Title: A randomised controlled trial to establish the clinical and cost effectiveness of expectant management versus pre-operative imaging with MRCP in patients with symptomatic gallstones undergoing laparoscopic cholecystectomy at low or moderate risk of common bile duct stones: The Sunflower Study
Funder: Department of Health and Social Care

Abstract: Design: Multi-centre pragmatic randomised controlled trial (RCT) with an internal pilot phase (Phase 1) and a Quintet Recruitment Intervention (QRI). Phase 1 will determine the feasibility of recruitment, adherence to the allocation and data collection processes. Progression to Phase 2 will depend on meeting the progression criteria set for Phase 1. The full RCT will evaluate the effectiveness and cost effectiveness of preoperative magnetic resonance pancreaticogram (MRCP) for the treatment of symptomatic gallstone disease. Participants will be randomised in a 1:2 ratio to MRCP:no MRCP (expectant management). Randomisation will be via a secure website to ensure allocation concealment. Setting: Secondary and tertiary care. The study will recruit from 50 centres. Target population: Adults referred for surgery with symptomatic gallstone disease at low or moderate risk of common bile duct (CBD) stones (based on abdominal ultrasound and liver function tests). Exclusion criteria: High risk of CBD stones, empyema/perforated gallbladder/severe pancreatitis, contraindications to MRCP, haemolytic disease, pregnancy, unable to consent and/or be followed up, ASA IV. Health technologies being assessed: Preoperative MRCP or no MRCP. Intra-operative cholangiogram will be prohibited unless needed to clarify anatomy. Measurement of costs and outcomes: Primary outcome for the full trial will be a composite of any hospital admission for treatment of a complication of gallstones, whether in the CBD or gallbladder within 18 months after randomisation. Admissions will be identified from hospital episode statistics (HES), adjudicated by independent judges blind to allocation in the pilot phase. Secondary outcomes will include: EQ-5D-5L and symptoms of gallstones at baseline (SF-12), on admission for laparoscopic cholecystectomy (LC) and at 3, 6, 12 and 18 months after randomisation (20% sample), items in the LC core outcome set, time from randomisation to surgery, NHS resource use. Costs and cost per QALY will be estimated. Events after discharge will be obtained through linkage with HES. Sample size: We aim to recruit 13,680 participants in total (4,560 MRCP, 9,120 no MRCP). This will provide 90% power to detect a non-inferiority margin >=1.5% in the primary outcome assuming an event rate of 7% at 2.5% one-tailed statistical significance. We expect to recruit about 2140 participants in Phase 1 and the remainder by the end of Phase 2. Criteria for progression from Phase 1 to 2: At least 30 centres open, > 1750 participants randomised, at least 90% of randomised participants adhere to the allocated pathway, evidence that the primary outcome can be reliably identified from routine data. Project Timetable: 72 months: 6m set-up; 48m recruitment (Phase 1: 16m; Phase 2: 32m); minimum 12m follow-up on all participants (median follow-up 18m); 6m analysis and report. Expertise in team: The team is multidisciplinary and includes patients, surgeons, radiologists, health economist, trialists/methodologists, a UKCRC-registered clinical trials unit, an MRC methodology Hub and a Royal College of Surgeons Trials centre.

Lay abstract: Surgery to remove the gallbladder is required if it contains gallstones that cause problems. About 70,000 operations are performed annually in England. Sometimes, gallstones cause other problems if they pass from the gallbladder into the nearby bile duct (e.g. jaundice/inflammation of the pancreas). Then it is necessary to remove the bile duct stones before or during the gallbladder operation. Because of this, patients requiring gallbladder surgery are assessed for risk of bile duct stones. If the risk is high, further tests are done to identify if bile duct stones are present. If the risk is moderate or low (although it can be difficult to distinguish between the two), then it is uncertain whether further tests to look for bile duct stones are necessary. As a result, some surgeons choose to perform tests and others don’t. A UK-wide research study found that a third of patients undergoing gallbladder surgery were tested, usually before surgery using an MRI scanner. This test involves a 1-hour visit to hospital and costs the NHS about £365. The test identifies bile duct stones but may delay gallbladder surgery (maybe by 2 months) which can lead to increased problems with gallstones whilst waiting. There are other uncertainties about the need for testing. Even if the test shows bile duct stones, the stones can pass into the bowel spontaneously; and removing the stones can cause complications. Not having the test avoids these risks but can lead to bile duct stones being left behind after surgery, which may also cause complications. Research to establish if going straight to gallbladder surgery without testing the bile duct beforehand is needed. The Sunflower Study will find out whether testing for bile duct stones before gallbladder surgery is worthwhile or not in patients with a low or moderate risk of having stones. Over 4 years, about 35,000 eligible patients in 50 UK hospitals will receive information about the study. Patients who consent to participate (13,680 expected) will be divided into two groups. One group will go straight to surgery (i.e. no additional test) and the other will be tested before surgery. The groups will be selected by a process called randomisation to ensure that groups have similar patients in terms of general health, age, gender etc. This allows a fair comparison to be made between the two groups. The ‘straight to surgery’ group will have twice as many people in as the ‘tested’ group to reduce the number of extra tests performed. Both groups will be followed for 18 months and information about the need for treatment of bile duct stones, complications of surgery and costs collected. Most surgeons in the UK are unfamiliar with participating in research studies like this one, so the study will include support and training for surgeons to ensure they communicate information about the study information clearly and fairly. The number of patients agreeing to take part and being followed up successfully will be checked in each centre and, after a probationary period, the information will be reviewed to make sure that it is possible to complete a full trial. This study will be carried out by an experienced multi-disciplinary team of surgeons, radiologists, researchers and patient representatives. We expect it will take six years. Independent people will review the study regularly and provide advice. The results will be made publicly available to inform future care of patients with gallbladder disease.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.4 SURGERY
Health categories: ORAL AND GASTROINTESTINAL