Beta-blockers or Placebo for Primary Prophylaxis (BOPPP) of oesophageal varices: study protocol for a randomised controlled trial
Authors: Patel Vishal C. , McPhail Mark J. , Uddin Ruhama , Jafari Hassan , Lawrence Vanessa , Le Boutillier Clair , Shearer James , Yaziji Nahel , Cape Angela , Ahmed Haroon , Ward Christopher , Walsh Peter , Besly Kevin , Zamalloa Ane , Kelly Joanna ,   BOPPP study group, Mukhopadhya Ashis , Vileito Alicija , Henderson Tracy , Webb Gwilym , Andrada Jerrian Joyce , Ford Abigail , Sieberhagen Cyril , Burston Claire , Brooks Carol , Wright Gavin , Miyesa Bushena , Williams Aimee , Patel Jay , Penacerrada Melchizedek , Appanna Gautham , Perez Gifthy , Elliott Joanne , Naik Keval , Smolen Susan , Beckwith Anna , Foxton Matthew , Bautista Carina , Cramp Matthew , Nweze Ada Laureen , Chakrabarty Gayatri , Rajkumar Indhuja , James Merlin , Masson Steven , Thomas Sheenu , Dixon Lucy , Hogg Sarah , Finlay Louise , Cheent Kuldeep , Camp Jessica , Stanley Adrian , Duncan Alexis , Walker Lauren , Napier Duncan , Hilltout Paula , Hill Linda , Uzu Hiromi , Joseph Moby , Pegler Suzannah , Walling Camille , Corless Lynsey , Kingsbury Anisoara , Nurun Tania , Das Debasish , Williams Anna , Foley Stephen , Goodwin Camelia , Gess Markus , Grout Margaret , Li Ka-Kit , Watchorn Olivia , Plummer Laura , Blackmore Laura , Tsintikidis Christos , Perryman Allysha , Bird George , Phiri Emily , Saleh Mohamed , Woghiren Adaze , Wickramasinghe Dilukshi , Wright Jodie , Miller Michael , Murray Shona , Cosgrove Leanne , Hutchinson John , Burton Julie , Stoner Emma , Lupton Stephanie , Kumar Mayur , Griffiths Nicola , Posada Anna , Fowell Andrew , Das Avisnata , Daniel Jincy , Andrews Anu Rose , Tripathi Dhiraj , Burke Emma , Eaves Emma , Emms Helen , Mansour Dina , Wilson Ann , Armstrong Maureen , Swann Rachael , McMeeken Faye , Perry Shona , Palaniyappan Naaventhan , Davies Elizabeth , Noon Kimberley , Adebayo Danielle , Khymani Sarosh , Thapa Deepa , Bhalme Mahesh , McKenna Emma , Chadwick Julie , Tod Jo , Barratt Nina , Wilce Annamaria , Austin Andrew , Addleton Catherine , Hudson Ben , James Rob , Zitter Lily , Hall Jane , Ryan Jennifer , Eastgate Christine , Britton Edward , Lofthouse Martina , Sharma Vikram , Hand James , Payaniandy Louise , Bravo Paula , Pericleous Marinos , Mtuwa Sheila , Mbama Wisdom , Jamil Khaleel , Verma Sumita , Hassadin Yaz , He Zhengmei , Cipinova Zdenka , McCorry Roger , Lloyd Allison , Lawther Heather , Zeino Zeino , Ward Lana , Burge Trudie , Hughes Sarah , Delo Joseph , Pelaez Criscel Jan , Whitley David , Dhar Ameet , Selvapatt Nowlan , Lanoria Maria , Berry Phil , Kotha Sreelakshmi , Cordle Jessica , Sunny Ankita , Sinha Rohit , Fairlie Louise , Henderson Jennifer , Craig Darren , Alabsawy Eman , Tregonning Julie , Summers Luke , Booth Sophy , Unitt Esther , Dale Susan , Perez Francisco Porras , Kent Melanie , Naylor Suzanne , Pembroke Tom , Rice Danielle , Shariff Mohammed , Zhao Xiaobei , Athwal Varinder , Biju Alphonsa , Crasta Sheetal , Carter Ben 
Published: April 2024

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.