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Beta-blockers or Placebo for Primary Prophylaxis (BOPPP) of oesophageal varices: study protocol for a randomised controlled trial |
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Trials. 2024 Apr 16;25(1):265. doi: 10.1186/s13063-024-08063-3.
Vishal C Patel # 1 2 3, Mark J McPhail # 4 5, Ruhama Uddin # 4, Hassan Jafari 6 7, Vanessa Lawrence 8, Clair Le Boutillier 8 9, James Shearer 8, Nahel Yaziji 8, Angela Cape 7, Haroon Ahmed 10, Christopher Ward 11, Peter Walsh 12, Kevin Besly 4, Ane Zamalloa 4, Joanna Kelly 7; BOPPP study group; Ben Carter 6 7
Collaborators
BOPPP study group:
Ashis Mukhopadhya, Alicija Vileito, Tracy Henderson, Gwilym Webb, Jerrian Joyce Andrada, Abigail Ford, Cyril Sieberhagen, Claire Burston, Carol Brooks, Gavin Wright, Bushena Miyesa, Aimee Williams, Jay Patel, Melchizedek Penacerrada, Gautham Appanna, Gifthy Perez, Joanne Elliott, Keval Naik, Susan Smolen, Anna Beckwith, Matthew Foxton, Carina Bautista, Matthew Cramp, Ada Laureen Nweze, Gayatri Chakrabarty, Indhuja Rajkumar, Merlin James, Steven Masson, Sheenu Thomas, Lucy Dixon, Sarah Hogg, Louise Finlay, Kuldeep Cheent, Jessica Camp, Adrian Stanley, Alexis Duncan, Lauren Walker, Duncan Napier, Paula Hilltout, Linda Hill, Hiromi Uzu, Moby Joseph, Suzannah Pegler, Camille Walling, Lynsey Corless, Anisoara Kingsbury, Tania Nurun, Debasish Das, Anna Williams, Stephen Foley, Camelia Goodwin, Markus Gess, Margaret Grout, Ka-Kit Li, Olivia Watchorn, Laura Plummer, Laura Blackmore, Christos Tsintikidis, Allysha Perryman, George Bird, Emily Phiri, Mohamed Saleh, Adaze Woghiren, Dilukshi Wickramasinghe, Jodie Wright, Michael Miller, Shona Murray, Leanne Cosgrove, John Hutchinson, Julie Burton, Emma Stoner, Stephanie Lupton, Mayur Kumar, Nicola Griffiths, Anna Posada, Andrew Fowell, Avisnata Das, Jincy Daniel, Anu Rose Andrews, Dhiraj Tripathi, Emma Burke, Emma Eaves, Helen Emms, Dina Mansour, Ann Wilson, Maureen Armstrong, Rachael Swann, Faye McMeeken, Shona Perry, Naaventhan Palaniyappan, Elizabeth Davies, Kimberley Noon, Danielle Adebayo, Sarosh Khymani, Deepa Thapa, Mahesh Bhalme, Emma McKenna, Julie Chadwick, Jo Tod, Nina Barratt, Annamaria Wilce, Andrew Austin, Catherine Addleton, Ben Hudson, Rob James, Lily Zitter, Jane Hall, Jennifer Ryan, Christine Eastgate, Edward Britton, Martina Lofthouse, Vikram Sharma, James Hand, Louise Payaniandy, Paula Bravo, Marinos Pericleous, Sheila Mtuwa, Wisdom Mbama, Khaleel Jamil, Sumita Verma, Yaz Hassadin, Zhengmei He, Zdenka Cipinova, Roger McCorry, Allison Lloyd, Heather Lawther, Zeino Zeino, Lana Ward, Trudie Burge, Sarah Hughes, Joseph Delo, Criscel Jan Pelaez, David Whitley, Ameet Dhar, Nowlan Selvapatt, Maria Lanoria, Phil Berry, Sreelakshmi Kotha, Jessica Cordle, Ankita Sunny, Rohit Sinha, Louise Fairlie, Jennifer Henderson, Darren Craig, Eman Alabsawy, Julie Tregonning, Luke Summers, Sophy Booth, Esther Unitt, Susan Dale, Francisco Porras Perez, Melanie Kent, Suzanne Naylor,
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Author information
1Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK. vishal.patel@nhs.net.
2Institute of Liver Studies, Faculty of Life Sciences and Medicine, School of Immunology and Microbial Sciences, King's College London, London, UK. vishal.patel@nhs.net.
3The Roger Williams Institute of Hepatology, Foundation for Liver Research, 111 Coldharbour Lane, London, SE5 9NT, UK. vishal.patel@nhs.net.
4Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK.
5Institute of Liver Studies, Faculty of Life Sciences and Medicine, School of Immunology and Microbial Sciences, King's College London, London, UK.
6Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
7King's Clinical Trials Unit, Institute of Psychiatry, Psychology & Neuroscience,, King's College London, London, UK.
8Health Service and Population Research Department, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
9Division of Methodologies, Florence Nightingale Faculty of Nursing, Midwifery & Palliative Care, King's College London, London, UK.
10Cardiff University, Division of Population Medicine, Cardiff, UK.
11NIHR Clinical Research Network South London, London, UK.
12British Liver Trust, Venta Court, Winchester, UK.
Abstract
Background: Liver disease is within the top five causes of premature death in adults. Deaths caused by complications of cirrhosis continue to rise, whilst deaths related to other non-liver disease areas are declining. Portal hypertension is the primary sequelae of cirrhosis and is associated with the development of variceal haemorrhage, ascites, hepatic encephalopathy and infection, collectively termed hepatic decompensation, which leads to hospitalisation and mortality. It remains uncertain whether administering a non-selective beta-blocker (NSBB), specifically carvedilol, at an earlier stage, i.e. when oesophageal varices are small, can prevent VH and reduce all-cause decompensation (ACD).
Methods/design: The BOPPP trial is a pragmatic, multicentre, placebo-controlled, triple-blinded, randomised controlled trial (RCT) in England, Scotland, Wales and Northern Ireland. Patients aged 18 years or older with cirrhosis and small oesophageal varices that have never bled will be recruited, subject to exclusion criteria. The trial aims to enrol 740 patients across 55 hospitals in the UK. Patients are allocated randomly on a 1:1 ratio to receive either carvedilol 6.25 mg (a NSBB) or a matched placebo, once or twice daily, for 36 months, to attain adequate power to determine the effectiveness of carvedilol in preventing or reducing ACD. The primary outcome is the time to first decompensating event. It is a composite primary outcome made up of variceal haemorrhage (VH, new or worsening ascites, new or worsening hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), hepatorenal syndrome, an increase in Child-Pugh grade by 1 grade or MELD score by 5 points, and liver-related mortality. Secondary outcomes include progression to medium or large oesophageal varices, development of gastric, duodenal, or ectopic varices, participant quality of life, healthcare costs and transplant-free survival.
Discussion: The BOPPP trial aims to investigate the clinical and cost-effectiveness of carvedilol in patients with cirrhosis and small oesophageal varices to determine whether this non-selective beta-blocker can prevent or reduce hepatic decompensation. There is clinical equipoise on whether intervening in cirrhosis, at an earlier stage of portal hypertension, with NSBB therapy is beneficial. Should the trial yield a positive result, we anticipate that the administration and use of carvedilol will become widespread with pathways developed to standardise the administration of the medication in primary care.
Ethics and dissemination: The trial has been approved by the National Health Service (NHS) Research Ethics Committee (REC) (reference number: 19/YH/0015). The results of the trial will be submitted for publication in a peer-reviewed scientific journal. Participants will be informed of the results via the BOPPP website ( www.boppp-trial.org ) and partners in the British Liver Trust (BLT) organisation.
Trial registration: EUDRACT reference number: 2018-002509-78. ISRCTN reference number: ISRCTN10324656. Registered on April 24 2019.
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