 3 Pharmexcel Limited, Welwyn Garden City, UK 4 PPI representative, Stoke-on-Trent, UK 5 University Hospitals Plymouth NHS Trust, Plymouth, UK 6 University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK 7 Royal Free London NHS Foundation Trust, London, UK 8 King's College Hospital NHS Foundation Trust, London, UK 9 Mid and South Essex NHS Foundation Trust, Basildon, UK 10 Portsmouth Hospitals University NHS Trust, Portsmouth, UK 11 Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 12 Clinical Trials Unit, University of Southampton, Southampton, UK 2 Leeds Teaching Hospitals NHS Trust, Leeds, UK 3 Pharmexcel Limited, Welwyn Garden City, UK 4 PPI representative, Stoke-on-Trent, UK 5 University Hospitals Plymouth NHS Trust, Plymouth, UK 6 University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK 7 Royal Free London NHS Foundation Trust, London, UK 8 King's College Hospital NHS Foundation Trust, London, UK 9 Mid and South Essex NHS Foundation Trust, Basildon, UK 10 Portsmouth Hospitals University NHS Trust, Portsmouth, UK 11 Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 12 Clinical Trials Unit, University of Southampton, Southampton, UK Helen Crisp Roles: Conceptualization, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing Oliver Tavabie Roles: Conceptualization, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing Yvanne Enever Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Richard Allen Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Milton Silverman Roles: Writing – Review & Editing Roles: Writing – Review & Editing Juan Acevedo Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Abhishek Chauhan Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Brian Hogan Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Vishal Patel Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Rajeshwar Mookerjee Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Gavin Wright Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Richard Aspinall Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Stuart McPherson Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Andrew Cook Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Rajiv Jalan Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Gautam Mehta Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Project Administration, Supervision, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Project Administration, Supervision, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW REVIEWER STATUS Liver disease is a major, and increasing, cause of death in the UK. The UK Chronic Liver Failure network (UK-CLIF) was developed as a multi-stakeholder network with the aim to advance cirrhosis research, with emphasis on geographical areas of high disease prevalence or limited research activity. The process involved network development through dissemination and snowball sampling techniques, with monitoring of network development and connections between participants, developed over two online meetings. Network membership included representatives from patients, carers, clinicians, researchers, R&D professionals, industry representatives, and the third sector. Subsequently, two facilitated in-person workshops were conducted with network participants. World Café methodology and participant dot voting was used to develop areas of priority and consensus in: (i) research infrastructure for cirrhosis clinical trials, (ii) clinical factors affecting research delivery, and (iii) research priorities for future trials. Thematic analysis demonstrated that the need for patient-centric trial materials, a lack of resource for clinicians to participate in research, and variability in the standard of inpatient care for cirrhosis, were barriers for cirrhosis clinical trials. Future activities for UK-CLIF include participation in a process of quality standard setting for inpatient care for cirrhosis, and coordination of a James Lind Alliance Priority Setting Partnership to develop research questions for liver cirrhosis. Liver disease is a growing problem in the UK, and rates of death have increased by a quarter since 2019. The aim of this project was to develop a network of people involved in clinical trials for advanced liver disease (cirrhosis), to help us deliver better quality studies and develop new treatments. Online meetings were held to develop the network, and then detailed workshops were held in Bristol and Liverpool with patients, carers, researchers, clinical trial experts and other people involved in clinical trials. These meetings found that clinical trials for liver patients should be tailored to patients, and there should be more researchers to do research. Additionally, the network will help to develop standards for patients with liver cirrhosis, so that liver care is similar across the UK, and also help to understand the most important research questions for liver patients in a project with the James Lind Alliance. Liver cirrhosis, clinical trials, alcohol Corresponding Author(s) Gautam Mehta ([email protected]) Grant information: This project is funded by the National Institute for Health and Care Research (NIHR) under its Health Technology Assessment (HTA) programme (Grant Reference Number 155694). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © Crown copyright, 2024 Crisp H et al.. This open access work is licensed under the Open Government Licence v3.0 How to cite: Crisp H, Tavabie O, Enever Y et al. Decompensated Liver Cirrhosis Research Network (UK-CLIF): Building consensus for hepatology trials in the UK [version 1; peer review: 3 approved]. NIHR Open Res 2024, 4:69 (https://doi.org/10.3310/nihropenres.13669.1) First published: 06 Nov 2024, 4:69 (https://doi.org/10.3310/nihropenres.13669.1) Latest published: 06 Nov 2024, 4:69 (https://doi.org/10.3310/nihropenres.13669.1) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Liver disease is now the most common cause of premature death amongst non-communicable diseases in the UK (Figure 1). The burden of liver disease has increased substantially since the Covid-19 pandemic, with mortality rates around ~25% higher in 2024 than 20191. Moreover, it has been widely documented that there are grave inequities in the provision of liver care and clinical outcomes from cirrhosis. Inpatient mortality from cirrhosis varies widely between non-specialist hospitals in England, and mortality rates within 60-days of admission are several times higher than comparable admissions for stroke or ischaemic heart disease2. In parallel, clinical trial performance in the UK, including within liver disease, has tailed off. As noted in the recent review of clinical trials by Lord O’Shaughnessy, within the last five years our relative performance in initiation and recruitment to phase 3 clinical trials has fallen with our relative ranking to other countries decreasing from 4th to 10th globally3. Within the area of liver cirrhosis a number of large clinical trials have been undertaken in the UK in recent years; however, new therapies for decompensated cirrhosis remain lacking and some large studies have closed early (e.g. NIHR award 16/99/02). Novel therapeutic approaches to the management of liver cirrhosis and urgently needed, and to achieve this several aspects of clinical trial design and delivery may be innovated in the post-pandemic era. The overarching aim of the UK-CLIF project is to establish a nationwide, multi-stakeholder network to address shortfalls in, and improve delivery and impact of, clinical research in decompensated cirrhosis. The specific objectives of UK-CLIF were to: (a) establish a prototype multi-stakeholder network to advance cirrhosis research, with emphasis on geographical areas of high disease prevalence or limited research activity; (b) co-develop consensus positions on fundamental aspects of cirrhosis research in the UK, such as research infrastructure for cirrhosis clinical trials and clinical factors affecting research delivery; (c) identify research priorities for future trials and collaborative research. Patients were involved in this project from the outset; two patients (RA, MS) were involved in the design of the proposal and were co-applicants to the NIHR HTA grant (155694). RA and MS also contributed to the design of the network and the workshops, and are co-authors of this manuscript. Additionally, over ten patients or members of the public contributed to the conduct of the workshops described below. RA and MS were also involved in the preparation of this manuscript, and in the design of online dissemination materials (www.ukclif.org). This project was not classified as research according to HRA criteria (https://www.hra-decisiontools.org.uk/research/) or by local R&D colleagues, hence informed consent was not sought from network participants. Network development. Key stakeholders were identified by the project team, and contacted to disseminate details of the network and grow membership participation using snowball sampling techniques (e.g. respondent-driven sampling). The initial stakeholders included members from several key sectors involved in liver disease research: patient representatives, charitable organisations and the third sector (British Liver Trust, British Association for the Study of the Liver), NHS hepatologists, NHS hepatology trainees, NHS liver intensive care specialists, liver nurse specialists, liver dietetics specialists, liver physiotherapists, and representatives from contract research organisations (CROs) and clinical trial units (CTUs). A prototype of the network was established through online meetings, and an online presence (website, branding, social media handle) was developed for growth of the network. Network mapping was conducted to monitor interactions and geographic representation; participants were asked if they had any connection with other meeting participants, and asked to categorise if this connection was a weak connection (aware of their work), or a strong connection (previous collaborative work). Network mapping was conducted after the first two online meetings, and compared with baseline. Facilitated workshops. Two independently facilitated World Café workshops were held in geographically distinct areas, to explore consensus positions on: (i) research infrastructure for cirrhosis clinical trials, (ii) clinical factors affecting research delivery, and (iii) research priorities for future trials. The World Café approach is designed to facilitate consensus development in an open and shared process, enabling input from all involved, regardless of power dynamics4. Workshops had a duration of 2.5 hours, and had a standardised format: Introductions around the room

to the UK-CLIF Network Outline of how the consensus-building process would work Participants rotating around facilitated discussions on the three topics Four or five key priorities from the discussions distilled by facilitators Participants ‘dot voting’ to select priority issues Each of the facilitators ‘hosted’ the small group for one of the discussion topics, through each of the three rounds. Groups were organised so that people were allocated to each topic in turn, with a mix of health care professionals, researchers and patients/carers in each group. After 25 minutes’ discussion people were asked to move to their next group. The membership of each small group changed in each round, so that participants had the opportunity to discuss issues with different people for each topic. During a break, the facilitators synthesised the three rounds of discussion at their table into four or five priority areas. When the participants reconvened, these were presented to the whole group and written up on flipcharts. Participants then carried out ‘dot voting’, with 8 votes per person to allocate between the 12 – 15 priorities identified. Each person could use their votes in any combination, from one vote for each of 8 priorities to 8 votes for one priority. Through this voting process, consensus positions and research priorities were established across the three themes. The development of network connections as measured by network mapping are shown in Figure 2. The findings of the facilitated workshops are outlined below.

of the World Café workshops are summarised in Table 1. Thematic findings addressing (i) research infrastructure and recruitment, and (ii) clinical factors, affecting research delivery in cirrhosis are listed. Some issues were raised by participants at both meetings (left column); the issues that were only raised in one meeting are also listed (centre and right columns). Common themes were: the need for patient-centric trial designs, protocol and strategies for engagement, the lack of resource for clinicians to participate in research, and variability in the standard of inpatient care for cirrhosis which may impact the ‘control’ arm for interventional studies in this group. Findings regarding (iii) research priorities in cirrhosis, were not analysed thematically as there was little cross-over between workshops; these data are presented in supplemental material. The top voted research priorities in the Bristol workshop were: greater use of quality of life as a trial endpoint, and de-prescription of medications as an intervention. The top priorities in the Liverpool workshop were: precision/personalised approaches to therapy (e.g. using -omics) and therapies preventing the first complication of cirrhosis. Individual voting scores for each workshop, and categorical data on participant type, are also presented in the underlying data5. This robust process described above has demonstrated stakeholder engagement, network development and facilitated discussion of consensus positions regarding fundamental aspects of liver cirrhosis research in England. The initial steps of network expansion let to coverage across most areas of England, with representatives including patients, carers, hepatologists, nurses, allied healthcare professionals, translational researchers, and representatives from industry and the third sector. Importantly, this diverse network was used to invite participants for the detailed, World Café workshops. The independently facilitated workshops highlighted three themes, developed by consensus, affecting translational research delivery for liver cirrhosis: patient-centric trial design, research-focussed career pathways and standardisation of inpatient care. These will be discussed in turn below. Patient-centric materials and trial design were raised, and voted for, at both the Bristol and Liverpool workshops. In particular, patient-centric processes were thought important to involve participants from underserved and hard to reach communities. Liver disease frequently affects groups that are underserved, predominantly through socio-economic factors. The median age of death from liver disease in the five most deprived areas of England and Wales is 62 years, compared with 71 years in the least deprived6. In other clinical areas, such as cardiovascular disease, when clinical trial recruitment was not representative of real-world practice translational benefits were not realised7. Therefore, there is a strong case to facilitate inclusion of hard to reach participants in cirrhosis trials, including co-design of trial protocols and patient-facing materials. In particular, the need to adapt recruitment strategies for patients with alcohol-related liver disease (ARLD) was discussed. The challenges of recruitment and retention of patients in this group has been described by investigators in the Unites States, although there are few UK trials targeting this group. A specific trial discussed was the AlcoChange study (ISRCTN 10911773), investigating a digital therapeutic in ARLD. Examples of patient-centric processes from this trial include remote consent, remote data collection and amenable visit schedules. The ongoing learning from this trial will priced valuable information for future studies in this patient group. A perceived lack of prioritisation of clinical research within NHS trusts was also raised as a barrier. This ranged from lack of infrastructure and physical resources, research staff and protected clinician time. Of note, the recent O’Shaughnessy report on UK clinical trials8, and the response from the UK government9, recommends a ‘Clinical Trials Career Path’ to be integrated into the NHS Long Term Workforce Plan. Additionally, the National Institute for Health and Care Research (NIHR) has launched competitive funding streams for infrastructure bids, such as the Commercial Research Delivery Centres bid, which are aligned with the aims to improve NHS research infrastructure articulated in our workshops as well as the O’Shaughnessy review. Nevertheless, this barrier to translational hepatology research merits ongoing attention. The third aspect discussed, and voted for, was the variation in cirrhosis care between secondary and tertiary centres, the consequent need for agreed national care standards and, ideally, a prospectively maintained registry of cirrhosis patients. In particular, this variation impacts the delivery of trials where ‘standard care’ is the control – increasingly so as interventions become more complex. This variation in standard care leads to heterogeneity of outcomes and decreased statistical power to demonstrate the efficacy of potentially useful treatments. Importantly, to address this, the UK-CLIF network has partnered with the British Society for Gastroenterology Liver Committee to develop quality standards for inpatient care of decompensated cirrhosis – this project is in progress. Finally, potential research priorities for the coming years were raised at both workshops (supplemental data). The highest-ranking topics were chosen by robust qualitative prioritisation methodology. However, it is clear for such a broad area as research questions a larger sample size is required. To achieve this, UK-CLIF has partnered with the James Lind Alliance to conduct a nationwide priority-setting process for liver cirrhosis (https://www.jla.nihr.ac.uk/priority-setting-partnerships/liver-cirrhosis/). This is an externally facilitated, transparent qualitative process, with balanced inclusion of patient, carer and clinician interests and perspectives. This process has commenced and will report in early 2025. This project was not classified as research according to HRA criteria (https://www.hra-decisiontools.org.uk/research/) or by local R&D colleagues, hence formal ethical approval and informed consent was not required. Details of the individual voting scores for each workshop, and categorical data on participant type, are presented as underlying data. There was no other data collected. Underlying data: Figshare: Underlying data for ‘Decompensated liver cirrhosis research network (UK-CLIF): Building consensus for hepatology trials in the UK’ HTA166694 Extended data.docx https://doi.org/10.6084/m9.figshare.26181128.v25 Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0) Project conception and design: HC, OT, GM; obtained funding: GM; workshop facilitation and data acquisition: HC, OT, GM; manuscript drafting: HC, OT, GM; manuscript review: all. Faculty Opinions recommendedReferences - 1. Office for Health Improvement and Disparities: Liver disease profile, April 2024 update. 2024; Accessed 15th June 2024. Reference Source - 2. Roberts SE, John A, Brown J, et al.: Early and late mortality following unscheduled admissions for severe liver disease across England and Wales. Aliment Pharmacol Ther. 2019; 49(10): 1334–45. PubMed Abstract | Publisher Full Text | Free Full Text - 3. The Association of the British Pharmaceutical Industry: NHS patients losing access to innovative treatments as UK industry clinical trials face collapse. 2022; Accessed 15th June 2024. Reference Source - 4. Maskrey N, Underhill J: The European Statements of Hospital Pharmacy: achieving consensus using Delphi and World Café methodologies. Eur J Hosp Pharm. 2014; 21(5): 264–66. Publisher Full Text - 5. Mehta G: HTA166694 Extended data.docx.figshare. Dataset. 2024. http://www.doi.org/10.6084/m9.figshare.26181128.v2 - 6. Office for Health Improvement and Disparities: The 2nd atlas of variation in risk factors and healthcare for liver disease in England. 2017; Accessed 15th June 2024. Reference Source - 7. Ferdinand KC, Elkayam U, Mancini D, et al.: Use of isosorbide dinitrate and hydralazine in African-Americans with heart failure 9 years after the African-American Heart Failure Trial. Am J Cardiol. 2014; 114(1): 151–9. PubMed Abstract | Publisher Full Text - 8. The Department of Health and Social Care: Commercial clinical trials in the UK: the Lord O’Shaughnessy review - final report. 2023; Accessed 15th June 2024. Reference Source - 9. The Department of Health and Social Care: Full government response to the Lord O'Shaughnessy review into commercial clinical trials. 2023; Accessed 15th June 2024. Reference Source Author details Author details 1 UCL Institute for Liver and Digestive Health, London, UK 2 Leeds Teaching Hospitals NHS Trust, Leeds, UK 3 Pharmexcel Limited, Welwyn Garden City, UK 4 PPI representative, Stoke-on-Trent, UK 5 University Hospitals Plymouth NHS Trust, Plymouth, UK 6 University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK 7 Royal Free London NHS Foundation Trust, London, UK 8 King's College Hospital NHS Foundation Trust, London, UK 9 Mid and South Essex NHS Foundation Trust, Basildon, UK 10 Portsmouth Hospitals University NHS Trust, Portsmouth, UK 11 Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 12 Clinical Trials Unit, University of Southampton, Southampton, UK 2 Leeds Teaching Hospitals NHS Trust, Leeds, UK 3 Pharmexcel Limited, Welwyn Garden City, UK 4 PPI representative, Stoke-on-Trent, UK 5 University Hospitals Plymouth NHS Trust, Plymouth, UK 6 University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK 7 Royal Free London NHS Foundation Trust, London, UK 8 King's College Hospital NHS Foundation Trust, London, UK 9 Mid and South Essex NHS Foundation Trust, Basildon, UK 10 Portsmouth Hospitals University NHS Trust, Portsmouth, UK 11 Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 12 Clinical Trials Unit, University of Southampton, Southampton, UK Helen Crisp Roles: Conceptualization, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing Oliver Tavabie Roles: Conceptualization, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing Yvanne Enever Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Richard Allen Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Milton Silverman Roles: Writing – Review & Editing Roles: Writing – Review & Editing Juan Acevedo Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Abhishek Chauhan Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Brian Hogan Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Vishal Patel Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Rajeshwar Mookerjee Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Gavin Wright Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Richard Aspinall Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Stuart McPherson Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Andrew Cook Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Rajiv Jalan Roles: Investigation, Writing – Review & Editing Roles: Investigation, Writing – Review & Editing Gautam Mehta Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Project Administration, Supervision, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Project Administration, Supervision, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests RA is National Specialist Advisor and Chair of the Clinical Reference Group for Hepatobiliary & Pancreas for NHS England. RJ is founder of Yaqrit Ltd. and co-founder of Hepyx Ltd. and Cyberliver Ltd. GM is co-founder of Hepyx Ltd. Grant information This project is funded by the National Institute for Health and Care Research (NIHR) under its Health Technology Assessment (HTA) programme (Grant Reference Number 155694). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright © Crown copyright, 2024 Crisp H et al.. This open access work is licensed under the Open Government Licence v3.0 metrics VIEWS $counts.viewCount downloads Citations CITE how to cite this article Crisp H, Tavabie O, Enever Y et al. Decompensated Liver Cirrhosis Research Network (UK-CLIF): Building consensus for hepatology trials in the UK [version 1; peer review: 3 approved]. NIHR Open Res 2024, 4:69 (https://doi.org/10.3310/nihropenres.13669.1) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. track receive updates on this article Track an article to receive email alerts on any updates to this article. Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 06 Nov 2024 Views 0 How to cite this report: Mitchell M. Reviewer Report For: Decompensated Liver Cirrhosis Research Network (UK-CLIF): Building consensus for hepatology trials in the UK [version 1; peer review: 3 approved]. NIHR Open Res 2024, 4:69 (https://doi.org/10.3310/nihropenres.14841.r33821) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-69/v1#referee-response-33821 https://openresearch.nihr.ac.uk/articles/4-69/v1#referee-response-33821 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 23 Dec 2024 Approved VIEWS 0 The manuscript describes the establishment of a network of hepatologists, specialty nurses, patients, caregivers and representatives from funding agencies who met to develop priorities for research in people with advanced chronic liver disease. The process for developing priorities through two ... Continue reading I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close The manuscript describes the establishment of a network of hepatologists, specialty nurses, patients, caregivers and representatives from funding agencies who met to develop priorities for research in people with advanced chronic liver disease. The process for developing priorities through two World Cafe workshops is well described. The process for developing consensus and outcomes of the discussions are reported, highlighting the importance of including people with the disease and their caregivers in the research process. The three key themes of the workshops are worth noting: patient-centric research to facilitate recruitment/retention in trials; research-focused career pathways and standardisation of inpatient care. These themes are critical for improving our knowledge through future research. The "extended data" with the number of members in the two workshops and number of votes cast for individual priorities is worth noting. Insights into the significant differences in the priorities identified by the two workshops (Bristol and Liverpool) would be helpful if known. Was there an attempt to link/reconcile the differing priorities between the two workshops? Stigma was mentioned as a barrier in research in "cirrhosis" and with regard to alcohol. Was there a discussion about language used to identify stages of disease, alcohol use, etc? Lastly, did the workshops discuss adopting the Baveno Consensus Conference recommendations to use compensate/decompensated advanced chronic liver disease rather than "cirrhosis" as the terminology? The authors have made a significant contribution to the field with their patient-centered workshops and discussions. Stigma was mentioned as a barrier in research in "cirrhosis" and with regard to alcohol. Was there a discussion about language used to identify stages of disease, alcohol use, etc? Lastly, did the workshops discuss adopting the Baveno Consensus Conference recommendations to use compensate/decompensated advanced chronic liver disease rather than "cirrhosis" as the terminology? The authors have made a significant contribution to the field with their patient-centered workshops and discussions. - Is the work clearly and accurately presented and does it cite the current literature? Yes - Is the study design appropriate and is the work technically sound? Yes - Are sufficient details of methods and analysis provided to allow replication by others? Yes - If applicable, is the statistical analysis and its interpretation appropriate? Not applicable - Are all the source data underlying the results available to ensure full reproducibility? Yes - Are the conclusions drawn adequately supported by the results? Yes

1. Lee BP, Witkiewitz K, Mellinger J, Anania FA, et al.: Designing clinical trials to address alcohol use and alcohol-associated liver disease: an expert panel Consensus Statement.Nat Rev Gastroenterol Hepatol. 2024; 21 (9): 626-645 PubMed Abstract | Publisher Full TextCompeting Interests: No competing interests were disclosed. Reviewer Expertise: Clinical trials in alcohol-associated hepatitis and alcohol associated liver disease. CITE HOW TO CITE THIS REPORT Mitchell M. Reviewer Report For: Decompensated Liver Cirrhosis Research Network (UK-CLIF): Building consensus for hepatology trials in the UK [version 1; peer review: 3 approved]. NIHR Open Res 2024, 4:69 (https://doi.org/10.3310/nihropenres.14841.r33821) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-69/v1#referee-response-33821 https://openresearch.nihr.ac.uk/articles/4-69/v1#referee-response-33821 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. Views 0 How to cite this report: Chávez-Tapia N and Fernandez-Garibay VM. Reviewer Report For: Decompensated Liver Cirrhosis Research Network (UK-CLIF): Building consensus for hepatology trials in the UK [version 1; peer review: 3 approved]. NIHR Open Res 2024, 4:69 (https://doi.org/10.3310/nihropenres.14841.r33828) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-69/v1#referee-response-33828 https://openresearch.nihr.ac.uk/articles/4-69/v1#referee-response-33828 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 13 Dec 2024 Norberto Chávez-Tapia, Medica Sur Clinic, Mexico, Mexico Valeria M Fernandez-Garibay, Medica Sur Clinic & Foundation, Mexico, Mexico Approved VIEWS 0 This manuscript describes the methodology to develop a research network for liver cirrhosis, coordinated through the World Café methodology. Considering the heuristic approach to creating this network, I suggest including some lines to describe the rationale for using this this ... Continue reading We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close This manuscript describes the methodology to develop a research network for liver cirrhosis, coordinated through the World Café methodology. Considering the heuristic approach to creating this network, I suggest including some lines to describe the rationale for using this this is important considering the limited information about the usefulness of methods for co-creation projects (Ref 1). It is essential to include a dissemination program for primary care physicians to accelerate the translation of the knowledge developed in this project to a broader audience. This innovative approach to developing a research network should also discuss how the relationship with the pharmacy industry or biotechnology companies will be to establish an equitable and transparent relationship. - Is the work clearly and accurately presented and does it cite the current literature? Yes - Is the study design appropriate and is the work technically sound? Yes - Are sufficient details of methods and analysis provided to allow replication by others? Yes - If applicable, is the statistical analysis and its interpretation appropriate? Not applicable - Are all the source data underlying the results available to ensure full reproducibility? Yes - Are the conclusions drawn adequately supported by the results? Yes

1. Agnello DM, Balaskas G, Steiner A, Chastin S: Methods Used in Co-Creation Within the Health CASCADE Co-Creation Database and Gray Literature: Systematic Methods Overview.Interact J Med Res. 2024; 13: e59772 PubMed Abstract | Publisher Full TextCompeting Interests: No competing interests were disclosed. CITE HOW TO CITE THIS REPORT Chávez-Tapia N and Fernandez-Garibay VM. Reviewer Report For: Decompensated Liver Cirrhosis Research Network (UK-CLIF): Building consensus for hepatology trials in the UK [version 1; peer review: 3 approved]. NIHR Open Res 2024, 4:69 (https://doi.org/10.3310/nihropenres.14841.r33828) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-69/v1#referee-response-33828 https://openresearch.nihr.ac.uk/articles/4-69/v1#referee-response-33828 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. Views 0 How to cite this report: Hsu CL. Reviewer Report For: Decompensated Liver Cirrhosis Research Network (UK-CLIF): Building consensus for hepatology trials in the UK [version 1; peer review: 3 approved]. NIHR Open Res 2024, 4:69 (https://doi.org/10.3310/nihropenres.14841.r33693) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-69/v1#referee-response-33693 https://openresearch.nihr.ac.uk/articles/4-69/v1#referee-response-33693 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 05 Dec 2024 Approved VIEWS 0 This manuscript describes the establishment of the UK Chronic Liver Failure network (UK-CLIF) to advance cirrhosis research, particularly in areas with high disease prevalence or limited research activity. The network, comprised of patients, carers, clinicians, researchers, and industry representatives, identified ... Continue reading I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close This manuscript describes the establishment of the UK Chronic Liver Failure network (UK-CLIF) to advance cirrhosis research, particularly in areas with high disease prevalence or limited research activity. The network, comprised of patients, carers, clinicians, researchers, and industry representatives, identified key priorities and areas of consensus in cirrhosis research, including research infrastructure, clinical factors, and future trial priorities. Key barriers to cirrhosis clinical trials, such as patient-centric trial materials, resource limitations, and variability in standards of care, were also identified. Strengths of this network include early involvement of patient representatives and multidisciplinary liver healthcare providers. A consideration for future iterations of network workshops could be to include input from mental health providers/addiction medicine specialists and palliative care providers who can add to the breadth of expertise, particularly to address issues such as early identification of cirrhosis, holistic care, and quality of life, which were all issues identified as priorities in this iteration. Strengths of this network include early involvement of patient representatives and multidisciplinary liver healthcare providers. A consideration for future iterations of network workshops could be to include input from mental health providers/addiction medicine specialists and palliative care providers who can add to the breadth of expertise, particularly to address issues such as early identification of cirrhosis, holistic care, and quality of life, which were all issues identified as priorities in this iteration. - Is the work clearly and accurately presented and does it cite the current literature? Yes - Is the study design appropriate and is the work technically sound? Yes - Are sufficient details of methods and analysis provided to allow replication by others? Yes - If applicable, is the statistical analysis and its interpretation appropriate? Not applicable - Are all the source data underlying the results available to ensure full reproducibility? Yes - Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: The gut microbiome in alcohol use disorder and steatotic liver diseases CITE HOW TO CITE THIS REPORT Hsu CL. Reviewer Report For: Decompensated Liver Cirrhosis Research Network (UK-CLIF): Building consensus for hepatology trials in the UK [version 1; peer review: 3 approved]. NIHR Open Res 2024, 4:69 (https://doi.org/10.3310/nihropenres.14841.r33693) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-69/v1#referee-response-33693 https://openresearch.nihr.ac.uk/articles/4-69/v1#referee-response-33693 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. Alongside their report, reviewers assign a status to the article: - Approved - Approved with reservations - Not approved | Invited Reviewers | ||| |---|---|---|---| | 1 | 2 | 3 | | | Version 1 06 Nov 24 | read | read | read | Sign up for content alerts You are now signed up to receive this alert Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. 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