Beta-blockers or placebo for primary prophylaxis of oesophageal varices (BOPPP study)

Study design: Multicentre, blinded, randomised controlled trial (RCT) of non-selective beta blockade (NSBB) v placebo in patients with small oesophageal varices (OVs). Setting: Secondary and tertiary care centres with endoscopy and gastroenterology services. Strategy for reviewing literature: This is a commissioned call. Target population: Patients with cirrhosis and small OVs. Inclusion Criteria: Cirrhosis (defined by two of clinical, biochemical, radiological and/or histological criteria), grade 1 OVs without red signs at screening or surveillance endoscopy, no episode of previous overt upper GI bleeding attributed to OVs. Exclusion Criteria: Age <18, unable to give informed consent, unable to undergo screening gastroscopy, pregnancy/lactating, history of overt upper GI bleeding attributed to OVs, previous portosystemic shunt, gastroduodenal ulceration, already on a beta-blocker, requirement for betablockade (known portal hypertension/decompensation/cardiovascular disease), known allergy/intolerance/contraindication to beta-blockers, baseline heart rate (HR) <50bpm, baseline systolic blood pressure <85mmHg, active malignancy. Intervention: Placebo or carvedilol 6.25mg once daily dose adjusted to 12.5mg after a week if tolerated or if HR <50-55 bpm is reached. 1o outcome: Variceal haemorrhage within 3 years, cost-effectiveness. 2o outcomes: All-cause mortality, increase in OV grade, hospitalisation with decompensated cirrhosis, MELD score increase, development of overt hepatic encephalopathy (HE), ascites, jaundice, renal impairment, HCC, myocardial infarction, liver transplantation. Study visits: Screening, randomisation, week 1 following initiation of investigative product for dose escalation, telephone call at 6 weeks and then every 6 months. Health technology being assessed: Carvedilol. Measurements of costs and outcomes: Variceal bleeding will be recorded at presentation, or hospital record, at year 3. 2o outcomes will be recorded from hospital records, case report form (CRF), or mortality registry. Health care costs will be assessed using hospital records and CRF. Quality Adjusted Life Expectancy will be estimated from quality of life measurement at 6 monthly intervals using the EQ-5D-5L. Cost-utility will be determined at 3 years, and at lifetime using a Markov model. Power calculation: Assuming 18% of recruited placebo patients will develop variceal bleeding by 3 years (median 4 years) follow up, and carvedilol will achieve a clinically important hazard ratio of 0.60. For 90% power, 1200 patients in total (600 per allocation group) required to be randomised detect a difference with a two-sided significance level of 0.05. Difference between current and planned care pathways: IMP, health related quality of life questionnaire. Project timetable and recruitment rate: Initial scoping study at King’s College Hospital of (160 patients) then further 18 months of recruitment of patients (aim-1200 patients over the 2-year period), with at least 3 years follow up. Expertise in team: KCH hosts the largest comprehensive clinical hepatology service in Europe and draws on national referral pathways to enhance study recruitment. King’s Clinical Trial Unit (KCTU) have extensive methodological, trial design, statistics, health economics and qualitative research, with a proven track record of delivering large multi-centre RCTs. A UK wide collaborative group have pledged support to this study.