TY - JOUR
T1 - Beta-blockers or Placebo for Primary Prophylaxis (BOPPP) of oesophageal varices
T2 - study protocol for a randomised controlled trial
AU - BOPPP study group
AU - Patel, Vishal
AU - McPhail, Mark
AU - Uddin, Ruhama
AU - Jafari, Hassan
AU - Lawrence, Vanessa
AU - Le Boutillier, Clair
AU - Shearer, James
AU - Yaziji, Nahel
AU - Cape, Angela
AU - Ahmed, Haroon
AU - Ward, Christopher
AU - Walsh, Peter
AU - Besly, Kevin
AU - Zamalloa, Ane
AU - Kelly, Joanna
AU - Carter, Ben
N1 - Funding Information:
This study was supported by the United Kingdom Clinical Research Collaboration-registered King\u2019s Clinical Trials\u00A0Unit at King\u2019s Health Partners, which is part funded by the NIHR Biomedical Research Centre for Mental Health at\u00A0South London and Maudsley NHS Foundation Trust and King\u2019s College London. The BOPPP trial team are grateful to all trial participants, without whom this trial would not be possible. We also acknowledge the contributions of the following: - Independent members of the Trial Steering Committee: Prof Eleanor Barnes, Dr Sam Thomson, Dr Charles Millson, Dr Oliver Van Hecke, Prof Alan Watkins, Dr Claire Snowdon, Elaine Mullings, Morwenna Orton and Peter Walsh. We would like to thank a former member of the TSC, Neville Hargrave, who contributed hugely to the design and conduct of the trial but unfortunately passed away in 2022. - Independent members of the Data Monitoring Committee: Kenneth Simpson, Jeremy Cobbold, Stephanie MacNeill - NIHR local clinical research networks - All PIs and trial staff at all recruiting sites (listed under the BOPPP study group) BOPPP study group. List of sites and collaborating authors. 1. Aberdeen Royal Infirmary - Dr Ashis Mukhopadhya, Alicija Vileito, Tracy Henderson 2. Addenbrooke\u2019s Hospital - Dr Gwilym Webb, Jerrian Joyce Andrada, Abigail Ford 3. Aintree University Hospital - Dr Cyril Sieberhagen, Claire Burston, Carol Brooks 4. Basildon University Hospital - Dr Gavin Wright, Bushena Miyesa, Aimee Williams 5. Bedford Hospital - Dr Jay Patel, Melchizedek Penacerrada 6. Bristol Royal Infirmary - Dr Gautham Appanna, Gifthy Perez, Joanne Elliott 7. Broomfield Hospital\u2014Dr Keval Naik, Susan Smolen, Anna Beckwith 8. Chelsea and Westminster Hospital - Dr Matthew Foxton, Carina Bautista 9. Derriford Hospital - Prof Matthew Cramp, Ada Laureen Nweze 10. East Surrey Hospital - Dr Gayatri Chakrabarty, Indhuja Rajkumar, Merlin James 11. Freeman Hospital - Dr Steven Masson, Sheenu Thomas, Lucy Dixon, Sarah Hogg, Louise Finlay 12. Frimley Park Hospital - Dr Kuldeep Cheent, Jessica Camp 13. Glasgow Royal Infirmary - Prof Adrian Stanley, Alexis Duncan, Lauren Walker 14. Gloucestershire Royal Hospital - Dr Duncan Napier, Paula Hilltout, Linda Hill, Hiromi Uzu 15. Great Western Hospital - Dr Moby Joseph, Suzannah Pegler, Camille Walling 16. Hull Royal Infirmary - Dr Lynsey Corless, Anisoara Kingsbury, Tania Nurun 17. Kettering General Hospital - Dr Debasish Das, Anna Williams 18. King's College Hospital - Dr Mark McPhail, Ane Zamalloa 19. King\u2019s Mill Hospital - Dr Stephen Foley, Camelia Goodwin 20. Kingston Hospital - Dr Markus Gess, Margaret Grout 21. Leicester General Hospital - Dr Ka-Kit Li, Olivia Watchorn, Laura Plummer 22. Lewisham General Hospital - Dr Laura Blackmore, Christos Tsintikidis, Allysha Perryman 23. Maidstone Hospital - Dr George Bird, Emily Phiri 24. Medway Maritime Hospital - Dr Mohamed Saleh, Dr Adaze Woghiren, Dilukshi Wickramasinghe, Jodie Wright 25. Ninewells Hospital (Tayside) - Dr Michael Miller, Shona Murray, Leanne Cosgrove 26. Pinderfields Hospital - Dr John Hutchinson, Julie Burton, Emma Stoner, Stephanie Lupton 27. Princess Royal University Hospital - Dr Mayur Kumar, Nicola Griffiths, Anna Posada 28. Queen Alexandra Hospital (Portsmouth) - Dr Andrew Fowell, Dr Avisnata Das, Jincy Daniel, Anu Rose Andrews 29. Queen Elizabeth Hospital (Birmingham) - Prof Dhiraj Tripathi, Emma Burke, Emma Eaves, Helen Emms 30. Queen Elizabeth Hospital (Gateshead) - Dr Dina Mansour, Ann Wilson, Maureen Armstrong 31. Queen Elizabeth University Hospital (Glasgow) - Dr Rachael Swann, Faye McMeeken, Shona Perry 32. Queens Medical Centre (Nottingham) - Dr Naaventhan Palaniyappan, Elizabeth Davies, Kimberley Noon 33. Royal Berkshire Hospital - Dr Danielle Adebayo, Sarosh Khymani, Deepa Thapa 34. Royal Bolton Hospital - Dr Mahesh Bhalme, Emma McKenna, Julie Chadwick 35. Royal Bournemouth Hospital - Dr Jo Tod, Nina Barratt, Annamaria Wilce 36. Royal Derby Hospital - Dr Andrew Austin, Catherine Addleton 37. Royal Devon and Exeter Hospital - Dr Ben Hudson, Rob James, Lily Zitter, Jane Hall 38. Royal Free Hospital - Dr Jennifer Ryan, Christine Eastgate 39. Royal Liverpool University Hospital - Dr Edward Britton, Martina Lofthouse 40. Royal London Hospital (Barts) - Dr Vikram Sharma, James Hand, Louise Payaniandy, Paula Bravo 41. Royal Surrey County Hospital - Dr Marinos Pericleous, Sheila Mtuwa, Wisdom Mbama 42. Royal Sussex County Hospital - Dr Khaleel Jamil, Dr Sumita Verma, Dr Yaz Hassadin, Zhengmei He, Zdenka Cipinova 43. Royal Victoria Hospital - Dr Roger McCorry, Allison Lloyd, Heather Lawther 44. Southmead Hospital - Dr Zeino Zeino, Lana Ward, Trudie Burge 45. St George\u2019s Hospital - Dr Sarah Hughes, Dr Joseph Delo, Criscel Jan Pelaez, David Whitley 46. St Mary\u2019s Hospital - Dr Ameet Dhar, Dr Nowlan Selvapatt, Maria Lanoria 47. St Thomas\u2019 Hospital - Dr Phil Berry, Dr Sreelakshmi Kotha, Jessica Cordle, Ankita Sunny 48. Sunderland Royal Hospital - Dr Rohit Sinha, Louise Fairlie, Jennifer Henderson 49. The James Cook University Hospital - Dr Darren Craig, Dr Eman Alabsawy, Julie Tregonning 50. Torbay Hospital - Dr Luke Summers, Sophy Booth 51. University Hospital Coventry - Dr Esther Unitt, Susan Dale 52. University Hospital of North Durham - Dr Francisco Porras Perez, Melanie Kent, Suzanne Naylor 53. University Hospital of Wales - Dr Tom Pembroke, Danielle Rice 54. Watford General Hospital - Dr Mohammed Shariff, Xiaobei Zhao 55. Wythenshawe Hospital - Dr Varinder Athwal, Alphonsa Biju, Sheetal Crasta
Funding Information:
This study was supported by the United Kingdom Clinical Research Collaboration-registered King\u2019s Clinical Trials Unit at King\u2019s Health Partners, which is part funded by the NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and King\u2019s College London.
Funding Information:
The BOPPP trial is sponsored by King\u2019s College Hospital NHS Foundation Trust. The trial was commissioned and is funded by the UK National Institute for Health and Care Research Health Technology Assessment Board (NIHR-HTA): Award ID: 17/32/04 https://www.fundingawards.nihr.ac.uk/award/17/32/04 ; the funding body was not involved in the data collection and processing, or the writing of this manuscript. The views expressed are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health and Social Care.
Publisher Copyright:
© The Author(s) 2024.
PY - 2024/4/16
Y1 - 2024/4/16
N2 - 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.
AB - 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.
KW - Adult
KW - Humans
KW - Esophageal and Gastric Varices/diagnosis
KW - Carvedilol/adverse effects
KW - Hepatic Encephalopathy/diagnosis
KW - Ascites/drug therapy
KW - Gastrointestinal Hemorrhage/diagnosis
KW - Adrenergic beta-Antagonists/adverse effects
KW - Hypertension, Portal/complications
KW - Liver Cirrhosis/complications
KW - Randomized Controlled Trials as Topic
KW - Multicenter Studies as Topic
UR - https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-024-08063-3
UR - http://www.scopus.com/inward/record.url?scp=85190610284&partnerID=8YFLogxK
U2 - 10.1186/s13063-024-08063-3
DO - 10.1186/s13063-024-08063-3
M3 - Article
C2 - 38627804
SN - 1745-6215
VL - 25
JO - Trials
JF - Trials
IS - 1
M1 - 265
ER -