Protocol for the development of a core outcome set for clinical trials in primary sclerosing cholangitis

Nasir Hussain^{1

2}, Christopher Ma³, Gideon Hirschfield⁴, Martine Walmsley⁵, Paula Hanford⁵, Mette Vesterhus^{6

7}, Kris Kowdley⁸, Annika Bergquist⁹, Cyriel Ponsioen¹⁰, Cynthia Levy¹¹, David Assis¹², Christoph Schramm^{13

14}, Christopher Bowlus¹⁵, Michael Trauner¹⁶, Olalekan Lee Aiyegbusi^{17

18}, Vipul Jairath^{19

20}, Palak J Trivedi^{21

2}

Affiliations

¹ NIHR Birmingham Biomedical Research Centre, Birmingham, UK.
² Centre for Liver and Gastrointestinal Research, University of Birmingham Institute of Immunology and Immunotherapy, Birmingham, UK.
³ Department of Medicine and Community Health Sciences, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada.
⁴ Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Ontario, Canada.
⁵ PSC Support, Oxford, UK.
⁶ Norwegian PSC Research Centre, Department of Transplantation Medicine, Division of Surgery, Oslo University Hospital, Oslo, Norway.
⁷ Department of Clinical Science, University of Bergen, Bergen, Norway.
⁸ Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, Washington, USA.
⁹ Department of Gastroenterology and Hepatology, Karolinska University Hospital, Stockholm, Sweden.
¹⁰ Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam University Medical Centres, Amsterdam, The Netherlands.
¹¹ Miller School of Medicine, University of Miami, Miami, Florida, USA.
¹² Department of Medicine, Section of Digestive Disease, Yale School of Medicine, New Haven, Connecticut, USA.
¹³ First Department of Medicine, Martin Zeitz Centre for Rare Disease and Hamburg Centre of Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁴ Hamburg Centre of Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁵ Department of Internal Medicine, University of California Davis, Davis, California, USA.
¹⁶ Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Wien, Austria.
¹⁷ Centre for Patient-Reported Outcomes Research, University of Birmingham, Birmingham, UK.
¹⁸ NIHR Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK.
¹⁹ Department of Medicine, Division of Gastroenterology, Western University, London, Ontario, Canada.
²⁰ Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada.
²¹ NIHR Birmingham Biomedical Research Centre, Birmingham, UK p.j.trivedi@bham.ac.uk.

PMID: 38926149
PMCID: PMC11216047
DOI: 10.1136/bmjopen-2023-080143

Protocol for the development of a core outcome set for clinical trials in primary sclerosing cholangitis

Nasir Hussain et al. BMJ Open. 2024.

. 2024 Jun 26;14(6):e080143.

doi: 10.1136/bmjopen-2023-080143.

Authors

Affiliations

¹ NIHR Birmingham Biomedical Research Centre, Birmingham, UK.
² Centre for Liver and Gastrointestinal Research, University of Birmingham Institute of Immunology and Immunotherapy, Birmingham, UK.
³ Department of Medicine and Community Health Sciences, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada.
⁴ Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Ontario, Canada.
⁵ PSC Support, Oxford, UK.
⁶ Norwegian PSC Research Centre, Department of Transplantation Medicine, Division of Surgery, Oslo University Hospital, Oslo, Norway.
⁷ Department of Clinical Science, University of Bergen, Bergen, Norway.
⁸ Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, Washington, USA.
⁹ Department of Gastroenterology and Hepatology, Karolinska University Hospital, Stockholm, Sweden.
¹⁰ Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam University Medical Centres, Amsterdam, The Netherlands.
¹¹ Miller School of Medicine, University of Miami, Miami, Florida, USA.
¹² Department of Medicine, Section of Digestive Disease, Yale School of Medicine, New Haven, Connecticut, USA.
¹³ First Department of Medicine, Martin Zeitz Centre for Rare Disease and Hamburg Centre of Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁴ Hamburg Centre of Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁵ Department of Internal Medicine, University of California Davis, Davis, California, USA.
¹⁶ Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Wien, Austria.
¹⁷ Centre for Patient-Reported Outcomes Research, University of Birmingham, Birmingham, UK.
¹⁸ NIHR Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK.
¹⁹ Department of Medicine, Division of Gastroenterology, Western University, London, Ontario, Canada.
²⁰ Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada.
²¹ NIHR Birmingham Biomedical Research Centre, Birmingham, UK p.j.trivedi@bham.ac.uk.

PMID: 38926149
PMCID: PMC11216047
DOI: 10.1136/bmjopen-2023-080143

Abstract

Background: Primary sclerosing cholangitis (PSC) is a progressive immune-mediated liver disease, for which no medical therapy has been shown to slow disease progression. However, the horizon for new therapies is encouraging, with several innovative clinical trials in progress. Despite these advancements, there is considerable heterogeneity in the outcomes studied, with lack of consensus as to what outcomes to measure, when to measure and how to measure. Furthermore, there has been a paradigm shift in PSC treatment targets over recent years, moving from biochemistry-based endpoints to histological assessment of liver fibrosis, imaging-based biomarkers and patient-reported outcome measures. The abundance of new interventional trials and evolving endpoints pose opportunities for all stakeholders involved in evaluating novel therapies. To this effect, there is a need to harmonise measures used in clinical trials through the development of a core outcome set (COS).

Methods and analysis: Synthesis of a PSC-specific COS will be conducted in four stages. Initially, a systematic literature review will be performed to identify outcomes previously used in PSC trials, followed by semistructured qualitative interviews conducted with key stakeholders. The latter may include patients, clinicians, researchers, pharmaceutical industry representatives and healthcare payers and regulatory agencies, to identify additional outcomes of importance. Using the outcomes generated from the literature review and stakeholder interviews, an international two-round Delphi survey will be conducted to prioritise outcomes for inclusion in the COS. Finally, a consensus meeting will be convened to ratify the COS and disseminate findings for application in future PSC trials.

Ethics and dissemination: Ethical approval has been granted by the East Midlands-Leicester Central Research Ethics Committee (Ref: 24/EM/0126) for this study. The COS from this study will be widely disseminated including publication in peer-reviewed journals, international conferences, promotion through patient-support groups and made available on the Core Outcomes Measurement in Effectiveness Trials (COMET) database.

Trial registration number: 1239.

Keywords: GASTROENTEROLOGY; Hepatobiliary disease; Hepatobiliary surgery; Hepatology; Inflammatory bowel disease; Patient Reported Outcome Measures.

PubMed Disclaimer

Conflict of interest statement

Competing interests: PJT has received grant support from the Wellcome Trust, the Medical Research Foundation, LifeArc, GSK, Guts UK, PSC Support, Intercept Pharma, Dr. Falk Pharma, Gilead sciences, Regeneron, and Bristol Myers Squibb. He has also received speaker fees from Albireo/IPSEN, Intercept and Dr Falk, and advisory board/consultancy fees from Cymabay, Intercept Pharma, Albireo/IPSEN, Pliant Pharma, Chemomab, Dr. Falk Pharma and GSK. OLA declares personal fees from Gilead Sciences, Merck and GlaxoSmithKline outside the submitted work and receives funding from the NIHR Birmingham Biomedical Research Centre (BRC), NIHR Applied Research Collaboration (ARC), West Midlands, NIHR Blood and Transplant Research Unit (BTRU) in Precision Transplant and Cellular Therapeutics at the University of Birmingham and University Hospitals Birmingham NHS Foundation, Innovate UK (part of UK Research and Innovation), Gilead Sciences Ltd, Merck, Anthony Nolan, and Sarcoma UK. MV has received speaker fees from Intercept, Lilly, Siemens Healthineers and GE Healthcare. CP received grant support from Gilead and Perspectum, consultancy fees from Pliant and Chemomab and speaker’s fees from Tillotts. MT received grant support from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda and UltraGenyx; honoraria for consulting from Abbvie, Albireo, Boehringer Ingelheim, BiomX, Falk, Genfit, Gilead, Hightide, Intercept, Jannsen, MSD, Novartis, Phenex, Pliant, Regulus, Siemens and Shire; speaker fees from Albireo, Bristol-Myers Squibb, Falk, Gilead, Intercept, MSD and Madrigal, as well as travel support from AbbVie, Falk, Gilead and Intercept. He is also co-inventor on patents on the medical use of norUDCA/norucholic acid filed by the Medical University of Vienna. MW (on behalf of PSC Support) has received travel/speaker fees from CymaBay, Gilead Sciences, Dr Falk Pharma UK and Perspectum Diagnostics, and consultancy fees from GSK. The views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health. Funders had no role in the design and conduct of the study, including preparation and review of the manuscript.

Figures

**Figure 1**
Flow chart demonstrating four-stage process of COS development. COS, core outcome set; PSC, primary sclerosing cholangitis.

See this image and copyright information in PMC

References

1. Hirschfield GM, Karlsen TH, Lindor KD, et al. . Primary Sclerosing cholangitis. Lancet 2013;382:1587–99. 10.1016/S0140-6736(13)60096-3 - DOI - PubMed
1. Karlsen TH, Folseraas T, Thorburn D, et al. . Primary Sclerosing cholangitis - a comprehensive review. J Hepatol 2017;67:1298–323. 10.1016/j.jhep.2017.07.022 - DOI - PubMed
1. Weismüller TJ, Trivedi PJ, Bergquist A, et al. . Patient age, sex, and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis. Gastroenterology 2017;152:1975–84. 10.1053/j.gastro.2017.02.038 - DOI - PMC - PubMed
1. Trivedi PJ, Crothers H, Mytton J, et al. . Effects of primary sclerosing cholangitis on risks of cancer and death in people with inflammatory bowel disease, based on sex, race, and age. Gastroenterology 2020;159:915–28. 10.1053/j.gastro.2020.05.049 - DOI - PubMed
1. Trivedi PJ, Bowlus CL, Yimam KK, et al. . Natural history, and outcomes of primary sclerosing cholangitis: a systematic review of population-based studies. Clin Gastroenterol Hepatol 2022;20:1687–700. 10.1016/j.cgh.2021.08.039 - DOI - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Protocol for the development of a core outcome set for clinical trials in primary sclerosing cholangitis

Affiliations

Protocol for the development of a core outcome set for clinical trials in primary sclerosing cholangitis

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources