Title: A randomised controlled trial comparing the clinical effectiveness and cost-effectiveness of laparoscopic cholecystectomy compared with observation/conservative management for preventing recurrent symptoms and complications in adults with uncomplicated symptomatic gallstones (C-Gall)
Funder: Chief Scientist Office, Scotland

Abstract: Design: Parallel group, multi-centre patient randomised superiority trial with 18 month follow-up. Embedded qualitative research will identify any challenges during an internal pilot phase. Setting: Secondary care Participants: Adults with symptomatic uncomplicated gallstone disease referred to a secondary care setting. Exclusion criteria: Unable to consent, ASA III and above, haemolytic disease, pregnancy, bile duct stones, acute pancreatitis, abnormal liver function, empyema/perforated gallbladder. Health technologies being assessed: (i) Laparoscopic cholecystectomy: (ii) Observation/conservative management: Primary outcomes: patient outcome measure - QOL as measured by area under the curve (AUC) at up to 18 months post-randomisation using the SF-36 (AUC measures at 3, 9 12 and 18 months). Economic outcome measure - incremental cost per QALY. Secondary outcomes: Condition specific quality of life (CSQ)a,b; complications; need for further treatment; persistent symptoms; health care resource use; costs. Data collection: The patient reported outcomes (SF-36; CSQ) will be assessed by participant-completed questionnaires at baseline, 3, 9 and 18 months post randomisation. A case report form (CRF) at the time of surgery providing details of the operative procedures, complications and resource use in hospital. Costs of the initial intervention procedures will be estimated from resource use data recorded on the case report forms coupled with routine unit cost data. Costs associated with subsequent contacts with primary and secondary care will be estimated at 3, 9 and 18 months post randomisation and checked at source. QALYs will be estimated from patients’ responses to the SF-36. Sample size: To detect a 0.33 of a standard deviation difference in the area under the curve (AUC) of the SF-36, 90% power with alpha 5%, 194 participants per group (388 total) are required. Such a difference in generic health status is considered clinically relevant and in terms of treatment effect size, in the small to medium range as observed in other clinical studies. To allow for the anticipated approximately 10% of participants for whom outcome data is completely missing, and therefore the AUC cannot be calculated, it is proposed to randomise 430 participants. Project timetable: The projected start date is 1 March 2016: the study duration will be 54 months. Milestones are: Pre-funding-multicentre research ethics and central R&D approvals Month 2-First steering group meeting. Month 4–18- Centre recruitment; recruit local staff. Month 7–30- Recruit patients (staggering centre start up). Month 12- a) Qualitative interviews completed b) Stop/go assessment (patient recruitment). c) Core outcome set completed.Month 18- Stop/go assessment (centre recruitment) Month 48- Final patient follow-up Month 49-53- Data cleaning and analyses Month 54- Final report Recruitment rate: The trial centres conduct an average of 500 cholecystectomies/year. At least 10-20% (50-100) of the patients would be eligible. With a 24 month recruitment period (months 7-30 inclusive) based on a conservative throughput of 50 eligible patients/year in 20 centres with the assumption that 50% of eligible patients in the first month and 50% in Aug and Dec will be missed. We expect that 40% of the remaining eligible patients will be willing to be randomised. The first 20 patients recruited by Month 6, 111 patients by Month 12 and the remaining 319 patients by Month 24 (n=430)

Lay abstract: Gallstones are common, especially in women, but in many people they do not cause any symptoms. About one in three people with gallstones develop symptoms. Symptoms usually include a severe pain in the upper right-hand side of the abdomen (known as ‘biliary colic’), and sometimes nausea and vomiting. At times the pain is accompanied by inflammation of the gallbladder (cholecystitis).Once gallstones start giving symptoms, painkillers, anti-inflammatory medicines and antibiotics are usually prescribed initially and surgery is advised to medically fit patients. Surgery to remove the gallbladder, known as cholecystectomy, is the most common way to treat biliary pain or cholecystitis due to gallstones. Approximately 70,000 cholecystectomies are performed every year in the UK, with significant costs for the NHS. In the UK, surgery is commonly offered to people who present at secondary care with pain or cholecystitis due to gallstones. However, it is known that some patients do not have any more symptoms after the initial episode of pain and that surgery may not be necessary. A policy of ‘conservative management’ (painkillers/antibiotics and lifestyle advice) could, therefore, be appropriate in this group of people. A review of current evidence suggested that ‘conservative management’ may provide a more efficient use of NHS resources. There were, however, great uncertainties in the data, with only two small studies run in Norway. There is a need for a definitive clinical trial to address these uncertainties. The study proposed here will identify patients for the trial at hospital settings for people referred by general practitioners with symptomatic gallstone disease. Patients will be recruited following informed consent to participate using processes approved by an NHS Research Ethics Committee. Once consented, the patient will be allocated randomly to either receive a surgical procedure to remove the gallbladder or to receive conservative management. Apart from treatment allocation and measurement of study outcomes, participants will have standard NHS follow up. Based on statistical calculations, we aim to recruit 430 participants over one and half years who will be followed up for at least 18 months across 20 UK hospitals. The main outcome of the study will be the difference between the two policies in the patients quality of life across an 18 month period from enrolment. We will assess this using a specifically designed questionnaire. To assess any longer term benefits of either policy we will use a mathematical model to give a prediction of quality of life over each participant’s lifetime. We will use the measurements we collect and the model to work out whether gall bladder removal is worthwhile to the NHS in terms of balancing any benefit to people’s health against the added costs (cost-effectiveness). The results of this study will enable patients, clinicians and policy-makers to decide the worth of conservative management as part of treatment of uncomplicated gallstone disease. We have assembled a national team of experts with experience in carrying out clinical trials of surgical procedures, including surgeons, trial methodologists, statisticians, economists and trial managers. The team also benefits from the valuable insight of a knowledgeable patient user group that will continue to be closely involved as the trial progresses. The funding will support essential staff and research resources necessary for this trial.

Research activity codes: 6.4 SURGERY
Health categories: ORAL AND GASTROINTESTINAL