Laparoscopic cholecystectomy versus conservative management for adults with uncomplicated symptomatic gallstones: the C-GALL RCT

Article history

The research reported in this issue of the journal was funded by the HTA programme as award number 14/192/71. The contractual start date was in April 2016. The draft manuscript began editorial review in April 2022 and was accepted for publication in February 2023. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ manuscript and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this article.

Copyright statement

Copyright © 2024 Innes et al. This work was produced by Innes et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.

2024 Innes et al.

Introduction

Gallstone disease (cholelithiasis) is one of the most common gastrointestinal disorders in industrialised societies. The prevalence of gallstones in the adult population is approximately 10–15%. 2–6 Gallstones are more common in women and people over the age of 40 years.

Clinical surveys conducted in Europe, North and South America, and Asia indicate that prevalence rates for gallstone disease range from 5.9% to 25% and tend to increase with age. 7–10 A clinical ultrasound survey conducted in the UK reported prevalence rates of 12% among men and 22% among women over 60 years of age. 9 A multicentre population-based study conducted in Italy has reported an annual incidence of gallstone disease of 0.66% in men and 0.81% in women. 11

In the UK and North America, the number of surgical procedures for gallstone disease increased steadily between the 1950s and 1990s, reflecting the rise in prevalence of identified gallstone disease and the use of cholecystectomy as the treatment of choice. Rates of surgical procedures stabilised in these countries towards the end of the twentieth century. 6

The natural course of gallstones is benign, with most people being asymptomatic and with relatively low progression from asymptomatic disease to symptomatic disease. 12 In an Italian population-based study, the overall frequency of symptom development in asymptomatic people was around 20% over a long follow-up period (mean 8.7 years). 12 Similarly, a systematic review published in 2007 reported that the progression of asymptomatic to symptomatic disease ranged from 10% to 25% in studies that followed up patients after their initial diagnosis (up to 15 years of follow-up). 13 The annual risk of developing symptoms has been estimated to be around 2–4%. 12

Most people with symptomatic uncomplicated gallstone disease probably do not develop complications; the annual rates of developing gallstone-related complications (e.g. acute cholecystitis, acute pancreatitis, acute cholangitis obstructive jaundice) have been reported to be as low as 1–3%. 14–16 The Italian Group for the Epidemiology and Prevention of Cholelithiasis study reported an annual incidence of complications of 0.7% for symptomatic patients. 17

Mortality from gallstone disease is rare, with typically < 1% of people dying from gallstone-related causes. 12,17,18

From a patient’s perspective, the defining symptom of gallstone disease is severe and lasting (i.e. > 30 minutes) abdominal pain. 19,20 Commonly, general abdominal symptoms intensify over a period and become regular pain attacks (biliary colic) and may require medical attention.

A recent large prospective study conducted in the UK (8909 participants) has shown that 10.8% of people experienced complications 30 days after surgery. 21 Furthermore, a proportion of people (up to 40%) may continue to experience pain and abdominal symptoms after surgery. 22 In particular, persistent pain similar to that experienced preoperatively has been reported in about 20% of people after cholecystectomy23,24 and de novo pain has been reported in up to 14% of people. 25

The term ‘postcholecystectomy syndrome’ is an umbrella term widely used to describe the range of symptoms that occur after cholecystectomy. 26 The term ‘persistent postcholecystectomy symptoms’ has been suggested as a more accurate description of these symptoms. 27 Symptoms include biliary and non-biliary abdominal pain, dyspepsia, heartburn, nausea, vomiting and jaundice. Persistent diarrhoea or constipation is often reported after cholecystectomy, and flatulence may arise de novo after surgery. 25 There is no consistent pathophysiological explanation for persistent postcholecystectomy symptoms and, in about 5% of people, the reason for constant abdominal pain remains unknown. 28,29

The rationale for the trial

Current clinical guidelines recommend expectant treatment for asymptomatic gallstones and hence laparoscopic cholecystectomy is considered for biliary pain or acute cholecystitis with radiological evidence of gallstones (i.e. symptomatic gallstones). 30 As per most of the international guidelines, cholecystectomy is the default option for people with symptomatic gallstone disease,30 and one of the most common and, in terms of total costs, costly elective surgical procedures performed in the NHS in the UK. Some 74,373 cholecystectomies were performed in England in 2019 at an average cost of £3581 per procedure31 (61,584 of these following elective admissions). 32 These figures indicate that although some patients are operated on in the acute hospital setting, many people with uncomplicated symptomatic gallstone disease are put on a waiting list and operated on electively after several months. Mean waiting time varies according to available resources; in the UK pre-COVID it has been reported to be around 12 months. 33

Observation and relief of symptoms, delivered mainly in primary care, may be a valid therapeutic option in people presenting with uncomplicated disease, depending on their age, clinical presentation and evolution of symptoms over time. Symptom management includes the prescription of analgesics alongside dietary advice and, when necessary, anti-inflammatory drugs or antibiotics. Moreover, as symptoms of uncomplicated gallstones are usually not urgent, it may be reasonable to consider a conservative option first, which could save a considerable amount of NHS resources.

Early natural history studies, and more recent observational and population-based studies, have suggested that a proportion of people with symptomatic gallstone disease no longer experience biliary pain after the onset of symptoms. 12,17,18,22,34 Larsen et al. 22 found that 45% of symptomatic people on watchful waiting were relieved from symptoms during a 1-year observation period. Similarly, Festi et al. observed that 58% of people with initially mild symptoms, and 52% of those with more severe symptoms, did not experience further pain episodes during a follow-up period of 10 years, or an increase in disease severity over time. 12 If about half of the people treated conservatively were likely to be symptom-free, up to 30,000 cholecystectomies per year could potentially be avoided with a likely saving for the NHS of around £68 million/year.

A National Institute of Health and Care Research (NIHR) Health Technology Assessment (HTA) found that, on average, cholecystectomy is more costly but more effective than observation/conservative treatment for symptomatic gallstones or cholecystitis. 35 Nevertheless, half of the people treated conservatively were symptom-free and did not require surgery in the long term (14-year follow-up) indicating that there is probably a proportion of patients with uncomplicated symptomatic gallstone disease who could benefit from a conservative approach. The specific results were that participants randomised to observation/conservative treatment were significantly more likely to experience gallstone-related complications [risk ratio (RR) 6.69; 95% confidence interval (CI) 1.57 to 28.51; p = 0.01], in particular acute cholecystitis (RR 9.55; 95% CI 1.25 to 73.27; p = 0.03), but less likely to undergo surgery (RR 0.50; 95% CI 0.34 to 0.73; p = 0.0004) and experience surgery-related complications (RR 0.36; 95% CI 0.16 to 0.81; p = 0.01) than those randomised to receive surgery. Fifty-five per cent of people randomised to observation/conservative treatment did not require an operation during the 14-year follow-up period, and 12% of people randomised to cholecystectomy did not undergo the scheduled surgical operation. These results were subject to major uncertainties in the reported economic model. Even when cholecystectomy occurred after conservative management, a conservative management strategy had between 40% and 60% chance of being cost-effective for alternative values of willingness to pay for an additional quality-adjusted life-year (QALY).

Furthermore, results were strongly influenced by the proportion of individuals initially treated conservatively who subsequently required surgery. Due to the limited evidence available and the current lack of UK NHS data, the C-GALL Research Group highlighted the need for a well-designed trial assessing the effects and safety of observation/conservative treatment compared with cholecystectomy.

Aims and objectives

The primary aim of the study is to assess the clinical and cost-effectiveness of observation/conservative management with laparoscopic cholecystectomy for preventing recurrent symptoms and complications in adults presenting with uncomplicated symptomatic gallstones in a secondary care setting.

The primary patient objective is to compare observation/conservative management with laparoscopic cholecystectomy in terms of participants’ quality of life (QoL) using the Short Form-36 items (SF-36) health survey bodily pain domain at up to 18 months after randomisation.

The primary economic objective is to assess the cost-effectiveness of observation/conservative management versus laparoscopic cholecystectomy in terms of the incremental cost per QALY.

The secondary objectives are to compare observation/conservative management with laparoscopic cholecystectomy in terms of condition-specific quality of life (CSQ); SF-36 domains (excluding bodily pain domain); complications; need for further treatment; persistent symptoms; healthcare resource use (HCRU); and costs. Secondary outcomes are assessed at 18 and 24 months after randomisation. The bodily pain domain of the SF-36 health survey will also be assessed up to 24 months after randomisation.

The null hypothesis being tested is that there is no difference between observation/conservative management and laparoscopic cholecystectomy. The alternative hypothesis is that laparoscopic cholecystectomy is superior.

Trial design

The study protocol has been published in an Open Access journal. 1 The study protocol and study paperwork will be available on the project webpage at https://www.fundingawards.nihr.ac.uk/award/14/192/71 (accessed January 2024).

C-GALL was a pragmatic, multicentre parallel-group patient randomised superiority trial (with internal pilot phase) to test if the strategy of laparoscopic cholecystectomy is more (cost-) effective than observation/conservative management at 18 months post randomisation. The aim was to recruit 430 adults with symptomatic uncomplicated gallstone disease (biliary pain), who were electively referred to a secondary care setting and considered suitable for cholecystectomy, to assess the clinical and cost-effectiveness of observation/conservative management with laparoscopic cholecystectomy for preventing recurrent symptoms and complications.

The trial design is summarised in Figure 1. Patients were recruited to the trial, and all were followed up to at least 24 months post randomisation and every 6 months thereafter to the end of the trial.

FIGURE 1.

C-GALL trial design. CRF, case report form.

The primary patient objective was to compare observation/conservative management with laparoscopic cholecystectomy in terms of participants’ QoL using the SF-36 bodily pain domain at up to 18 months after randomisation.

The primary economic objective was to assess the cost-effectiveness of observation/conservative management versus laparoscopic cholecystectomy in terms of the incremental cost per QALY. This information was collected at each follow-up time point (3, 9, 12, 18 months and 6 months thereafter post randomisation till end of trial).

Embedded process evaluation

An embedded process evaluation was incorporated into the study design to identify challenges relating to trial design and/or conduct that could be addressed and modified. The process evaluation component included, where necessary: analysis of participant flow data; audio recording of recruitment consultations with potential trial participants; and semistructured telephone interviews with patients and trial participants [trial consenters, trial non-consenters, those who crossed over trial groups, those who returned questionnaires (returners) and those who did not (non-returners)], and in-depth semistructured telephone interviews with clinical site staff. The trial process evaluation is described in more detail in Chapter 6.

Participants

Participants were adults with symptomatic uncomplicated gallstone disease (biliary pain from previous biliary colic or acute cholecystitis) who were electively referred to a secondary care setting and considered suitable for cholecystectomy. Adult patients with diagnosed gallstone disease electively referred to a secondary care setting via general practitioner (GP) referral, accident and emergency (A&E) department or elsewhere, not requiring emergency surgical or endoscopic intervention were approached by the research teams. The following inclusion criteria were used to identify eligible participants.

Identification

Potential participants were recruited from secondary care hospitals across the UK. Participants were identified by the local research team at these participating centres. Following identification of potential participants, an invitation letter and patient information leaflet (PIL) detailing the trial were sent out, inviting them to attend a hospital outpatient clinic visit, where the trial and their treatment would be discussed. Potential participants not identified prior to a clinic visit, or at sites that were unable to send the PIL in advance, were given the PIL at their outpatient clinic visit. The PIL also highlighted that the clinical consultation might be audio-recorded; in sites who had agreed to do this, participants were asked to consent to do so.

At the hospital outpatient clinic visit, the local research team outlined the trial and asked the patient if they were willing to discuss participation and have their conversation audio-recorded. If the patient did not wish to have their conversation audio-recorded the consultation went ahead as normal, and the patient still had the choice to take part in the trial. For those patients who were happy to discuss the trial, a member of the local research team completed a trial screening form using information from the prospective participant and from the clinical record to document fulfilment of entry criteria. Eligibility criteria were then cross-checked with the patients’ clinical records. If the patient was eligible and in provisional agreement, a local research team member met with the patient immediately in the clinic. Eligible participants who expressed an interest in participating had the study explained to them by local research staff and were asked if they had any questions or concerns about participating in the trial. If they agreed to take part, they gave written consent to be randomised.

Recruitment and consent

All staff involved in recruitment and consent had evidence of up-to-date good clinical practice (GCP) training. Written informed consent was sought from those patients interested in participating in the trial. Patients were given sufficient time to accept or decline involvement and were free to leave the study at any time. Patients made the decision to participate during the initial consultation, during a subsequent visit to hospital, or alternatively at home. If the patient decided to take part during the initial consultation, this became the baseline visit. For patients who decided to take part during a subsequent visit to hospital, this became the baseline visit. If the patient agreed to be contacted at home, they received a telephone call from the local research nurse (RN) to discuss any queries. Patients who decided to participate following telephone counselling could either send their completed documents (consent form and baseline questionnaire) through the post to the local team at their treating hospital or bring it with them if they were returning to hospital for another consultation.

Randomisation/treatment allocation

Eligible participants consenting to the trial were randomised to receive either laparoscopic cholecystectomy or observation/conservative management in a 1: 1 allocation ratio, using the randomisation application at the trial office at the Centre for Healthcare Randomised Trials (CHaRT). The randomisation application was available via a 24-hour telephone Interactive Voice Response randomisation system or a web-based application. The minimisation algorithm used recruitment site, gender (male/female) and age (< 35; 35–64; ≥ 65 years) as minimisation covariates to allocate treatment. A random element (20% chance) was incorporated into the minimisation algorithm.

For patients who consented to take part in the trial at their initial consultation, randomisation happened during this visit, and they were informed of their allocated treatment group immediately. If the patients were not present in the clinic, they were contacted by the research teams to inform them of the allocated treatment group.

Interventions evaluated

1. Laparoscopic cholecystectomy (surgical management): the current standard surgical procedure for the management of symptomatic gallstone disease. The gallbladder is removed with the stones within it using keyhole techniques (laparoscopy). The procedure is undertaken under a general anaesthetic. It usually involves three to four small incisions in the abdomen, which allow the surgeon to dissect the gallbladder from its attachments and safely divide the key anatomical structures (the cystic duct and artery) that link it to the main bile ducts. The gallbladder is then separated from the under surface of the liver. Usually the gallbladder (containing the stones) is removed within a retrieval bag via one of the small incisions. The operation takes between 45 and 120 minutes, and many patients are admitted for one night, although day-case laparoscopic cholecystectomy is safely undertaken in otherwise fit patients with appropriate social support. All surgical cases are initially started laparoscopically (keyhole) with an intention to remove the gallbladder. Occasionally it might have to be converted to open surgery either to deal with a complication or due to difficulty in progressing safely. Moreover, an alternative procedure may be performed if there is anticipated difficulty in removing gallbladder safely (i.e. drainage of the gallbladder, subtotal cholecystectomy, etc.).

2. Observation/conservative management: in the context of gallstone disease, this involves the prescription of analgesics to relieve the biliary pain, if and when required. Typical therapy includes paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. ibuprofen), narcotic analgesics (e.g. opiates), antispasmodics (e.g. Buscopan), together with generic healthy lifestyle advice. In the longer term, observation/conservative management may involve strategies for symptom control (e.g. analgesia and antispasmodics) alongside the advice to follow a healthy diet and eat regular meals.

Participants who were randomised to the observation/conservative management group of the study were also given a copy of the medical management PIL which provided them with information about what to do if they had a flare-up of their condition and advice on diet.

Blinding of personnel in the study

Baseline data were reported by study participants before randomisation using self-completed questionnaires. Blinding was not possible due to the interventions.

Data collection

The patient-reported outcomes SF-36, CSQ and HCRU were collected at recruitment [baseline (before surgery), except HCRU] and then at 3, 9, 12, 18 and 24 months (post randomisation) and 6 monthly thereafter until the end of trial, December 2021. An additional questionnaire, participant costs, was issued at 18 months. Case report forms (CRFs) were completed after gallstone surgery had taken place (with details of operative procedures), complications, and resource use in hospital. A RN completed a CRF at 24 months for all participants to confirm if they had received any gallbladder-related surgery, and if so the type of procedure and the date it was received.

The schedule for data collection is outlined in Table 1.

Baseline

For each participant two CRFs were completed at baseline: participant details and baseline. The participant details CRF recorded name and full contact details, date of birth, gender and ethnicity. The baseline CRF recorded clinical information (including height, weight, information about the gallbladder, confirmation of diabetes and hypertension). The data from the CRFs were entered into the study website.

At baseline, participants completed the baseline questionnaire: SF-36 and CSQ. At the end of the baseline consultation, a reminder card was given to all participants to record information about any surgery they went on to have for their gallstones. Participants were asked to return this to the trial office in a prepaid envelope.

Follow-up

Participants were followed up by questionnaire (issued by post, e-mail or telephone) which collected patient-reported outcomes (SF-36; CSQ; HCRU) at 3, 9, 12, 18 and 24 months (post randomisation) and 6 monthly thereafter until the end of trial. If participants did not respond to the first issue of the questionnaire, a reminder was sent 3 weeks later. If no response was received after 3 weeks, then this was followed up with a telephone call, and if no contact could be made a final questionnaire for this time point was issued. In addition, at 18 months an additional questionnaire, participant costs, was issued to collect information on participant costs in using health services.

Where data were collected by telephone, participants were offered the option of only completing the responses required to capture the primary outcome, safety and surgery data.

A participant newsletter was issued in August 2019 in an attempt to encourage questionnaire response. This included personalised information about their stage in the trial, how many questionnaires were left to complete and, more generally, trial progress.

A RN completed CRFs after any gallstone surgery had taken place, providing details of the operative procedures, complications and resource use in hospital. Costs of the initial intervention procedures were estimated from resource use data recorded on the CRFs coupled with routine unit cost data. Costs associated with subsequent contacts with primary and secondary care (due to symptomatic gallstones) were estimated from patient questionnaires at 3, 9, 12,18 and 24 months (post randomisation) and 6-monthly thereafter until the end of trial and checked at source. QALYs were estimated from patients’ responses to the SF-36.

Where completed follow-up questionnaires identified that a participant had received an operation to remove their gallbladder or received a further treatment or surgery to treat their gallstone symptoms, this was followed up with the site RN to complete the appropriate CRFs.

A RN completed a CRF at 24 months for all participants to confirm if they had received any gallbladder-related surgery, and if so the type of procedure and the date it was received. If participants had been found to have had a surgery, the relevant CRFs were then completed.

Data processing

Research nurses at each of the participating centres entered both baseline and CRF data for their participants onto the study website through an online portal. Follow-up questionnaire data, which were sent from the participant directly to the trial office, were entered into the study website by trial office staff.

As part of the trial’s monitoring plan, the trial office carried out data accuracy checks on a sample of baseline data entered by each site. No data accuracy checks were carried out on the data entered by trial office staff upon receipt of follow-up questionnaires.

Participant withdrawal

Participants remained in the trial unless they chose to withdraw consent or if they were unable to continue for a clinical reason. All changes in status (with the exception of complete withdrawal of consent) meant the participant was followed up for all trial outcomes wherever possible. All data collected up to the point of complete withdrawal were retained and used in the analysis.

Outcomes

Safety and breaches

Ground rules for statistical analysis

The trial analysis followed a statistical analysis plan (SAP), which was agreed by the Project Management Group (PMG) and Trial Steering Committee (TSC) before analysis was started. Apart from the trial statistician, all other authors were blinded to the data when agreeing the SAP. The main analyses were based on the intention-to-treat (ITT) principle (i.e. analysed as randomised irrespective of non-compliance or crossover) and took place after the 24-month follow-up was completed for all participants. Baseline and follow-up data were summarised using appropriate statistics and graphical summaries. Statistical significance was at the two-sided 5% level with corresponding 95% CIs derived. All analyses were carried out using Stata 16. 36

Economic evaluation

Within this study both a ‘within-trial’ and a model-based economic evaluation were conducted. These are described in detail in Chapters 4 and 5.

Ethics approval and monitoring

C-GALL received favourable ethics opinion from North of Scotland Research Ethics Committee (REC) A, on 23 May 2016 (REC reference number 16/NS/0053).

Sponsorship

The University of Aberdeen and NHS Grampian co-sponsored the trial.

Management of the trial

The trial management team (consisting of the Trial Manager, Data Coordinator and the Co-Chief Investigators), based within CHaRT, University of Aberdeen, provided day-to-day support for the recruiting centres. Recruiting centres were led by a local Principal Investigator (PI). The PIs in most cases were supported by RNs, trial co-ordinators or dedicated staff, who were responsible for all aspects of the local organisation, including recruitment of participants, delivery of the interventions and notification of any problems or unexpected developments during the study period. The study was supervised by the PMG, which consisted of representatives from the study office and grant holders.

Oversight of the study

Protocol amendments

There were 10 protocol amendments, and these are summarised in Appendix 2, Table 37. All were minor clarifications within the protocol. All were reviewed by the sponsor and the study funder before being submitted to, and then approved by, the REC.

Important changes to the methods after trial commencement

Core outcome set

A COS for uncomplicated symptomatic gallstones was developed and is described in more detail in Chapter 7.

Study Within A Trial

The C-GALL study was involved in the Christmas Card Study Within A Trial (SWAT). 39 Full details of the methods and results can be accessed in the associated publication. 40

In brief participants receiving postal questionnaires in eight host studies (including C-GALL) were randomised to receive a Christmas card or no Christmas card. The primary outcome of the SWAT was response to the next postal questionnaire that was due. The results of the SWAT showed that sending a Christmas card did not increase response rates compared to not sending a Christmas card.

The C-GALL study was also involved in the STICKER SWAT. 41 Participants receiving postal questionnaires in two studies (including C-GALL) are randomised to have a sticker with the trial logo included on the outgoing envelope or a plain envelope. This SWAT is ongoing and, as such, results are not yet available but will be reported in the future.

Recruitment to the C-GALL trial

Participants were recruited to the C-GALL trial between August 2016 and November 2019. In total, 436 participants were randomised from 20 centres within the UK (Table 2), 218 to each group. The trajectory of recruitment from all centres is shown in Figure 2. Initial recruitment was limited to four pilot centres (Aberdeen Royal Infirmary, Nottingham City Hospital, Musgrove Park Hospital, Taunton and Royal Free Hospital, London). Roll-out to other centres began in April 2017. Recruitment was slower than originally projected and an 18-month extension to recruitment was requested and approved. A revised recruitment projection was initiated in March 2018 (see long dashed line in Figure 2).

FIGURE 2.

Recruitment over time.

Participant flow

The Consolidated Standards of Reporting Trials (CONSORT) diagram for the C-GALL trial is shown in Figure 3. There were 2667 patients identified to be potentially eligible for inclusion into the trial, of which 1298 were excluded. The main reasons for patients’ exclusion were that they were ineligible (647/1298, 49.9%). Ineligibility was due to unconfirmed symptomatic gallstones (233/647, 36.0%), clinical diagnosis of symptomatic gallstone disease not confirmed by imaging (144/647, 22.3%) and being medically unfit for surgery (105/647, 16.2%). Of the 1369 eligible patients, 933 were not randomised with 910/933 (97.5%) having a preference. Main preference reasons were participants preferred laparoscopic cholecystectomy (538/910, 59.1%), observation/conservative management (167/910, 18.4%) and did not want to be randomised (91/910, 10.0%). Further details on reasons why patients were excluded and not randomised are shown in Appendix 3, Table 38.

FIGURE 3.

Participant flow (CONSORT) diagram.

Of the 436 participants randomised, one participant was a post-randomisation exclusion in the observation/conservative management group due to the participant immediately withdrawing from the study due to a previously unstated preference for laparoscopic cholecystectomy. One participant was randomised twice in the laparoscopic cholecystectomy group through error. At 24 months, in the observation/conservative management group, 136 (62.1%) participants responded to participant questionnaires (PQs) and 12 (5.5%) had declined further follow-up. In the laparoscopic cholecystectomy group, 138 (63.6%) participants responded to PQs and 11 (5.1%) had declined further follow-up and one participant had died. Appendix 3, Table 39 shows the response rates for each of the follow-up time points.

Baseline characteristics

The baseline characteristics are shown in Table 3. Overall, the randomised groups were well balanced in baseline characteristics. The mean age of participants was approximately 50 years, over 78% were female and over 85% were white. In the observation/conservative management group, 60.4% had a normal gallbladder wall confirmed by transabdominal ultrasonography or another imaging technique compared with 55.3% in the laparoscopic cholecystectomy group. The mean SF-36 norm-based bodily pain score was 44.5 (SD 11.7) in the observation/conservative management group and 43.3 (SD 11.1) in the laparoscopic cholecystectomy group.

Non-responders to questionnaires tended to be younger (mean 46 vs. 52 years), have worse SF-36 bodily pain (mean 41.8 vs. 46.6) and worse disease-specific measures at baseline compared to responders.

Treatment received

At 18 months, 54 (24.9%) in the observation/conservative management group and 146 (67.3%) in the laparoscopic cholecystectomy group received surgery. Further surgery details up to 18 months are provided in Appendix 3, Table 40. At 24 months, 64 (29.5%) in the observation/conservative management group, and 153 (70.5%) in the laparoscopic cholecystectomy group received surgery with a median time to surgery of 9.0 months (IQR 5.6–15.0) and 4.7 months (IQR 2.6–7.9), respectively. The majority of the surgical operations were elective in both groups, and over 95% were performed laparoscopically. In the observation/conservative management group, surgery was straightforward for 36/64 (56.3%) compared with 94 (61.4%) in the laparoscopic cholecystectomy group. In the observation/conservative management group, 54/64 (84.4%) did not have a normal gallbladder and of these 44 (81.5%) had chronic cholecystitis. In the laparoscopic cholecystectomy group, 143/153 (93.5%) did not have a normal gallbladder and of these 130 (90.9%) had chronic cholecystitis. Further surgery details at 24 months are shown in Table 4.

For those who had not had surgery by 24 months (Table 5), 15 (6.9%) were on a waiting list and 7 (3.2%) declined any further follow-up from hospital records in the observation/conservative management group; 13 (6.0%) and 5 (2.3%) in the laparoscopic cholecystectomy group.

Primary outcome

Figure 4 shows the mean of SF-36 norm-based bodily pain score. At 18 months, the mean SF-36 norm-based bodily pain score was 49.4 (SD 11.7) in the observation/conservative management group and 50.4 (SD 11.6) in the laparoscopic cholecystectomy group (Table 6). For the primary analysis, the mean AUC over 18 months was 46.8 for both groups with no difference: MD –0.0, 95% CI (–1.7 to 1.7); p-value 0.996.

FIGURE 4.

Mean SF-36 norm-based bodily pain score up to 24 months. Higher score indicates better quality of life. Bars represent ± SD.

Sensitivity and complete case analyses are shown in Appendix 3, Table 41.

Compliance analysis

Figure 5 shows the mean of SF-36 norm-based bodily pain score by compliance, where compliance was defined as participants receiving their allocated treatment within 24 months (excluding those two participants in the cholecystectomy group where surgery was done as an emergency case). For the compliance analysis of AUC over 18 months, there was no evidence of a difference: MD –0.0, 95% CI (–5.1 to 5.1); p-value 0.997 (see Table 6).

FIGURE 5.

Mean SF-36 norm-based bodily pain score up to 24 months by compliance. Higher score indicates better quality of life. Compliance was defined as participants who received their allocated treatment within 24 months (apart from the laparoscopic cholecystectomy group if surgery was an emergency).

Subgroup analyses

Figure 6 shows the prespecified subgroup analyses for AUC SF-36 norm-based bodily pain score, gender, age (< 35, 35–64, ≥ 65 years) and ethnicity (white vs. other) at 18 months (primary outcome). Overall, there was no evidence that the treatment effect was moderated by any subgroups. Appendix 3, Figures 18 and 19 show the subgroup analyses for the sensitivity and complete case analyses.

FIGURE 6.

Subgroups for observation/conservative management vs. laparoscopic cholecystectomy up to 18 months for AUC SF-36 bodily pain primary analysis. Boxes represent differences in AUC and lines are confidence intervals.

Secondary outcomes

Appointments with health professionals, medications prescribed and further investigations

Details of appointments with health professionals, medications prescribed and further investigations related to their gallstones by 18 months are shown in Appendix 3, Table 47. By 24 months (Table 10), 108/202 (53.5%) of participants in the observation/conservative management group and 127/203 (62.6%) in the laparoscopic cholecystectomy group required appointments with healthcare professionals with the majority visiting their GP, or an NHS hospital A&E or referred to outpatient department. Further medication for their gallstones was prescribed to 67/202 (33.2%) participants in the observation/conservative management group and 59/203 (29.1%), respectively, and further investigation was required in 11/202 (5.4%) participants in the observation/conservative management group and 10/203 (4.9%) in the laparoscopic cholecystectomy group.

Impact of coronavirus disease 2019

All randomised participants reached the 3-month follow-up time point before the COVID-19 pandemic began (defined as 11 March 2020 by the WHO). 38 In addition, 97/167 (58.1%) in the observation/conservative management group and 102/161 (63.4%) in the laparoscopic cholecystectomy group had completed their 18 months of follow-up before this date (see Appendix 3, Table 48). The AUC difference for the SF-36 norm-based bodily pain score by 18 months was MD –0.1, 95% CI (–1.8 to 1.6); p-value 0.94 in the subset of data pre-COVID-19. There was no evidence that this differed from the intention-to-treat (ITT) estimate.

In summary, the C-GALL group delivered the trial in the UK NHS setting, across 20 secondary care sites, and randomised 434 participants. We found no evidence of differences in bodily pain (primary outcome), QoL, complications or in need for further treatment between the policies at up to 24 months follow-up. There was statistically significant evidence that gallbladder-specific measures of quality of life improved in the cholecystectomy randomised group at 24 months.

Introduction

This chapter reports on the within-trial economic evaluation of laparoscopic cholecystectomy compared with observation/conservative management for the treatment of adults presenting uncomplicated symptomatic gallstones in a secondary care setting conducted during the C-GALL trial. 1 The analysis considers a 24-month time horizon. A longer time horizon is explored with a Markov model extrapolation allowing for further relevant costs and consequences associated with gallstones, laparoscopic cholecystectomy and observation/conservative management in Chapter 5. Health service resources are scarce and healthcare technologies should be adopted or maintained as part of the NHS healthcare package only if they can be demonstrated to provide good value for money. Economic evaluation can aid decision-making on the adoption, or not, of new healthcare technologies by providing information on the relative efficiency of the technologies under consideration.

Objectives of the economic evaluation

The primary economic objective of the within-trial cost-effectiveness analysis was to estimate the difference in cost and QALYs between observation/conservative management and laparoscopic cholecystectomy at out to 24 months post randomisation. The secondary economic objective addressed in Chapter 5 is to model the longer-term cost-effectiveness of observation/conservative management versus laparoscopic cholecystectomy.

Methods

This economic evaluation followed established methods42,43 and reporting standards44 with a prespecified protocol and health economics analysis plan. The UK NHS healthcare system perspective was adopted for all the economic analyses (see Chapters 4 and 5).

Outcome measures

Quality-adjusted life-years were defined as the measure of effectiveness for the cost–utility analysis. QALYs were estimated using participants’ responses to the SF-36 questionnaire completed at baseline, 3, 9, 12, 18 and 24 months post randomisation. The SF-36 questionnaire was selected as the recall time for this instrument is the last 4 weeks. We believe this recall time has a better chance to reflect participants’ QoL variations due to acute events associated with gallstones compared to other instruments such as the EuroQol-5 Dimensions (EQ-5D) with a focus on ‘your health today’. 55 Participant responses were assigned a utility score based on the Short Form-6 Dimensions (SF-6D) UK tariff. 45,46 The appropriate algorithm for the SF-36 version 2 was recreated in Stata56 to obtain the health state utility weights. QALYs were estimated using the AUC approach, assuming linear change in utility between the observed follow-up time points.

Statistical analysis of trial economic data

Results

Cost–utility analysis results

The base-case cost–utility analysis results based on the MI data set and adjusted by minimisation factors and baseline SF-6D utility score are reported in Table 14.

TABLE 14 - Base-case analysis results – MI

Differences adjusted by study minimisation variables and baseline SF-6D score.

Intervention	Total cost (£)	Incremental cost (£)a (95% Crl)	Total QALYs	Incremental QALYa (95% Crl)	ICER
Laparoscopic cholecystectomy	2510		1.413
Observation/conservative management	1477	–1033 (–1413 to –632)	1.395	–0.019 (–0.06 to 0.02)	55,235

The adjusted mean costs per participant were £2510 and £1477 for the laparoscopic cholecystectomy and observation/conservative management groups, respectively, resulting in an adjusted cost difference of –£1033 (95% CrI: –1413 to –632). The mean adjusted QALYs per participant were 1.413 and 1.395 for the laparoscopic cholecystectomy and observation/conservative management groups, respectively, producing an adjusted QALY difference of –0.019 (95% CrI: –0.06 to 0.02) for the 24-month follow-up period. Therefore, ITT with laparoscopic cholecystectomy as the first option results in significantly higher mean costs and non-significantly higher-mean QALYs compared with observation/conservative management. The ICER between observation/conservative management and laparoscopic cholecystectomy was £55,235. Therefore, moving from the standard practice of laparoscopic cholecystectomy to observation/conservative management would result, on average, in lower costs and QALYs with a saving of £55,235 per QALY forgone.

The results from the 1000 bootstrapped iterations of the regression analysis nested MI are presented in the cost-effectiveness plane (Figure 7). Incremental costs and QALYs for observation/conservative management versus laparoscopic cholecystectomy are reported in this scatterplot. All the iterations show negative mean cost differences, meaning that observation/conservative management is less costly than laparoscopic cholecystectomy. Although 16% of the iterations resulted in higher QALYs for observation/conservative management, the MD in QALYs (–0.019) favoured laparoscopic cholecystectomy. The red dashed line in Figure 7 represents the £20,000 cost-effectiveness threshold. This threshold separates iterations that result in either trial group being cost-effective. Iterations sitting to the right (left) and below (above) the red dashed line indicate that observation/conservative management (laparoscopic cholecystectomy) is cost-effective. Just 7% of the iterations sit above and to the left of the £20,000 threshold59 dashed line; that is just 7% of the iterations show QALY differences large enough for laparoscopic cholecystectomy to be cost-effective (see Figure 7).

FIGURE 7.

Trial-based incremental cost-effectiveness scatterplot for observation/conservative management vs. laparoscopic cholecystectomy (base case; imputed data – 1000 bootstrap iterations).

The cost-effectiveness acceptability curves (CEACs) for laparoscopic cholecystectomy and observation/conservative management are reported in Figure 8. The CEACs show the probability of observation/conservative management or laparoscopic cholecystectomy being cost-effective at alternative cost-effectiveness threshold values. The CEAC for observation/conservative management shows a 94% probability of being cost-effective at £20,000 threshold value. This probability decreases at higher threshold levels reflecting the higher mean cost and QALYs resulting from laparoscopic cholecystectomy, but conservative management has the higher probability of cost-effectiveness up to a cost-effectiveness threshold of £55,000.

FIGURE 8.

Cost-effectiveness acceptability curves for observation/conservative management and laparoscopic cholecystectomy groups (trial-based analysis; base case; imputed data – 1000 bootstrap iterations).

Summary and discussion

The results for the within-trial cost–utility analysis reported in this chapter indicate that ITT with observation/conservative management was, over a 24-month follow-up period, less costly than cholecystectomy (MD –£1033). This cost difference was driven by the higher number of cholecystectomy procedures undertaken in the laparoscopic cholecystectomy group as there was no difference in the cost of other events triggering hospital admissions between the groups. A non-significant QALY difference of –0.019 was observed. This is consistent with the C-GALL trial main statistical analysis that showed no difference in primary outcome of SF-36 bodily pain AUC up to 24 months. The significant cost difference, together with a small non-significant QALY difference favouring cholecystectomy (cholecystectomy is more effective by 0.019 QALYs), resulted in an ICER of £55,235. That is, moving from the standard practice of ITT with laparoscopic cholecystectomy to observation/conservative management would result, on average, in lower costs and QALYs with a saving of £55,235 per QALY lost. The probabilistic analysis showed observation/conservative management having a high probability of being cost-effective (97%) and the sensitivity analyses showed these results to be robust to the alternative costing approach using micro-costing for cholecystectomies. Prespecified subgroup analyses (by gender, age or ethnicity) showed that these findings were generally consistent across subgroups.

The main strength of this within-trial analysis relates to the randomised controlled trial (RCT) study design. The resource use and health-related QoL data used were collected prospectively for individual participants as part of the C-GALL trial. Unbiased and accurate estimation of costs and QALY differences are possible due to the randomised treatment allocation. The pragmatic nature of the C-GALL trial together with the ITT principles facilitates the generalisability of the findings to the patient population treated routinely in the UK NHS. A further strength is that the economic analysis was conducted according to a prespecified and agreed health economics analysis plan.

The pragmatic RCT design is a strength of the analysis. The imposed restrictions on elective procedures such as cholecystectomy might have de facto implemented observation/conservative management on both trial groups for some participants for a limited period of time. A second important limitation relates to the short follow-up and the natural history of gallstone disease. Cholecystectomy might be indicated in the future for those participants in the observation/conservative management group as well as those still waiting for surgery in the cholecystectomy groups. Schmidt et al. 60 reported on 14-year follow-up for a RCT that randomised 137 participants to observation or cholecystectomy. The authors reported that median time to cholecystectomy for those participants in the observation group was 28 months. The cost of cholecystectomy was the driver of the cost difference. Participants crossing over from observation/conservative management to the laparoscopic cholecystectomy group may result in improved cost-effectiveness for laparoscopic cholecystectomy over a longer time horizon. Therefore, there is a clear case for a longer-term follow-up of the C-GALL trial. Until then, an extrapolation exercise beyond the trial follow-up is conducted in Chapter 5 using a Markov model over a 10-year time horizon.

Introduction

The aim of this chapter is to report on the model-based extrapolation to extend the economic analysis horizon beyond the 24-month trial follow-up, up to 10 years. While a clear answer for the cost-effectiveness of observation/conservative management versus laparoscopic cholecystectomy was obtained from the within-trial analysis, it was anticipated that further participants would need to undergo surgery for their gallstone disease after 24 months12,60 and that this could have an impact on the cost-effectiveness results. Moreover, current method guidelines for the conduct of economic evaluations61 recommend using a time horizon long enough to capture all relevant differences in costs and consequences between the strategies being compared. Therefore, a simple Markov model was developed to estimate longer-term economic differences beyond the 24-month trial follow-up.

Methods

Model structure

The Markov model was constructed in TreeAge Pro software (TreeAge Software, Inc., Williamstown, MA) and was informed by reviewing decision models identified in the literature. 35 A similar structure was used for both trial groups and is illustrated in Figure 9. A cohort of individuals referred to secondary care and with confirmed symptomatic gallstones enter the model in the ‘No surgery’ health state and are assigned to either laparoscopic cholecystectomy or observation/conservative management. Individuals receive treatment as observed in the C-GALL trial on an ITT basis. As such, the model considers the waiting time which occurred in the trial follow-up for the first 24 months, with survival analysis used to extrapolate time from randomisation to surgical procedures. AEs (and costs) related to gallstone disease such as biliary colic or cholecystitis are experienced by a proportion of individuals in the ‘No surgery’ health state. Individuals undergoing surgery (cholecystectomy) accrue the cost of the surgical episode and move to the tunnel state ‘Recovery from surgery’ where a reduction in quality of life associated with the surgical intervention is accounted for. Markov tunnel states are a series of temporary states, lasting only one cycle, that must be visited in a fixed sequence. 62 On exit from the tunnel Markov state, individuals either have their symptoms resolved or not, moving to the corresponding Markov state (i.e. ‘Symptoms solved’ or ‘Symptoms persist’). Finally, Markov models need at least one state that cannot be left, named absorbing states, for the Markov process to end. In the C-GALL economic evaluation model, the absorbing state ‘Death’ is included, which can be entered from any other state based on age-specific mortality rates reported in the UK life tables. 63

FIGURE 9.

Simplified schematic for the C-GALL Markov model.

The state occupancy and estimated payoffs are updated on a constant monthly Markov cycle.

Clinical input parameters

Surgery

The crucial clinical parameter in the model is the time-dependent risk of undergoing cholecystectomy. All participants in the C-GALL trial were followed for a minimum of 24 months. In addition, PQs were sent every 6 months for those completing the trial follow-up at 24 months. Therefore, information about surgical procedures beyond 24 months was available for some participants for up to 48 months post randomisation. Figure 10 shows the KM curve for cholecystectomies for all participants in the C-GALL trial.

FIGURE 10.

Kaplan–Meier plot of time in years for cholecystectomy by treatment allocation. Lap. cholecystectomy, laparoscopic cholecystectomy; O/C management, observation/conservative management.

Parametric survival functions (i.e. exponential, Weibull, Gompertz, log-logistic and generalised gamma) were fitted to 48-month data. However, visual inspection made clear that all curves provided a poor visual fit to observed data, underestimating the earlier proportion of surgeries and overestimating the proportion of surgeries at 48 months (and possibly after). An alternative piecewise approach was then taken, with the first 9 and 12 months of data dropped from the analysis, and parametric curves fitted to the remaining tails of the distributions. The statistical fit of the fitted curves, assessed using the Bayesian and Akaike information criteria, are reported in Appendix 4, Table 52. The estimated survival curves and the percentages of participants expected to have surgery at 10 years were discussed within the C-GALL PMG (Table 16). Furthermore, Schmidt et al. 60 stated that almost no operations took place beyond 5 years, when reporting on the 14-year follow-up of a study that randomised 137 participants to observation or cholecystectomy. Given the proportion of C-GALL participants known to have had surgery at 24 months, coupled with those declining surgery in the laparoscopic cholecystectomy group, and based on the advice of the clinical experts, it was agreed that the proportion of participants having cholecystectomy at 10 years would be around 50% and 80% for the observation/conservative management and laparoscopic cholecystectomy groups, respectively. Therefore, it was agreed to use the generalised gamma function fitted to the 9-month time-to-surgery data for the base-case analysis and the Gompertz and log-logistic functions (also fitted to the 9-month data) for sensitivity analyses.

TABLE 16 - Number of participants estimated to undergo surgery by treatment allocation and alternative survival function

	Observation/conservative management, n (%)		Laparoscopic cholecystectomy, n (%)
	With surgery	Without surgery	With surgery	Without surgery
C-GALL data at 24 months	64 (29.5)	153 (70.5)	153 (70.5)	64 (29.5)
Survival functions fitted to post 9-month time-to-surgery data
Exponential	163 (75.2)	54 (24.8)	211 (97.1)	6 (2.9)
Weibull	127 (58.3)	90 (41.7)	196 (90.2)	21 (9.8)
Gompertz	88 (40.7)	129 (59.3)	172 (79.2)	45 (20.8)
Log-logistic	121 (55.6)	96 (44.4)	188 (86.8)	29 (13.2)
Generalised gamma	111 (51)	106 (49)	180 (82.8)	37 (17.2)
Survival functions fitted to post 12-month time-to-surgery data
Exponential	165 (75.9)	52 (24.1)	All	None
Weibull	142 (65.7)	75 (34.3)	207 (95.5)	10 (4.5)
Gompertz	105 (48.2)	112 (51.8)	185 (85)	32 (15)
Log-logistic	133 (61.4)	84 (38.6)	199 (91.7)	18 (8.3)
Generalised gamma	123 (56.8)	94 (43.2)	195 (89.9)	22 (10.1)

Monthly transition probabilities were obtained directly from the KM curves for the first 24 months of the model to mirror the survival observed in the C-GALL trial, and from the fitted survival curves thereafter.

Model validation

A number of steps were taken in order to secure the internal validity of the model. Testing was conducted throughout the model implementation such as verification of the model formulae using Microsoft Excel^® (Microsoft Corporation, Redmond, WA, USA) (white-box testing). The final model results were checked when varying the model input parameter values (e.g. defining all utility scores equal to one and zero discount rate to check whether total QALYs equal total life years) to assess the consistency of the model performance given specific variation in the model input values (black-box testing).

The validity of the projected estimates of cholecystectomies was assessed by plotting the model Markov traces with the Kaplan–Maier curves for the C-GALL trial (Figure 11). Visual inspection shows the Markov traces follow closely the C-GALL Kaplan–Maier curves. In addition, the rate of cholecystectomies at 10 years extracted from the model base case are 48% and 79% for observation/conservative management and cholecystectomy groups, respectively. This is in line with the expected rates discussed in the PMG (i.e. 50% and 80%, respectively).

FIGURE 11.

Kaplan–Meier and model Markov trace plot of time for cholecystectomy by treatment allocation. GGamma, generalised gamma; KM, Kaplan–Meier; Lap. Chole, laparoscopic cholecystectomy; O/C M, observation/conservative management.

Finally, within-trial analysis and model results were compared. For this, the model was run for a 24-month time horizon using the unit cost for the day-case cholecystectomy as this unit cost was similar to the cost of the cholecystectomy episode resulting from the within-trial analysis. The cost-effectiveness results for this comparison are reported in Appendix 4, Table 53. While the model expected costs and expected QALYs up to 24 months are lower than the corresponding values for the within-trial analysis, the difference in costs and QALYs between the two analyses produce consistent but substantially different ICERs (i.e. £55,235 and £88,930 for the within-trial and model-based analyses, respectively). The difference in costs reflects the fewer cost categories incorporated in the modelling analysis. The difference in the incremental QALYs is the result of the alternative approach used to obtain the AUC (linear interpolation for the within-trial analysis vs. simple extrapolation for the model) and the fact that neither cost or QALYs are adjusted for minimisation factors in the model-based analysis.

Results

Base-case analysis

The results for the base-case cost–utility analysis are reported in Table 19. As anticipated, the expected costs and QALYs are higher for the 10-year time horizon compared to the 24-month follow-up for the within-trial analysis. The higher costs are explained by the higher proportion of individuals going to surgery and the longer time period considered. Differences in costs and QALYs decrease compared with the within-trial base-case analysis (see Table 14). However, the ICER rises, indicating that the expected saving per QALY loss is increased.

TABLE 19 - Base-case model results

∆, increment.

Strategy	Cost (£)	∆ cost (£)	QALYs	∆ QALYs	ICER (£/QALY)	Probability cost-effective
						£13,000	£20,000	£30,000
Laparoscopic cholecystectomy	3020		5.910			0.000	0.016	0.109
Observation/conservative management	2016	–1003	5.894	–0.013	78,063	1.000	0.984	0.891

The expected costs and QALY differences from the PSA are reported in Figure 12. Cost and QALY differences are measured in the y- and x-axis, respectively. All PSA results show observation/conservative management is less costly than laparoscopic cholecystectomy. Only 23% of the results show observation/conservative management is more effective; however, the QALY difference in favour of laparoscopic cholecystectomy is not large enough for this strategy to be considered cost-effective in the base case. Moreover, the red dotted line represents the £20,000 cost-effectiveness threshold. Just 1.6% of the PSA iterations cross over the left of this line; that is, the probability of laparoscopic cholecystectomy being cost-effective at a £20,000 threshold is just 1.6% for the base-case analysis (see Table 19).

FIGURE 12.

Model-based incremental cost-effectiveness scatterplot for observation/conservative management vs. laparoscopic cholecystectomy (base case; probabilistic sensitivity analysis – 1000 iterations).

The CEACs showing the probability of observation/conservative management or laparoscopic cholecystectomy being cost-effective at alternative cost-effectiveness threshold values are reported in Figure 13. The CEAC for observation/conservative management shows a 98% probability of being cost-effective at £20,000 threshold value. This probability decreases at higher threshold levels reflecting the higher mean cost and QALYs resulting from laparoscopic cholecystectomy, but observation/conservative management has the higher probability of cost-effectiveness up to a cost-effectiveness threshold of £78,000 (data not shown).

FIGURE 13.

Cost-effectiveness acceptability curves for observation/conservative management and laparoscopic cholecystectomy groups (model-based analysis; base case; probabilistic sensitivity analysis – 1000 iterations).

Discussion

The results from the 10-year extrapolation modelling exercise reported in this chapter suggest that laparoscopic cholecystectomy is more costly than observation/conservative management. Only under extreme assumptions, such as assuming all surgeries conducted as emergency procedures in the observation/conservative group and as day-cases for the laparoscopic cholecystectomy group, was the cost difference favouring observation/conservative management reversed. However, higher resource used should be related to individuals presenting with more severe clinical cases. Clinical cases at presentation may be more severe in the observation/conservative management group once individuals have waited several months without surgery. Moreover, a small but consistent QALY difference favouring laparoscopic cholecystectomy was observed for the base case and all sensitivity analyses. These cost and QALY differences translated into an ICER of £78,063 for the base case, meaning that important savings could be obtained for a relatively small QALY loss. A final scenario analysis used SF-6D-adjusted utility scores up to 48 months post randomisation. This produced a QALY difference large enough to reverse the base-case results, reducing the ICER to £14,698.

A strength of the modelling exercise is that it is supported by randomised data collected in a prospective, large multicentre and pragmatic RCT. Survival analysis was used to extrapolate time from randomisation to surgical procedures and time to event and cost data were used to estimate rate and costs associated with presurgical AEs. In addition, the reduction in QoL for individuals undergoing cholecystectomy was estimated using SF-6D scores collected in the trial covering a period of 6 months before and after cholecystectomy.

There are a number of limitations in our analysis. The estimated survival curve data were directly incorporated into the decision modelling software in a deterministic way and therefore there was no parameter uncertainty associated with the survival analysis in the PSA. As such, the probabilistic analysis might underestimate the overall parameter uncertainty in the model. Nevertheless, alternative survival functions were defined to cover the range of extreme but plausible scenarios with the base-case results being robust to the different survival distributions used. Furthermore, there was no difference in the utility score attached to the Symptoms resolved and Symptoms persist Markov health states after surgery. As the proportion of cholecystectomies are higher in the cholecystectomy group, a reduced quality of life due to symptoms after surgery would make cholecystectomy less cost-effective and therefore our assumtion is conservative. However, the long-term quality-of-life data are needed to assess if this assumption is valid beyond the 24-month trial follow-up.

In summary, the cost–utility analysis based on the C-GALL trial participant data suggests that observational/conservative management might be cost-effective at 24-month follow-up. However, the extrapolation over 10 years introduced uncertainty over this short-term result and could in some scenarios reverse the findings. The current decision uncertainty could be reduced with a long-term follow-up of the C-GALL trial participants.

Introduction

The C-GALL trial evaluated very different interventions for the treatment of gallstone disease: laparoscopic cholecystectomy or observation/conservative management. Based on evidence from other surgical versus non-surgical intervention trials, it was anticipated that the trial would face a number of challenges, particularly around informed consent and recruitment, from both the perspective of patients and recruiting clinicians. 69–71

An embedded process evaluation was incorporated at the design stage of the trial to identify challenges relating to trial design and or conduct that could be addressed and modified. The process evaluation component was designed to be responsive to the ‘needs’ of the trial, allowing flexibility to address core problems in relation to recruitment and/or retention in a timely manner. The overall structure and methods of data collection within the process evaluation were guided by the QuinteT Recruitment Intervention (QRI) and lent heavily on participant flow data, audio recordings of trial discussions and interviews with trial participants. 72 However, a significant change to the traditional QRI method was the application of a behavioural science approach to understand problems of trial recruitment and retention. Clinical trials depend on behaviours: they rely on people (patients, clinicians, trial staff) performing actions (such as receiving or delivering a trial intervention, attending a clinic, returning a questionnaire or approaching eligible participants) that they would not do otherwise. Emerging evidence suggests behavioural science has the potential to add value with regard to improving the conduct of trials. 73

Within this process evaluation we applied the theoretical domains framework (TDF) as a method to help inform data collection and analysis. The TDF is an established framework that integrates 33 theories of behaviour into 14 domains that inhibit or enable behaviour (knowledge, skills, social/professional role and identity, beliefs about capabilities, beliefs about consequences, optimism, reinforcement, intentions, goals, memory/attention/decision processes, environmental context and resources, social influences, emotion and behavioural regulation). 74 A handful of projects interested in trial recruitment and retention have now successfully applied the TDF as a tool to detail the challenges, from the perspectives of both patients and healthcare professionals, through a behavioural lens. 75–78 The TDF was chosen as the framework of choice for components of this process evaluation, as it also lends itself to evidence-based methods for intervention development through mapping onto behaviour change techniques (BCTs) through established methods. 79 BCTs are defined as the smallest active ingredient of an intervention such as feedback on behaviour or action planning, and they can be used alone or in combination with other BCTs. 80 This process evaluation applied these methods from the science of behaviour change to address problems of recruitment and retention in trial. We developed and implemented behaviour change interventions to target the challenges identified during the behavioural investigation.

The process evaluation team worked with the Co-Chief Investigators, PMG and site staff to identify and address challenges to trial recruitment and retention across two sequential phases:

• Phase 1 focused on identifying and understanding the ‘problem’ for trial recruitment and/or retention using multiple methods and data sources.

• Phase 2 sought to develop solutions to the ‘problem’ identified in Phase 1 through the development and delivery of interventions, with the wider trial team, to target the conduct challenges.

Methods

The process evaluation was approved through the main trial application from NHS North of Scotland Research Ethics Committee (16/NS/0053). Informed consent was obtained from all participants.

Findings

Phase 1: identifying and understanding challenges for trial recruitment and retention

Recruitment

Twenty-one of the twenty-two C-GALL sites were included in the participant flow-data analysis. One site was not included in this analysis due to inactivity. Of these twenty-one, three had very low recruitment numbers due to them becoming active recruiting centres late in the trial, and one site was closed down due to poor recruitment numbers. As such, these four sites were not progressed for analysis. All further data presented are based on 17 sites. Diagnostic data from the participant flow revealed that for most sites (n = 13; 76%) the main challenge for recruitment existed in converting approached patients to randomisations. The biggest barrier to randomisation was patient preference, largely for surgery (Table 25). A total of 16 sites provided 180 audio recordings for analysis (median number of recordings per site = 10). A further five sites did not audio-record consultations, due to sites not agreeing or forgetting to record. Consultations included consultant surgeons, RNs and patients who were sometimes accompanied by family members (partner or child). Analysis of the transcripts identified four core challenge areas for recruiters discussing the trial:

TABLE 25 - Summary data by site regarding participant flow, examples quotes, targets for feedback and level of feedback

All quotes are from site staff unless otherwise specified.

Site ID	‘Problem’ identified from participant flow data	Audio	Example quotesa	Targets for feedback	Feedback
1	Crossovers	Y	Patient: ‘It is the surgery I am thinking I’d rather have’ Site staff: ‘We can see what randomisation says and then we can take it from there’	Positive: site is the second top recruiting site for the whole of the C-GALL trial Negative: site is also the site with the highest rate of patients crossing over	Site specific
2	Approached to randomised patients who are declining trial participation by expressing a preference for surgery	Y	Not available at time of feedback	Positive: are discussing the trial with 97% of eligible patients Negative: has the second lowest proportion of approached patients being randomised	Generic
3	Approached to randomised patients who are declining trial participation by expressing a preference for surgery	Y	Site staff: ‘The trial’s only there if you’re interested. If you feel that you have a preference, then that’s absolutely fine’ Patient: ‘I think for my circumstances I think I would opt to just have it taken out and hopefully it would deal with everything’. Site staff: ‘Okay’	Positive: approaching 80% of eligible patients to talk to them about C-GALL Negative: only 20% of trial discussions go on to lead to randomised participants Why: majority have a preference for surgery	Site specific
4	Crossovers	Y	‘Let’s do the randomisation right? And see what you are allocated. You might be allocated surgery and that’s happy days. If you are not allocated surgery, you can tell us immediately to swap you over’ ‘So obviously let’s see … what you are randomised into. If you are randomised to surgery, that’s the answer. If you are not randomised to surgery, and then we can have a discussion, and then you are allowed to cross over at any time’	Self-identified the problem of crossovers	Site specific
			‘You are not stuck. You can immediately within the same minute say, “no I want surgery” and we’ll swap you over’ ‘You can cross over to the surgical arm without any problems, or even giving an explanation. This is a completely flexible trial’ ‘If you are randomised to no surgery and you want surgery, you can cross over. You are in the driving seat; we are just trying to observe and learn from your disease process’
5	Approached to randomised patients who are declining trial participation by expressing a preference for surgery	Y	Site staff: ‘What’s your initial thoughts on that?’ Patient: ‘Yeah, that’s okay’	Positive: approaching 97% of eligible patients to talk to them about C-GALL	Generic (No audio uploaded at time of feedback. Quote provided as example content of site discussions retrieved post feedback)
		Y	Site staff: ‘Do you want to go for surgery? Are you wanting to see how things go?’ Patient: ‘Just happy’ Site staff: ‘Are you interested in the study or what do you think?’ Patient: ‘Just happy to get it gone’	Negative: site had only 22% of participants go on to be randomised Why: 63% of those who decline to take part have a preference for surgery
			Site staff: ‘You just want an operation?’ Patient: ‘Yeah, just get it gone’
6	Approached to randomised patients who are declining trial participation by expressing a preference for surgery	N		Positive: upwards of 85% of eligible patients talked about C-GALL Negative: only 19% of participants go on to be randomised Why: 61% of those who decline to take part had a preference for surgery	Generic
7	Eligible to approached and crossovers	Y	‘And if you’re in the study what we do is we allocate you to one of those two arms in the study, and one is that we do the gallbladder operation, and the other arm is we do what’s called watchful waiting, and either way we keep a very close eye on you and see what happens. And if we need to take your gallbladder out during the study, if you’re allocated to watchful waiting for instance and then you suddenly came in with a dreadful attack of gallbladder problems then obviously, we do what’s needed clinically to take your gallbladder out. But maybe from the circumstances you don’t get any further attacks, so that’s the reason it’s difficult to advise you on what we do’	Positive: randomising 40% of patients approached about the C-GALL trial (average) Negative: only 71% of participants being told about the C-GALL trial Negative: site has the third largest number of patients intending to crossover	Generic (No audio uploaded at time of feedback. Quote provided as example content of site discussions retrieved post feedback)
8	Approached to randomised patients who are declining trial participation by expressing a preference for surgery	N		Positive: upwards of 80% of eligible patients talked about C-GALL Negative: only 25% of participants go on to be randomised Why: 42% of those who decline to take part had a preference for surgery	Generic
9	Approached to randomised patients who are declining trial participation by expressing a preference for surgery	Y	‘I think that having the operation is the best thing to do’ ‘if you don’t ever want the pain again you could have the operation’	Positive: discussing the trial with 100% of eligible patients Negative: only 29% of trial discussions lead to randomised participants	Site specific
			‘you may go for surgery and be no better off, I suspect you’ll be better off’	Why: 73% of those who decline to take part had a preference for surgery. Surgery is consistently mentioned to be the best option
10	Approached to randomised patients who are declining trial participation by expressing a preference for surgery	Y	‘We know that obviously if we do the operation, it would be done by keyhole, 95% of the time. Good chance of helping your symptoms, but we do know that after having had your gallbladder out, up to a third of patients still have ongoing pain… Obviously if you go down the line of being observed, and things become worse, then we would see you again to look at taking your gallbladder out, should that be required. Obviously if you got put down the line of having your gallbladder out, if you changed your mind, then that’s absolutely fine. You are under no obligation. Would you be happy to be part of the study?’	Positive: upwards of 87% of eligible patients Negative: 43% of trial discussions lead to randomised participants Why: 49% of those who decline to take part had a preference for surgery	Generic (No audio uploaded at time of feedback. Quote provided as example content of site discussions retrieved post feedback)
11	Approached to randomised patients who are declining trial participation by expressing a preference for surgery	Y	‘We find the gallbladder – this is all under general anaesthetic, so you are asleep – find the gallbladder, free it up, and we take the gallbladder with the gallstone out, because you can’t leave any of that behind because you are at the risk of forming more. That’s the best way to stop any further problems (…) There’s a risk of damage to upper abdominal structures – bowel, blood vessels, liver, in that area (…) if you go onto the non-operative arm, you’ll take painkillers if you need it, or antibiotics, or whatever, and then that will be part of your questionnaire when it gets sent out’	Positive: approaching 93% Negative: 47% of trial discussions lead to randomised participants Why: 87% patient preference for surgery	Site specific
12	Approached to randomised patients who are declining trial participation by expressing a preference for surgery	Y	Site staff: ‘So, you’d rather have it removed?’ Patient: ‘I’d rather have it out, yeah’ Site staff: ‘Yeah, okay. Well, fair enough’	Positive: 90% approached Negative: 43% led to randomisations	Site specific
			Patient: ‘Is there no other way for the gallbladder if you have stones? Is it just surgery or that’s it?’ Site staff: ‘Yes’	Why: 42% patient preference for surgery
13	Approached to randomised patients who are declining trial participation by expressing a preference for surgery	Y	Not available at time of feedback	Positive: 97% of eligible approached Negative: only 40% of participants approached were then randomised Why: 90% of patient preference for surgery	Generic
14	Eligible to approached	Y	Not available at time of feedback	Positive: has highest percentage of participants approached randomised Negative: lowest amount initially approached, high percentage of patient preference for surgery	Generic
15	Approached to randomised patients who are declining trial participation by expressing a preference for surgery	Y	‘The attitude has always been, we do an operation we remove your gallbladder, and you get better when we look back on people, that 20 years ago that’s what we did, we can help 80% of them did, but up to 20% of people did not feel better (…) We can consider an operation … that is option 1, option 2, we do know that increasingly that some people get better by losing weight, having healthier diet (…) we are also looking at doing research’	Positive: 53% of eligible patients approached Negative: 12% of those trial discussions lead to randomised participants Why: 52% of those who decline to take part had a preference for surgery	Site specific
16	Approached to randomised	Y	‘So, if you go down the surgical route, then obviously the advantages – you get rid of the stones. Not only are you taking the gallstones away, we take the gallbladder as well, so they don’t come back, and it gets rid of the source of the pain for good’	Negative: only 39% of participants approached were randomised	Generic (No audio uploaded at time of feedback. Quote provided as example)
17	No immediate issues	Y	Not available at time of feedback	One of the highest percentage of participants approached to randomised	Generic
18	Small overall numbers and no immediate issues	N			Generic
19	Small overall numbers and no immediate issues	Y	Not available at time of feedback		Generic
20	Small overall numbers and no Rimmediate issues	N			Generic
21	Site was in process of closing	N			Generic

• providing a balanced presentation about both treatments

• discussing and exploring preferences

• discussing uncertainty

• discussing crossovers.

Examples of excerpts from the audio consultations are provided in Table 25.

Retention

Audio recordings of trial discussions

A subset of 38 audio recordings from 4 sites were included in the analysis of discussion of retention with 3 sites providing 10 recordings each and the fourth site providing 8. The findings from this aspect of the process evaluation have been published in full elsewhere. 68 In brief, most of these consultations (n = 30/38; 79%) did not include any discussion of trial retention. Where retention was discussed, the median proportion of consultation time in which retention was discussed was 3.8%, with the longest discussion of retention lasting 89 seconds and shortest lasting 20 seconds. Presence of discussion of retention also varied by site, with one of the four sites never discussing retention in any of the consultations included in the analysis. Where consultations did discuss retention, some contained inaccuracies (n = 1, 9%), some failed to detail the frequency of follow-up questionnaires (n = 1, 9%) and the majority focused on the participant’s right to withdraw (n = 6, 54%). In some instances, the patient initiated the conversation around retention, with respect to frequency of follow-up. Examples of excerpts from the consultations relevant to trial retention are presented in Table 26.

TABLE 26 - Example quotes relevant to trial retention

Theme	Quote
Timing and purpose of questionnaires	‘So, with the quality of life, I mentioned there was a baseline – and with those forms you’ll get sent one 3 months, 9, 12, and 18 …’. ‘They will be very similar to the baseline ones if you want to go into the study. And the study centre will send those out’ RN Site B
	Surgeon: ‘Umm I mean you can always say uhh uhh that ah regardless of which treatment group you do – the study allocates to you, for example if it says observation then uh you will uh will require observation in about 3 months’ time. Is that right?’ (Doctor asking RN)
	RN: ‘Umm yeah, we just send you the questionnaire by email or by phone – so you will just answer them every couple of months. That’s all we will do. There is nothing where you physically have to come or need to be examined or anything like that’ Site C
	‘Emm what we do is that we send you a questionnaire in the post. 3, 6, 9, 12, and 18 months. So, it’s every 3 months you get questions in the post. Kind of day-to-day thing about how your pain is and things and such’.
	‘It does not involve another visit back for us. Emm, If you do get randomised to surgery – emm, it’s a kind of a standard way to check for that. And then we also send you the questionnaires in the post as well’ Surgeon Site D
Participant’s right to withdraw	‘Like Mr X said, it is a randomised controlled study – so if somebody agrees to go into the study there is some baseline information that we do when they consent. So there is a consent process that I’d go through. Umm a consent form that you fill in. And you can withdraw your consent at any time. So if you fill in your consent from today, decided you wanted to do it – and then went home, thought about it – and thought, actually no this isn’t right for me; you can withdraw at any time. Umm and again with the follow ups – so the follow up questionnaires you can always decide that when life gets busy and get in the way – if you decide actually, oh I’ve not got time to do these questionnaires, or too much other things going on – again you can choose to withdraw from the follow up as well. So if you decide to go into the study it is not set in stone. You can withdraw at any time alright?’ RN Site B
	‘With the follow-up, it’s the same for both arms for the questionnaires. I will show you a copy so you know what is expected of you. This is the baseline. But it is the same for all of them. There is no massive essays. It’s a tick box – and I don’t know if you want to have a look through that. Umm it’s all about the general health, following activities of daily living, discussing pain …’ RN Site B
	‘That’s pretty good, perfect! And the questionnaire don’t forget the questionnaires. In a way that is kind of confirming your ongoing consent’ Surgeon Site B

Interviews with trial participants during the trial

Nine interviews were conducted with trial participants who had not returned at least one questionnaire during their participation in the C-GALL trial. The median age of these participants was 53 years old (range: 35–75 years) and the majority (n = 7/9; 78%) identified as female. This was comparable to the entire population of C-GALL trial non-responders at the point of data analysis (February 2020; 79% female with a median age of 51 years). The length of interviews ranged from 25 minutes to 1 hour 28 minutes (median = 36 minutes).

Domains and associated belief statements were categorised into overarching themes to summarise the main messages arising from the data (Figure 14). The specific beliefs, the TDF domains they are associated with, and the sample quotes are presented in Table 27. The relationship between TDF domains and the overarching themes is presented in Figure 14. A total of seven themes were identified. These were:

FIGURE 14.

Overarching themes and associated domains. ECR, environmental context and resources; SPRI, social professional role and identity; TDF, theoretical domains framework.

TABLE 27 - Table of findings with theoretical domain framework frequencies and belief statements

Domain (frequency = participants who mention domain/number of total participants)	Specific belief	Sample quote
Environmental context and resources (9/9)	The format, layout and postal administration of the questionnaire was (not) convenient for me	‘That’s it, yeah. It comes with an envelope to just pop it straight back in the post. You don’t have to put a stamp on or write the envelope, so I don’t see any issues with it’ Participant 1 ‘I much preferred it when I could give oral answers to a simplified version in which she said, “These are just the main questions that we need to know”. That didn’t take nearly as long, and it was quite focused and straightforward’ Participant 2
	It was (not) easy to schedule completion and return of the questionnaires with other priorities in my life	‘Well, as I say, I put it aside and then never got to it. So, clearly life got in the way for me. Yes, yes’ Participant 2 ‘No, not at all. It would never be a problem to sit down for ten minutes and answer the questions’ Participant 1
	Completing the questionnaire was (not) enjoyable and/or straightforward	R: ‘And any struggles to do with any parts of the study at all so far?’ ‘No. Actually, in the questionnaire I asked about my health and this, that and the other, it was quite enlightening to thought about things’ Participant 7
		‘Tick box things. I think, probably … Sometimes, I ticked a box and I’m thinking, “Well, I’m ticking it, but maybe I need to explain a bit more”. Probably I’m ticking it because I was not on one side …. You know what I mean?’ Participant 5 ‘There was a lot of, “Hmm, how I do I answer this one? I’m not quite sure”’ Participant 9
Social influences (9/9)	I did not feel pressurised to complete and return the questionnaires	R: ‘And did anyone support you to return the questionnaire?’ P: ‘No, I mean, my partner’s here but he doesn’t really take any notice of my post anyway. No, I’ve got no pressures from anyone. Nobody encourages me either. At first, my sister half encouraged me to take part because I was about 90% sure I was going to do it, and then after talking to her and a couple of others, just things that were said I just said, Yeah, I’ll do it’ (also coded under belief statement, support from family members)
	I (did not) receive support from family members to complete and return the questionnaires	‘Once I’ve filled it in, my husband supports me in terms of he gets it to you, as in he posts it for me because I don’t go out to post it when I’ve got work or whatever. But that’s the only support, (inaudible) support, my husband is understanding. He understands the pain and he helps me when I’m suffering and stuff, but no, I don’t have any other support, not really’ Participant 6
		R: ‘And does anyone support you to return the questionnaire?’ P: ‘No, like I say, I just do it straightaway’ R: ‘And it’s all off your own back, you’re able to post it yourself and such’ P: ‘Yeah’ Participant 8
Beliefs about consequences (9/9)	Completing and returning the questionnaires will help people with gallstones in the future	P: ‘Just to help other people further down the line, really. If the questionnaire helps the study, it can obviously benefit other people further down the line’ Participant 8
	The questions were not relevant to my circumstances	‘I think filling it in would have been medical management, and I’ve not had any medical management. It was a bit like, yeah, I’ve not had anything to help with it so I was just filling it in in terms of the first time’ Participant 8. ‘Well, there were a few. I mean, I started off well and then because nothing had happened … I hadn’t had any pain or anything and then I’d put them aside and then somebody would send another one and say, “You haven’t completed it”’ Participant 2
	It’s important to fill in the questionnaires for the research team	‘No, like I said, just the information for yourselves to go towards the study and get the information that you need, really. That’s the only thing that pushed me to do it if that makes sense’ Participant 8
Reinforcement (7/9)	(No) incentives or rewards would have encouraged me to complete and return the questionnaires	‘I suppose so. Obviously if it’s going to benefit and you’re going to get something back, it would be nice …’ Participant 8 ‘Yeah, I just want to do it because I want to do it. I don’t really want anybody to try and bribe me to do it or encourage me to do it due to any kind of incentive, no. In some ways, actually that would put me off’ Participant 1
Behavioural regulation (8/9)	It would (not) have been better to receive the questionnaire in a different format	‘Yeah, I suppose that’s possible. Over the phone would be fine; face to face wouldn’t be ideal because I don’t live that close to [study centre]. Over the phone would be all right, I wouldn’t mind that, but in some ways that would be more difficult to fit into your day as well. Filling it out on a piece of paper, you can do that when you’ve got a few minutes to get it done and from my point of view, I’d probably find that easier to fit in’ Participant 1 ‘Initially. I mean, even if they were sort of three, six months apart, it would have been something. I find it easier to talk to a person probably than have to fill in these forms’ Participant 5
	I (do not) make a plan to help me complete and return the questionnaires	‘I would actually think, “Well, I’ve got to get this done” and do it and then send it off. Saying that, yes, probably … You’re right, I would probably say, “Oh, I’m going to sit down this evening, fill this questionnaire in and then get it sent off.” So, yes, in that way, there was a plan’ Participant 5 ‘The questionnaire thing for me is a barrier because I’ll think, “Oh, I’ll put it to the side, I’ll do it when I’ve got time,” and I never get the time. I’ve got my second one to fill and it’s been there for months. Really bad!’ Participant 6
	The time point of receiving the questionnaires influences questionnaire completion	‘I suppose if the questions had been really complicated or difficult to answer, maybe. Or if you just can’t remember what exactly has happened over the time. I suppose the time between questionnaires, if it’s every three months then that’s not too bad, but if it was longer than that then I’d definitely have trouble remembering exactly what symptoms I’d had and how many times and all the fine details’ Participant 1 ‘We’re all busy and I think I’d have been more engaged with it, had I had a lot of symptoms and I was really desperately wanting to get sorted out, which I actually feel a little bit more now’ Participant 2
Beliefs about capabilities (9/9)	I was (not) confident that I could return the questionnaire(s)	R: ‘How confident are you that you could return a questionnaire when requested?’ P: ‘100%, I know I can’ Participant 1 ‘As I say, it was the paperwork just kind of threw me and … I should have been more on top and organised with that, but’ Participant 2
Intentions (9/9)	I am (not) committed to completing and returning the questionnaires	P: ‘Well, there’s not a lot … It’s commitment to answering the actual survey questions that took … not the survey, the questionnaires that come in. You’ve got to commit to that. I think you have to, because otherwise there’s no point you doing it’ Participant 5 ‘There’s something about these forms that you just look at them … like a tax form … You just look at it and think, “Oh, I’ll do it later.” You know’ Participant 2
Knowledge (9/9)	The activities and tasks involved in the trial did (not) meet my expectations	‘It’s the same as most questionnaires like that where you’ve got, I think, to give a level of how much something’s inconvenienced you. Yeah, just what you’d expect from a questionnaire. Sorry, I’m not very helpful on this one!’ Participant 1 ‘Well, actually the paperwork that comes through, some of the questions that we’re asked were sort of non-sp-…’ (inaudible) non-specific Participant 5
	I was (un)aware of when the trial/my participation ended	‘I think at the appointment initially, they said that the trial had been extended. They didn’t give me a timeframe for how long it would go on for’ Participant 1 ‘Yeah, I know it’s every six months that they wanted me to do a questionnaire … two is coming to mind, two plus’ Participant 6
Skills (9/9)	Literacy and communication are key skills required to complete the questionnaires	‘But actually, the actual skill involved is trying to be … I mean, hopefully, you’re literate enough to be able to do it …’ Participant 5
	You need a good memory to complete the questionnaire accurately	‘It’s hard, it’s very hard. “During the past four weeks, to what extent has your physical health and emotional … how have they interfered with your personal life or your home life?” Things like that. You forget, do you know what I mean? You kind of forget in that four weeks what’s happened. They should ask me about it there and then, so this questionnaire, “How are you feeling today?” or whatever, or last week, or “When was your pain bad?” But the last four weeks, I can’t remember how it interfered with my neighbours, with my family. It is a valid question, it’s just me, I’m a busy person, I don’t have …’ Participant 6
Emotion (9/9)	Completing and returning the questionnaire(s) (does not) trigger unpleasant emotions such as boredom	R: ‘Yes, I understand. This may be a bit of an odd question but bear with me. What sorts of feelings come to mind when you think of returning a questionnaire?’ P: ‘Just slightly bored’ Participant 2 R: ‘What sort of feelings come to your mind when you think of returning a questionnaire? Any sort of feelings you experience?’ P: ‘Not really, I think I’m quite matter-of-fact about it all’ Participant 7
	Completing the questionnaire brings me satisfaction and a sense of responsibility	‘Well, you’ve completed a job, you know that it’s important, it helps in clinical trials, it’s helping finding out stuff. That’s the upside of doing it, and you feel satisfaction, that you’re making a difference’ Participant 4
Social professional role and identity (9/9)	My personality and social role influence my impression of the questionnaire in terms of content and format	‘My (inaudible) thing is, honestly, I’m a social person. I like to speak to somebody, have a consultation and you will get your answers’ Participant 6 ‘I’m not one for paperwork, so … it’s not something I look forward to’ Participant 3

1. Unclear expectations of trial participation: included beliefs about activities and tasks in the trial not meeting expectations, highlighting participants were (un)aware of when their participation in the trial ended, the relevance of the questionnaire to their circumstances (i.e. when not experiencing pain), and confusion over receiving the same questionnaire on multiple occasions.

2. Personal attributes for questionnaire completion: the need to remember levels of pain experienced was mentioned as a skill required to complete the questionnaire, as was the need to concentrate which was sometimes reported as a barrier to completion and return.

3. Significance of questionnaire non-return: participants reported feeling guilty for not returning questionnaires largely linked to them feeling they were letting the trial team down. Others felt satisfaction by completing and returning the questionnaires and saw the activity as their duty as a trial participant and that their contribution would help research.

4. Commitment to returning questionnaires given other priorities: some participants reported they did not feel committed to completing and returning the questionnaire as it was not a priority for them, reporting they were too busy. In contrast, some participants recognised the negative consequences of not returning the questionnaire (such as wasting the researchers’ time) and so felt committed to completing.

5. Individual preferences for presentation mode and timing of the questionnaires: there was variability among participants regarding preferences for questionnaire format with some preferring postal and others stating they would have preferred to complete it electronically or to speak with someone.

6. Internal and external strategies to encourage questionnaire return: a range of strategies were reported that participants had used to help them complete questionnaire such as making a plan to complete and return, keeping a note of symptoms and completing the questionnaire as soon as they received it. There were mixed views about whether the use of incentives to encourage response would have been appropriate, but most participants suggested that receiving a prompt or reminder would have been/were helpful.

Sources of support in returning the questionnaires: participants reported that in some cases they received support from family members to return the questionnaires, but for the majority this was done independently. The trial office was noted as providing some level of support for all, which included reminder or completion of the questionnaire over the phone. Participants did not feel pressurised to complete and return the questionnaire, with some stating this was a barrier to completion.

Theoretical domains framework domains, associated belief statement and associated example quotes are presented in Table 27.

Phase 2: development and delivery of interventions to target recruitment and retention challenges

Strategies to improve trial recruitment and retention were developed, through discussion with Co-Chief Investigators and the PMG, in response to the data collected during the Phase 1 investigation. Feedback to trial sites was provided on a rolling basis, targeting sites in response to problems identified through the participants’ flow diagnostic data.

Site investigator meeting

A site investigators meeting was held in Birmingham in November 2018. This meeting was attended by 17 site representatives (which included consultant surgeons and RNs) from across 10 sites. Findings from the analysis of retention discussion in the audio consultations and participant interviews were shared and discussed. Meeting attendees were encouraged to reflect on the findings and asked to consider what they could do to help improve retention, and specifically, what changes they could make during trial recruitment to raise the profile of what was expected in terms of trial retention.

E-mail feedback on recruitment activity: site specific and generic

Guided by the diagnostic participant flow data, sites were provided with e-mail feedback on their current recruitment activity in relation to other centres (SEAR). The e-mail started with a thank you and general reminder of the aim of the trial and then a positive message about an aspect of their recruitment activity, for example, approaching all eligible patients. The content of the e-mail then moved on to highlight the target behaviour that we wanted them to change (e.g. randomising more of those approached by exploring preference), and data were shared on their performance in relation to other sites (see Figure 15, for example text). In addition to the broad areas of content, we also included BCTs within the e-mail text. A list of potential BCTs was proposed and discussed among the immediate process evaluation team regarding relevance and feasibility of inclusion in e-mail feedback to sites to target trial recruitment. Twelve BCTs were deemed relevant and feasible for delivery and incorporated into the site specific and generic feedback (Table 28).

FIGURE 15.

Example e-mail content for site feedback (e-mail sent on behalf of the Clinical Co-Chief Investigator).

TABLE 28 - Behaviour change techniques identified as relevant for inclusion in site feedback

BCT	Example text
1.2 Problem-solving	There are a number of generic tips on ways to discuss recruitment with potential participants in the attached materials. You could set aside some time to look at these and reflect back on the previous few recruitment conversations you’ve had – do you think there is anything you could improve upon?
1.4 Action planning	During the consultation, offering a balanced explanation of both treatments and exploring patient preferences may ensure both treatments are given equal consideration. Specific suggestions on how to discuss these elements can be found in the attached materials.
2.2 Feedback on behaviour	Site X is discussing the trial with upwards of XX% of eligible patients.
2.7 Feedback on outcomes of behaviour	Although this is extremely positive, I also need to share with you that Site X is also the site that has one of the lowest percentages of participants that go on to be randomised. As you can see below, only XX% of trial discussions lead to randomised participants.
3.2 Social support (practical)	Additionally, the trials team would like to offer your site the opportunity to receive further individualised feedback and training on recruitment. Please contact [research assistant] if you would like to arrange a date.
5.1 Information about health consequences	As you will know, achieving our recruitment targets is crucial to being able to answer the research question posed by the C-GALL trial – what is the best treatment approach for patients with uncomplicated symptomatic gallstones?
5.3 Info about social and environmental consequences	Crossovers, especially those in one direction, are problematic for a few reasons. Firstly, they suggest that participants have a strong preference for surgery and are unlikely to have been in equipoise when they agreed to participate. Secondly, a high number of crossovers will make the trial results unreliable and make it impossible for C-GALL to answer the research questions.
5.5 Anticipated regret	I need to minimise the numbers of crossovers so that all the hard work we are doing to recruit participants is not wasted.
6.2 Social comparison	The average across sites is XX% with some sites achieving upwards of XX%.
9.1 Credible source	Letter sent on behalf of Co-Chief Investigators.
10.4 Social reward	Thank you very much for your efforts on the C-GALL trial. I am really grateful for your ongoing support to achieve our recruitment targets.
12.2 Restructuring the social environment	Why not get together with the rest of the research team in Site X and agree a plan about how to discuss C-GALL in the future.

Thank you very much for your efforts on the C-GALL trial. I am really grateful for your ongoing support to achieve our recruitment targets. As you will know, achieving our recruitment targets is crucial to being able to answer the research question posed by the C-GALL trial – what is the best treatment approach for patients with uncomplicated symptomatic gallstones?

I would like to acknowledge the fantastic recruitment figures at Site X which reflects all your hard work. Site X is discussing the trial with upwards of XX% of eligible patients.

Although this is extremely positive, I also need to share with you that Site X is also the site that has one of the lowest percentages of participants that go on to be randomised. As you can see below, only XX% of trial discussions lead to randomised participants, the average across sites is XX% with some sites achieving upwards of XX%. So, although you are doing really well speaking to so many patients about the trial, this, unfortunately is not translating into a high proportion being randomised.

I see that around XX% of those who decline to take part had a preference for surgery. This is particularly high compared to the average of XX% across sites. During the consultation, offering a balanced explanation of both treatments and exploring patient preferences may ensure both treatments are given equal consideration. Specific suggestions of how to discuss these elements can be found in the attached materials.

The BCT-enhanced content information was included in the body of the e-mail. In addition to this main text, two attachments were provided. The first contained feedback on the content of the audio recordings with site-specific examples (where available) alongside examples of what had worked well at other sites (Table 29). The second attachment included a one-page ‘top tips’ sheet which aimed to address the core challenges identified in the consultations (Box 1). The sheet focused on tips regarding how to structure the conversation and explain trial-specific processes (e.g. randomisation), building on the examples of good practice provided in the first document they received. It also provided questions for them to ask participants to help explore treatment preferences. All sites were provided with this ‘top tips’ sheet along with either site specific or generic feedback on consultations.

TABLE 29 - Feedback from consultations – attachment to e-mail

	Examples from your site	Examples of what works well at other sites
Balanced presentation about both treatments	‘So, some people get infection of the gallbladder, which you may have already had, which can become more problematic. The risk of that is around about 10%/15% per year, okay. Other risks is something called pancreatitis, which the risk of that is about 1% to 2% a year, and that can be quite, potentially quite serious, and that is why historically if you like we’ve taken out a lot of gallbladders because people are worried that they don’t want that to happen to individuals. But that said, the surgery itself poses risks, and some people still find they get pain and symptoms and things after the operation as well … If you don’t have an operation, you are at risk of having an infection related to your gallbladder, which is probably what you had before’	‘There is one in three chance you may not get better after surgery, and there is a 10% risk of complication, so these are the risks of surgery. There are risks of medical management that there is a 0.7% chance per year for you to pick up a complication which might end up you having surgery at some point, so the arguments are quite balanced’
	P: ‘Yeah, okay’ R: ‘You can get another … there is other risks in terms of what we call pancreatitis. The risk of that is lower than the risk of getting an infection, but it is potentially quite a serious problem … it can need quite long hospital admission, and it’s even potentially life threatening, all right … The risk of that is relatively low, about 1% to 2% of people with gallstones will have that problem at some point in a year you know, but whether that will happen to you or not is almost impossible to predict, all right’.
Discussing preferences Use direct and indirect questions – e.g. why do you prefer this treatment?, acknowledge their reasons and balance their views – e.g. highlight advantages of less preferred treatment and disadvantages of preferred	R: ‘Are you interested in the study or what do you think?’ P: ‘Just happy to get it gone’ R: ‘You just want an operation?’ P: ‘Yeah, just get it gone’ R: ‘You understand that there obviously are risks and’ (overspeaking) P: ‘Yeah, yeah, yeah’ R: ‘Fair enough’.	Patient: ‘I would rather have the surgery’ ‘Okay, no, that’s entirely your own choice … By having surgery it won’t necessarily get rid of the pain. It may not be, the pain may not be coming from the gallbladder and the gallstones, this is another reason why they suggest the trial … But you do get a priority; if you went on the trial and you were randomised for the management side of it but then all of a sudden the pain was too unbearable, you have got an open appointment to come back whenever you want to. It’s entirely – I’m not trying to persuade you one way or the other’
Discuss uncertainty Remind that worldwide there is no evidence that one treatment is better than the other and link this to why C-GALL being done	I don’t think there’s a right and wrong answer, and I think that’s the thing, it’s difficult, almost impossible to predict in terms of whether you’re going to have an issue, when and where, and that’s why I’m talking to you about this study because I genuinely believe that I’m not … it’s not clear exactly what we should do. But like I say, some patients come to me with a very clear thing, ‘I want this doing, I don’t want this happening again’, and that’s it … and some don’t.	Now at the moment there is no good evidence to suggest which one is the better treatment and … because you fall in that criteria in which we are not sure about whether surgery is the right thing, or carrying on medical management is the right thing. We don’t know what the right option is … So the outcomes are balanced between two treatments and we don’t know which one is better than the other, and that’s the reason of running this trial.
Discussing crossovers	Well one thing I would add about the trial is that it’s not the kind of way we should … it’s meant to be set up. But if things change it doesn’t mean that you exclusively have to still stick with that allocation if that makes sense. So some patients for example I have involved the trial, they’ve been put into the medical management arm and watched for 18 months but then their symptoms have got quite a bit worse and they now want an operation, and that means that they just change, but they’re still part of the study but they’re part of the study that say, ‘Well this approach didn’t work for me’.	Explore preferences with patients, stress the need for participant to consider all treatments and equipoise, and don’t give impression to be biased to one treatment or the other. Don’t volunteer information about cross overs but give opportunity for participant to ask questions and address these.

E-mail feedback was provided to all 21 sites, with generic and site-specific feedback dependent on presence of audio recordings. Sixteen of the sites were responsible for recruiting 400 of the 421 total patients (95%) recruited to the C-GALL trial. This suggests that the hypothesised incremental improvements in recruitment from receiving feedback will have had the opportunity to be realised across these high recruiting sites.

BOX 1 - Tips for discussing with patients (attachment to e-mail)

• This document provides suggestions for the clinical researcher team to help explain the C-GALL trial to patients

• This document is not a script – it provides suggestions that should help to improve informed decision-making and the informed consent discussion

• Please consider using some of these suggestions to complement your own consultation style/approach.

Key strategies for structuring the conversation about participation in the C-GALL trial

• Mention and discuss the C-GALL trial with all eligible patients early on during consultation

• Explain what participation involves (randomisation, treatment allocation, completion of questionnaires)

• Provide well-balanced information about both treatments and be consistent across all patients

• Discuss randomisation process (e.g. we allocate treatment at random) early on during consultation as preferences are then often expressed

• Encourage patients to keep an open mind until you have had the chance to present the trial

• Remind patients about the uncertainty (e.g. worldwide there is no evidence that one treatment is better than another)

• Highlight that the patient will not be advantaged or disadvantaged if they were to select a treatment or be randomised

• Mention that the patient is suitable to receive both treatments and there are risk and benefit in both approaches (detailed in PIL)

• Explore reasons underlying a patient’s preference through direct and indirect questions (e.g. Why do you prefer this treatment?), acknowledge their reasons, and balance their views about treatments (e.g. highlight the advantages of the less preferred treatment and disadvantages of the preferred treatment)

• Stress the need for participant to consider all treatments and equipoise but don’t give the impression to be biased towards either treatment

• Give the patients an opportunity to ask questions

• Stay positive and reassuring all the time. Do not predict the outcome of the trial/study (if asked)

Amendments to the trial patient information leaflet

The PMG discussed the findings from the participant interviews and audio recordings and considered these in the context of the existing content of the trial PIL. It was agreed that the existing PIL could provide additional information regarding expectations about trial retention. Specifically, more information on when trial participants would receive questionnaires and how long they would receive them for that is frequency and duration. The importance of completion and return of the questionnaire was also reinforced as important to assess the impact of the different treatments, even if participants did not experience any symptoms. The importance of questionnaire data to produce reliable results was also emphasised. These amendments were made to the trial PIL and approved by the REC with an updated version implemented in June 2019 (see Appendix 2).

Updates to cover letters and newsletters to target questionnaire response

Recommendations to improve questionnaire return were made to the PMG based on the findings from the behavioural diagnosis findings in the Phase 1 interviews with trial participants. A list of relevant BCTs was generated from existing templates and C-GALL trial paperwork and compared to those identified as relevant from the patient interview findings. A total of 12 BCTs were identified as being relevant for return of participant-completed questionnaires in the C-GALL trial. Specific content was developed or enhanced within the cover letters and newsletter for trial participants to ensure these techniques were covered.

Table 30 presents the specific BCTs, the suggested text for inclusion in the letters, and the justification for inclusion based on interview findings. Changes to the questionnaire cover letters and to trial newsletters were implemented in June 2019.

TABLE 30 - Proposed BCTs and suggested text for inclusion in letters/newsletters

BCT	Suggested text	Justification for inclusion from participant interview findings
1.4 Action planning 11.3 Conserving mental resources	‘The questionnaire requires you to answer questions about your general health over the past 3 months. It can help to keep a note of your symptoms in a diary throughout your participation in this trial. This will help you to complete the questionnaires quickly and as accurately as possible’.	Participants suggested that they struggled to remember their symptoms over the time period specified on the questionnaire. Many participants also said that it helped/would have helped to keep a note of their symptoms to facilitate accurate reporting.
1.9 Commitment	‘The C-GALL trial requires a strong commitment from you and [local hospital] to stay in the study until the end. This means your [local research team/consultant] has placed considerable trust in the patients they asked to join them in this research. Your [consultant] will not be able to fulfil their part in this study without the continued co-operation and participation of their patients’.	The majority of participants indicated the importance of committing to the study, which influenced questionnaire completion and return. Indicating that study participation requires commitment from participants to complete questionnaires at different time points may be effective.
5.1 Information about health consequences 5.2 Salience of consequences	‘As you are aware, living with gallstones can be debilitating. Your participation in this study will help us gain insight into how different treatment options influence well-being. This will help us to identify ways we can support individuals with gallstones to improve their quality of life’.	Participants reported that they had hoped their participation in the study will help people with gallstones in the future. This was also cited as encouraging trial participation.
2.7 Feedback on outcome of behaviour	‘The information you provide in these questionnaires will contribute to the integrity of the results’.	Some participants mentioned that they felt guilty (or would have felt guilty) for failing to return the questionnaire. Many acknowledged that this was because they knew the questionnaires were important for the study. Emphasising this could serve a potent reminder.
9.1 Credible source 6.3 Information about others’ approval 10.4 Social reward 3.2 Social support (practical)	Newsletter: [Picture of Co-Chief Investigators] ‘Co-Chief Investigators, Professor Craig Ramsay and Professor Irfan Ahmed would like to thank participants for their contribution to the trial to date. Without your support, we couldn’t do our research’ [Picture of Trial Manager and Data Coordinator] ‘The trial management team would like to express sincere thanks to those who have responded to the questionnaires we have administered so far. This is a vital component of the trial and we appreciate that it takes time and effort to complete. If you have any queries about the questionnaires, please feel free to get in touch via e-mail [indicate e-mail] or telephone [insert number]’	Thanking participants within clinical trials could have an impact on their motivation to participate. A couple of participants in the qualitative study also indicated their appreciation for the support from the trial office. This was identified as a facilitator to questionnaire return: including pictures/quotes from the trial team and trial contact information will highlight the practical support available to them.
2.2 Feedback on behaviour	If possible, include information about how many questionnaires have been completed, how many are left to complete and an indication of when their participation in the trial ends, tailored to the individual. Could draw attention to it by including this information within a table.	Participants often reported that they could not remember how many questionnaires they had completed/returned. Many participants also reported being unaware of when their participation in the trial ends – including this information will provide them with knowledge of their participation status and could increase their motivation to complete the trial.
4.1 Instruction on how to perform the behaviour	‘As part of the C-GALL study you are asked to complete five questionnaires at different time points. These questionnaires are identical but are designed to measure your well-being over a certain amount of time. It is important to complete the questionnaires even if you have not had surgery or are not experiencing any symptoms around the time that you receive the questionnaire’.	Many participants reported that they felt the questionnaire contained items that were not relevant to their circumstances, either because they had not had surgery or they were not experiencing symptoms around the time of questionnaire administration. Some were also confused about receiving the same questionnaire on multiple occasions.

Discussion

The purpose of this process evaluation was to inform the delivery of the trial, and in particular to focus on the critical components of recruitment and retention of trial participants. We applied existing methods used to improve recruitment to surgical trials and enhanced their practicality by also considering challenges to trial retention. In addition, we applied a behavioural science lens through which to view the trial process problems – a novel contribution to process evaluations in ongoing trials to directly inform and improve recruitment and retention.

Audio recordings of trial consultations provide a rich data set to understand the complexities of decision-making around trial participation. Several studies using this approach have now demonstrated the value of content review and feedback on recruitment discussions. 82 Similar to these existing embedded efforts to improve recruitment in trials we also experienced challenges associated with encouraging healthcare professionals at all sites to audio-record the consultations in which the trial was discussed. Of the 22 recruiting centres in C-GALL, 16 provided at least one consultation audio recording. Exploring ways to best encourage and support sites to routinise the audio recording of the consultations in which the trial is discussed needs to be revisited for future trials.

Findings from the audio recordings and participant interviews led to the PMG reviewing and revising the PIL to enhance the information on trial retention. Existing research has demonstrated that information on the consequences of not completing a trial is not routinely provided in trial PILs. 87 When considered alongside our interview findings that indicate participants were not clear on the expectations of them during trial follow-up indicate the need for more directive information on trial retention is required from trial outset. This is further supported by research that highlighted potential trial participants deem understanding what they will have to do as a trial participant when making the initial decision to participate as highly important. 88 We amended the C-GALL PIL based on the findings of our embedded process evaluation, but the learning generated is transferable for application to future trials.

Rather than being firmly prescriptive in its design, the embedded process evaluation allowed a targeted adaptive approach in order to be responsive to the needs of the trial. This flexibility was a core strength of the activity and allowed additional value to be gleaned from the investigations of trial process, for example, through exploring discussion of trial retention during recruitment consultations. This also allowed the process evaluation to contribute to the wider methodological literature through its investigation of trial retention in this way. 68 The other strength of the activity was the use of behavioural theory to inform data collection, analysis and solution development. The application of behavioural science to problems of trial process is gaining attention. 73 Our process evaluation built on these existing developments but elevated the approach by conducting a series of linked activities from multiple data sources to inform the development of participant-centred strategies.

There were a number of weaknesses. Notably, the sample of interviews with trial participants who were not able to complete the trial till the end constituted a small proportion of those who were initially invited. As such, the views represented by those interviewed may not represent the majority of participants who did not complete and return trial questionnaires. The other potential weakness of the study is that we did not formally evaluate any of the strategies which were implemented based on the findings of the process evaluation. Preliminary evaluation of the impact of the e-mail feedback (using before and after analysis) suggested it was effective but more robust evaluation (e.g. interrupted time series or randomised evaluation) is required and will be a focus of future activities. As mode of follow-up changed (from postal questionnaire to telephone follow-up) due to the pandemic, it was not possible to evaluate the participant-facing strategies focusing on trial retention (PIL, cover letter, newsletter).

Conclusion

The embedded process evaluation in C-GALL allowed exploration and targeted solution-focused strategies that aimed at improving recruitment and retention across the trial. The adaptive nature of the design of the evaluation allowed issues to be investigated in both a proactive and reactive response, improving efficiencies and outputs for the trial. There are some generalisable findings and recommendations for good practice for ongoing and future trials. These include ensuring that details of follow-up processes are shared with participants in both written and verbal information that is shared during informed consent, and highlighting the importance of completing questionnaires (including at multiple time points). The innovative adoption of a behavioural science approach to much of the process evaluation contributed novel insights into trial conduct challenges. Future efforts should focus on the formal evaluation of the approach and solutions developed.

Introduction

Recommendations from the recent NIHR guideline on Gallstone Disease66 have clearly demonstrated that insufficient high-quality information has been produced for patients on the effect of cholecystectomy on patient outcomes. The guideline recommends that ‘research is needed to establish the long-term patient benefits and harms, so that appropriate information can be provided to patients to aid decision-making and long-term management of their condition’. 66 However, due to the way they have been designed and conducted many completed trials are not as informative on patient care, as they could be due to lack of standardisation across studies, outcome definition, collection and reporting. This heterogeneity of outcomes across studies also hampers useful synthesis of primary studies in meta-analyses and ultimately negatively impacts on decision-making by all stakeholders. In addition to the heterogeneity of outcomes currently reported and the problems this causes, measuring the wrong outcomes (i.e. those that are not valued by clinicians or, more importantly, patients) could also be a real risk for many studies if stakeholders are not consulted during the trial design process. One way that these problems with heterogeneity of trials and the consequent relevance of their results to stakeholders can be addressed is through the development and use of COSs. 90,91 At study inception there were no registered or published COS for symptomatic uncomplicated gallstone disease.

Core outcome set aims to define a minimum set of outcomes that should be considered ‘core’ for the evaluation and reporting of specific interventions or conditions (i.e. the set of outcomes that should always be considered and ideally measured in effectiveness trials). 90,91 There is a growing body of literature to provide support for development of COS. 90 Specifically, they are developed using consensus methods involving stakeholder groups, such as health professionals and patients, so as to ensure that the outcomes being defined are both clinically and personally relevant for the individuals involved. 90,91 Generation of a COS is not expected to be mutually exclusive to the measurement of other outcomes. However, a core set will foster greater consistency in outcome reporting between studies and lead to more meaningful data being available to contribute to future meta-analysis. 90,91 Moreover, COS can minimise the threat of outcome reporting bias by ensuring consistency between what is measured and what is reported. 90,91 Ultimately, they should improve the overall efficiency of trials through focused outcome collection and reporting, and the quality of the evidence they produce, enabling better informed healthcare decisions to be made.

The general methodology describing the development of a COS (a systematic review of the literature to identify outcomes reported to date; interviews with stakeholders to explore additional outcomes of importance; and a consensus-based approach to determine which outcomes should be considered core) was adopted in this research to develop a COS for symptomatic uncomplicated gallstone disease. Details of this project were registered in advance and included in the Core Outcome Measures in Effectiveness Trials (COMET) Initiative database. 92

Aims and objectives

Methods

Study overview

The development of the COS followed best practice and involved two sequential stages. 93 The methods for each stage are outlined below and presented in Figure 16. The scope was restricted to interventions (surgical and non-surgical) that treat symptomatic uncomplicated gallstone disease in adults.

FIGURE 16.

Core outcome set development overview. a, 1 Delphi participant did not specify a clinical role.

Stage 1. Identification of outcomes relevant for symptomatic uncomplicated gallstone disease: generation of the outcome list.

The identification of relevant outcomes was informed by two sources: existing evidence and new primary research. The specifics of these are detailed below.

Results

Generation of outcome list

Sample characteristics

The search of existing literature identified 137 studies (129 from trials and PROMs and 8 qualitative studies) eligible for inclusion (Figure 17). A total of 137 publications, from 129 RCTs with 4 reporting gallstone disease-specific PROMs and 8 qualitative studies were included. The majority of the included trials involved one type of surgery versus another type of surgery. 108–113 There were only a few non-surgical interventions.

FIGURE 17.

PRISMA systematic review diagram for evidence synthesis.

The PROMS varied in the aspect of focus of the measure with only two PROMs focused on gallstone disease,114–116 one on gastrointestinal diseases,117 and the other on quality of life after abdominal surgery. 118 All of the PROMs reported to measure multidimensional constructs, for example, QoL. The PROMs varied in the number of constructs they aimed to assess (ranging from 4 to 8) and the number of items they asked participants to report on (ranging from 5 to 41, median = 27).

Of the eight included studies using qualitative methods, seven used interviews [face to face (n = 5) or telephone (n = 2)] and one used focus groups for data collection. All of the treatments being explored in the studies were surgical, but the types of surgery varied. 117,119,120 Table 32 provides a summary of the characteristics of participants included in the quantitative and qualitative literature review.

TABLE 32 - Summary characteristics and demographics of included studies

One study (Marks 2013) was conducted in the UK, USA and Italy and is included in the count for each country.

Note

Number of studies (n = xx studies) in table relates to how many studies reported each relevant characteristic.

Characteristic	Quantitative review	Qualitative review
Number of study participants	(n = 119 studies)	(n = 8 studies)
Median	75	19.5
Range	14–618	6–100
Total	10,757	256
No of males/females	(n = 96 studies)	(n = 7 studies)
Median	21/53.5	4/16
Range	0–255/15–415	2–15/4–37
Total	2,632/6,166	43/113
Age (years)	(n = 14 studies)	–
Median (years)	46.1	–
Range (years)	40–53	19–81
Country	(n = 128 studies)	(n = 8 studies)
UK	7a	1
EEA (excluding UK)	44a	3
USA	12a	1
Other	66	3
No. of centres	(n = 129 studies)	(n = 8 studies)
Single centre	113	8
Multicentre	16
Total no of outcomes reported	330	17

The primary qualitative research included 6 individual interviews, 1 focus group (n = 5 participants) and analysis of 20 consultations (5 each from 4 different hospital sites) which provided data from a total sample of 31 patients (Table 33). They included 26 women and 5 men, 26 of whom had been approached to take part in the C-GALL trial (12 trial consenters and 14 trial non-consenters), and 5 patients who had not been approached about the trial but who had all had a cholecystectomy.

TABLE 33 - Demographics of participants included in the research to identify outcomes for Delphi

During the course of the trial observation/conservative management was defined as medical management.

Research type and number of participants (n)	Gender	Approached to take part in the C-GALL trial, Yes/No and number (n)	Trial consenters (allocated to receive surgery or observation/conservative management)a or decliners
Interviews at recruitment (n = 6)	Female = 6	Yes (n = 6)	Allocated surgery = 4 Allocated medical management = 1 Trial non-consenter = 1
Audio consultations (n = 20)	Female = 16 Male = 4	Yes (n = 20)	Allocated surgery = 4 Allocated medical management = 3 Trial non-consenter = 13
Focus group participants (n = 5)	Female = 4 Male = 1	No	Not applicable

Outcomes identified from existing literature and new primary research

A total of 386 individual recorded outcomes were identified across the combined evidence from existing literature and new primary research: 330 outcomes (which were reported 1147 times) from trials evaluating interventions, 22 outcomes from studies reporting PROMs, 17 outcomes from existing qualitative studies and 17 outcomes from primary qualitative research.

The review of existing qualitative literature identified five additional outcomes for inclusion in the long list, not identified by the trials or studies reporting PROMS, namely: dizziness, fainting, trust, weight and prevention of additional disease. The primary qualitative research identified a further three additional outcomes (breathing problems, cough and mortality) that were not in the previous patient-focused evidence (studies reporting PROMs and qualitative literature), with two of these (breathing problems, cough) making unique contributions to the overall outcome list.

The 390 individual reported outcomes across the four data sources were reduced into a ‘short’ list of outcomes which could be measured in comparative effectiveness trials (i.e. phase III pragmatic effectiveness trials) of interventions to treat uncomplicated symptomatic gallstone disease (see Appendix 6). Several outcomes were dropped from the long list as they were deemed not eligible as clinical endpoint outcomes for use in trials of this type (e.g. system and process outcomes such as duration of surgery which might be important in earlier phase trials). Therefore, the final list covered 27 broad outcome domains that contained 54 distinct outcomes.

Defining the core set

Discussion

COSs for use in effectiveness trials comparing surgical approaches (to a range of comparators) have seen a significant increase in development over recent years. For example, the COMET registry contains 183 entries including the word ‘surgery’ in its database and includes a broad range of specialties from cancer to trauma and cosmetic surgery. 121 The value of the COS developed in the project reported here is for trials of interventions to treat uncomplicated gallstone disease, of which there are many trials evaluating various interventions. 35 While the COS reported in this paper was designed for use in effectiveness trials, like many other COS (both within surgery and other specialties), it could have value for research and clinical practice. 122,123 However, further work to determine international relevance, identification of measures to collect the outcomes, and further validation with additional stakeholders is also of importance.

Core outcomes set focus on the ‘what’ of outcome measurement and reporting rather than the ‘how’ which would include defining time points at which the measurement should be made. Therefore, future research should determine how to measure the outcomes identified in this COS. Some of this work has been conducted. A recent systematic review assessing the methodological quality of PROMs in patients undergoing laparoscopic cholecystectomy identified six validated measures. 124 That review was not able to recommend a specific PROM for use in laparoscopic cholecystectomy due to the limited number of studies and poor quality of the measures identified. 124 A more recent review also identified considerable variation in the measurement and reporting of patient-reported outcomes after laparoscopic cholecystectomy. This more recent review identified the need for a COS that would incorporate patient-reported outcomes and the consideration of longer-term outcomes. 125

Strengths and limitations

Given the challenges with recruitment and sustained participation of the Delphi, it will be important to engage with a wide range of healthcare professionals and trialists to ensure this COS for uncomplicated symptomatic gallstone disease is consulted on as widely as possible prior to implementation. Further work may also be required among additional clinical stakeholder groups (e.g. general practitioners, service commissioners) to ensure the core outcomes represent outcomes they would also consider core when evaluating a range of interventions for the treatment of uncomplicated symptomatic gallstones. In addition, determining the transferability of this COS to other settings (i.e. low- and middle-income countries) would also be important to ensure wide applicability and implementation.

A key strength of the work is the extensive outcome mapping exercise on which the COS builds. Even though a small number of patients contributed to the consensus meeting, the outcomes that had been previously identified as of importance to participants were informed by an extensive synthesis of patients reported relevant outcomes through systematic literature review and primary research. 89

Conclusions

The study has developed the first COS for use in effectiveness trials evaluating interventions for uncomplicated symptomatic gallstone disease. It was prospectively registered on the COMET Initiative database and development, and reporting has been informed by existing standards for COSs. 90,126 The final COS includes 11 outcomes deemed critically important by both patients and healthcare professionals. Further work is required to identify appropriate ways to measure the core outcomes and to verify its findings in a wider stakeholder group.

Principal findings

Comparison of findings with other studies

Two small Norwegian RCTs, involving 201 participants, demonstrated that 55% of people randomised to observation did not require an operation during the 14-year follow-up period and 12% of people randomised to cholecystectomy did not undergo the scheduled operation. 35 This contrasts with 70% randomised to observation/conservative management not undertaking surgery at 24 months in C-GALL and 30% in the surgery group not undergoing cholecystectomy. Scrutinising (in)efficient use of cholecystectomy: a randomized trial concerning variation in practice (SECURE)30 conducted a non-inferiority multicentre RCT in the Netherlands of immediate cholecystectomy versus a restrictive strategy, whereby participants underwent cholecystectomy only when the participants fulfilled five prespecified criteria for surgery at any clinic visits. The SECURE trial noted that 30% (non-compliance) of the participants allocated to the restrictive policy underwent cholecystectomy, despite not fulfilling criteria for surgery, and attributed this to either the surgeon or the patient deciding that cholecystectomy was the best therapeutic option despite the outcome of the triage instrument. The SECURE study concluded that the current surgical management of patients with gallstones and abdominal symptoms is suboptimal, that a restrictive policy was not a solution and that physicians need to be more careful in advising a surgical approach in patients with gallstones and abdominal symptoms. The C-GALL trial findings were consistent with the SECURE conclusion and, in addition, provided stronger evidence from a broader range of patients since C-GALL included participants with biliary colic or acute cholecystitis (SECURE only included biliary colic participants).

Strengths of the trial

C-GALL’s strengths included the pragmatic RCT design and methodological rigour. The benefit of the sample size is reflected in the precision with which outcomes were estimated. This multicentre trial also gives confidence in the generalisability of findings to the NHS. Our recruited sample had a mean age of 51 years and was representative of patients presenting with uncomplicated symptomatic gallstones in a secondary care setting. 127 Among our sample, participants were predominantly female, white (86%) with Asian/Asian British (6.9%) and black/African/Caribbean/black British (2.8%). This contrasts well with English/Welsh statistics, 86%, 7.5% and 3.3%, respectively. 128 We are therefore confident that the results were representative of the UK population with gallstones.

This trial was pragmatic where patients in the UK may not always receive the treatment they are offered and waiting lists for surgical treatment existed. We carefully tracked treatment after randomisation and monitored compliance. A major strength included our sensitivity analyses, including compliance analysis, imputation for missing data and potential impact of COVID-19. These analyses did not change our findings.

The cost-effectiveness analysis had several strengths. Firstly, the RCT design allowed the collection of data on resource use and QoL collected prospectively for comparable groups. Secondly, in cost analysis, critical model data were supported by RCT data (e.g. survival analysis; QoL data for the reduction in QoL weight before and after surgery).

We incorporated an embedded process evaluation with qualitative interviews to better understand and reduce recruitment and retention challenges. The process evaluation gave some generalisable findings and recommendations for good practice for ongoing and future trials including how to improve the informed consent and follow-up processes.

A key strength of the COS was the extensive outcome mapping exercise, including both existing and primary research, on which the COS builds. The development of a COS for uncomplicated symptomatic gallstone disease will help to ensure that important outcomes to patients and the NHS are collected in the future.

Reporting equality, diversity and inclusion

As described earlier, the participant population were closely matched in age and ethnicity to the UK population with gallstones. We optimised participation through the use of recordings of screening/recruitment appointments to provide feedback to the recruiters’ potential conscious/unconscious biases. The research team included a group of PPI partners from across the UK that were actively involved throughout the study contributing to COS development, study materials and contributing to discussions of the study results with the TSC and the trial investigators as well as preparation of the plain language summary. The study team represented a broad range of expertise in quantitative and qualitative methodologies. Less experienced members of the team were encouraged to lead discrete components of the study (under senior supervision), lead ancillary publications from that work and lead the study’s contribution to SWAT. For example, publications related to the COS were authored by less experienced members of the team.

Limitations of the trial

An unexpected difficulty was the longer than expected time on the waiting list for the delivery of surgery for those patients who were allocated to cholecystectomy. When designing the trial, it was anticipated that this wait would be, on average, 6 months. Therefore an 18-month follow-up was chosen as the primary outcome follow-up time to reflect a time equivalent to 12 months after surgery. However, during the study, we observed that patients often experienced longer times to surgery initially due to existing NHS resources that resulted in long waiting lists. To address this, we added a 24-month follow-up time point. Our sensitivity analyses on compliance with the treatment suggested that the waiting list was unlikely to be biasing the study findings. The existence of the waiting list may limit the generalisability to some other countries’ jurisdictions. A further limitation was the non-blinding of participants and treating surgeons to allocation. In this trial, the pragmatic research question was testing the most effective treatment strategy in real-life setting, leading to an inevitable lack of blinding. Although statistically significant differences in gall bladder-specific measures were found, the importance of the size of the differences was unclear with no previously published estimates of important differences. Nevertheless, considering Cohen’s standardised effect sizes of 0.25 of a SD to be important, the observed study differences were larger and about 0.4 of a SD. Lastly, non-responders to the questionnaire tended to be younger and have worse self-reported pain and quality of life at recruitment compared to responders. Such non-response is often found in trials. The MI approach and sensitivity analyses limited the effect of this possible non-response bias.

Implications for health care

Current clinical guidelines recommend offering laparoscopic cholecystectomy for biliary pain or acute cholecystitis and radiological evidence of gallstones. 30 Hence, surgical management remains the default option for people with symptomatic gallstone disease and one of the most common elective surgical procedures performed in the NHS. 30 In the UK, many people with uncomplicated symptomatic gallstone disease are put on a waiting list and operated on electively after several months. The C-GALL trial demonstrates that in adults presenting with uncomplicated symptomatic gallstones in a secondary care setting observation/conservative management may be as effective and cost-effective as laparoscopic cholecystectomy in the short term. The crossover between groups suggests that it remains key to identify patients who will and will not benefit from surgery and that discussion about the options, benefits and risks of both approaches should be part of the consent process. 129

Implications for research

Costs and benefits will continue to be incurred in both groups beyond 24 months, so future research should focus on (1) long-term follow-up data to establish the lifetime cost-effectiveness (e.g. using a simple cohort design) and (2) identification of the cohort of patients that should be offered surgery.

Conclusion

Overall, our results suggested that in the short term (up to 24 months) observation/conservative management may be a cost-effective use of NHS resources in selected patients but subsequent surgeries in the randomised groups and differences in quality of life beyond 24 months could reverse this finding, and longer-term follow up is needed to verify the safety and cost-effectiveness of this approach.

Contributions of authors

Karen Innes (https://orcid.org/0000-0001-8512-4368) (Trial Manager) contributed to the design of the trial, was responsible for the day-to-day management of the trial and contributed to the interpretation of results and writing/editing the report.

Irfan Ahmed (https://orcid.org/0000-0002-2172-4177) (Co-Chief Investigator, Professor) contributed to the conception and design of the trial, was involved in recruitment, recruited, and was responsible for the day-to-day oversight of the trial, interpretation of results and writing/editing the report.

Jemma Hudson (https://orcid.org/0000-0002-6440-6419) (Statistician) conducted the statistical analysis and contributed to the interpretation of results, writing/editing the report and reviewing the final report.

Rodolfo Hernández (https://orcid.org/0000-0003-2619-8230) (Health Economist) contributed to the conception and design of the study, the analysis of the health economics data, the development of the health economics model, the drafting of the health economics chapters, the interpretation of the trial results, plus commented on other chapters of the report.

Katie Gillies (https://orcid.org/0000-0001-7890-2854) (Qualitative Researcher) contributed to the conception and design of the trial, oversaw the process evaluation and core outcome set development and analysis, contributed to the interpretation of results and writing/editing the report.

Rebecca Bruce (https://orcid.org/0000-0001-8508-1206) (Data Co-ordinator) was responsible for aspects of the day-to-day management of the trial and contributed to the interpretation of results and editing the report.

Victoria Bell (https://orcid.org/0000-0001-9518-9296) (Assistant Trial Manager) was responsible for aspects of the day-to-day management of the trial and contributed to the interpretation of results and writing/editing the report.

Alison Avenell (https://orcid.org/0000-0003-4813-5628) (Clinical Chair in Health Services Research) contributed to the conception and design of the trial, the interpretation of results and writing/editing the report.

Jane Blazeby (https://orcid.org/0000-0002-3354-3330) (Professor of Surgery) contributed to the design of the trial, conduct of the trial, interpretation of results and writing/editing the report.

Miriam Brazzelli (https://orcid.org/0000-0002-7576-6751) (Senior Research Fellow) contributed to the conception and design of the trial, the interpretation of results and writing/editing the report.

Seonaidh Cotton (https://orcid.org/0000-0002-7883-0608) (Senior Trail Manager) contributed to oversight of the day-to-day management of the trial and contributed to the interpretation of results and writing/editing the report.

Bernard Croal (https://orcid.org/0000-0002-6375-3507) (Patient and Public Representative) as a named grant holder, contributed to the conception and design of the trial, conduct of the trial, recruitment and follow-up of participants, interpretation of results and writing/editing the report. He also focused on the patient and public involvement (PPI) components of the trial which fed important information back to the trial.

Mark Forrest (https://orcid.org/0000-0002-2395-8823) (Senior IT Development Manager) contributed to the design of the trial software and data curation, interpretation of results and writing/editing the report.

Graeme MacLennan (https://orcid.org/0000-0002-1039-5646) (CHaRT Director) contributed to the statistical analysis, the interpretation of results and writing/editing the report.

Peter Murchie (https://orcid.org/0000-0001-9968-5991) (Academic GP) contributed to the conception and design of the trial, the interpretation of results and writing/editing the report.

Samantha Wileman (https://orcid.org/0000-0002-1031-1449) (Quality Assurance Manager) contributed to the conception and design of the trial, the interpretation of results and writing/editing the report.

Craig Ramsey (https://orcid.org/0000-0003-4043-7349) (Co-Chief Investigator, Professor) contributed to the conception and design of the trial, was responsible for the day-to-day oversight of the trial, interpretation of results and writing/editing the report.

Acknowledgements

The authors wish to thank the men and women who participated in C-GALL. We also thank the CHaRT data co-ordinators and trial managers who helped support the study: Zoe Batham, Louise Campbell, Janice Cruden, Dianne Dejean, Jackie Ellington, Andrea Fraser and Bev Smith (Data Co-ordinators), Tracey Davidson and Alison McDonald (Trial Managers).

We are grateful to Kirsty McCormack and John Norrie for their help and advice in developing the grant proposal, to the Programming Team in CHaRT for developing and maintaining the study website. We thank Juliette Snow and Rachael West for their help with contracting, and Louise Cotterell, Kerry Duffus and Anne Buckle for their assistance in managing the budget. Our thanks also go to the Research Governance team (Louise King, Stacey Dawson, Lynn McKay) at the University of Aberdeen for their advice and support during the study.

Thanks to Jamie McAllister (NHS Grampian) for providing unit cost data for the within-trial economic analysis.

Thanks to Chen et al. for allowing the C-GALL group the use of the Otago Condition-Specific Questionnaire (OCSQ) for gallstone disease, developed by Chen et al. in the University of Otago, New Zealand. 1,2

1. Chen TY, Landmann MG, Potter JC, van Rij AM. Questionnaire to aid priority and outcomes assessment in gallstone disease. ANZ J Surg. 2006;76(7):569–74.

2. Chen TY. A novel set of condition-specific quality of life questionnaires in elective general surgical patient prioritization and outcome assessment [dissertation]. Dunedin (NZ): University of Otago; 2012. Retrieved from http://hdl.handle.net/10523/2588

Members of the PMG for their ongoing support and advice. The independent members of the TSC and DMC, and the staff at the recruiting sites (listed below) who facilitated recruitment, treatment and follow-up of trial participants.

Project Management Group

Craig Ramsay, Irfan Ahmed, Alison Avenell, Victoria Bell, Jane Blazeby, Miriam Brazzelli, Rebecca Bruce, Bernard Croal (Grant Holder PPI Representative), Mark Forrest, Katie Gillies, Rodolfo Hernandez, Jemma Hudson, Karen Innes, Graeme MacLennan, Peter Murchie, John Norrie, Samantha Wileman.

Trial Steering Group

David Beard (Chair), Ian Beckingham (Independent Member), John Leeds (Independent Member TSC), Dee McDonald (Patient Representative) and PMG members.

Data Monitoring Committee

Catherine Hewitt (Chair), Jonathan Lund (Independent Member), Tim McAdam (Independent Member) and Amir Nisar (Independent Member).

Embedded Process Evaluation Team

Eilidh Duncan, Jennifer Dunsmore, Louisa Lawrie, Rumana Newlands.

Core Outcome Set Team

Mohammed Bekheit, Moira Cruickshank.

Patient and Public Involvement (PPI) group

Special thanks to those who participated in the PPI group: Edna Bell, Anna Glassey, Denise Gorman, Carolyn Hutchison, Marion Morton, Alec Paterson, Sheena Rendall, Wendy Stuart, Annamaria Wolf and to Katie Banister for her involvement in the PPI activities.

Members of the C-GALL trial group responsible for recruitment in the clinical centres were as follows:

Aberdeen: James Milburn (Principal Investigator), Irfan Ahmed (Principal Investigator), Momin Malik, Sandra Mann, Amy Nicol (Nee – Angus), Tracy Scott, Lorna Van Lierop

Bedford: Dipankar Chattopadhyay (Principal Investigator), Beena David, Carina Galpin, Mel Penacerrada, Kanapathi Rajaratnam, Retno Walandari

Birmingham: Robert Sutcliffe (Principal Investigator), Elizabeth Cornes, Sharon Garner, Manijeh Ghods, Ewen Griffiths, Ravi Marudanayagam, Andrew McDarby, Claire McNeill, Sonia Puig-Compano, Keith Roberts, Arlo Whitehouse

Borders: Jamie Young (Principal Investigator), Joy Dawson, Dave Gribble, Laura Stephen

Cardiff: David O’Reilly (Principal Investigator), Rezwana Chowdhury, Antonio Foliaki, Martin Grigg, Laura Jones, Lucy Knibbs, Gail Williams, Jolene Witherspoon, Caroline Young

Coventry: Jawad Ahmad (Principal Investigator), Susan Dale, Natalie Kenny, Edward Lopez, Gabriele Marangoni

Durham: Zaher Toumi (Principal Investigator), Sarah Clark, Louise Duncan, Stef Hobson, Andrea Kay, Ami Laidlaw, Diana Nayman, Ami Wilkinson

Fife: Peter Driscoll (Principal Investigator), Karlygash Ausel, Laura Beveridge, Keith Boath, Geert Koffeman, Sue Pick

Glasgow: Simon Gibson (Principal Investigator), Anissa Benchiheub, Carol Dalton, Paul Glen, Steven Henderson, Gillian Rice

Heart of England: Markos Daskalakis (Principal Investigator), Sally Abbott, Safia Begum, Maryam Hussain, Tabinda Kharodia, Julie Markley, Faye Moore, Raj Nijjar, VJ Shabangu, Karim Sillah, Rishi Singhal, Samantha Stafford, Paul Super, Olga Tucker

Liverpool: Christopher Halloran (Principal Investigator), Lorna Fleming-Bird, Julie Haydock, Francesca Westwell

Newport: Andrew Beamish (Principal Investigator), Michael Nutt (Principal Investigator), Ashraf Rasheed (Principal Investigator), Lindianne Aitken, Evelyn Baker, Nancy Hawkings, Georgia Mallison, Heeam Nassa, Grace Okoro, Claire Price, Sandapa Punchihewa, Laura Smith, Jemma Tuffney, Elaine Wall, Cerian Williams

North Tees: Talvinder Gill (Principal Investigator), Mazuin Abutalib, Ish Ahmed, Rajendirin Ashwin, Liz Baker, Leo Brown, Bussa Gopinath, Deena Harji, Siddek Isreb, Aya Musbahi, Milind Rao, Murugappan Shanmugam, Kyaw Toe, Suvi Virupaksha, Debbie Wilson

Nottingham: Ravinder Vohra (Principal Investigator), Tracy Brear, Debra Campion, Jody Carvell, James Catton, David Chadwick, Sam Dutta, Tanvir Hossain, Maria Laye, Kate Marks, Simon Parsons, Shirley Pyke, Judith Rozentals, John Saunders, Nilanjana Tewari, Rhian Warman, Neil Welch, Fady Yanni

Plymouth: David Stell (Principal Investigator), Abigail Patrick, Aleasha Udal, Natasha Wilmshurst

Royal Free: Brian Davidson (Principal Investigator), Christine Eastgate, Helder Filipe, Yvonne Gleeson, Kurinchi Gurusamy

Sandwell: Andrew Torrance (Principal Investigator), Veronica Campbel, Julie Colley, Mokhtar Eltair, Samia Hussain, Yogesh Kumar, Rajnish Mankotia, Jenny Porter, Liam Preece, Elizabeth Williams

Taunton: Marianne Hollyman (Principal Investigator), Sarah Brown, Katrina Butcher, Viktoria Cripps, Rebecca Goodchild, Libby Graham, Ami Mackay, Matthew Mason, Peter Mekhail, Alison Moss, Hamish Noble, Maria O’Leary, Corinne Pawley, Andrew Robertson, Charmaine Shovelton, Muwaffaq Telfah, Frances Venn, Richard Welbourn, Esther Zebracki

Warwick: Paul Marriott (Principal Investigator), Indy Atwal, Bridget Campbell, Vasileios Charalampakis, Angela Day, Angela Doyle, Sophie Mason, Penny Parsons, Alexandra Smith, Karen Spicer, Frances Walsh, Kathryn Webb

Yeovil: John Spearman (Principal Investigator), Joanna Allison, Kate Beesley, Nathan Curtis, Godwin Dennison, Linda Howard, Alison Lewis, Jess Perry

Sites opened but never recruited

Aintree: Hassan Malik (Principal Investigator), Matthew Caffrey, Shirley Cooper, Rafael Diaz-Nieto, Declan Dunne, Joanne Earley, Stephen Fenwick, Melanie Harrison, Tanya Ingram, Robert Jones, Sophie Marsh, Sarah Stevenson, Cath Toohey

Dundee: Iain Tait (Principal Investigator), Mairead Tennent

Patient data statement

This work uses data provided by patients and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people’s patient records, to understand more about disease, develop new treatments, monitor safety and plan NHS services. Patient data should be kept safe and secure, to protect everyone’s privacy, and it’s important that there are safeguards to make sure that they are stored and used responsibly. Everyone should be able to find out about how patient data are used. #datasaveslives You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/data-citation

Data-sharing statement

All data requests should be submitted to the corresponding author for consideration. Access to available anonymised data may be granted following review.

Ethics statement

C-GALL received favourable ethics opinion from North of Scotland Research Ethics Committee (REC) A, on 23 May 2016 (REC reference number 16/NS/0053).

Information governance statement

The University of Aberdeen and NHS Grampian are committed to handling all personal information in line with the UK Data Protection Act (2018) and the General Data Protection Regulation (EU GDPR) 2016/679. Under the Data Protection legislation, University of Aberdeen and NHS Grampian are joint Data Controllers, and you can find out more about how we handle personal data, including how to exercise your individual rights and the contact details for our Data Protection Officer here: https://www.abdn.ac.uk/about/privacy/

Disclosure of interests

Full disclosure of interests: Completed ICMJE forms for all authors, including all related interests, are available in the toolkit on the NIHR Journals Library report publication page at https://doi.org/10.3310/MNBY3104.

Primary conflicts of interest: Katie Gillies reports other financial or no financial interest as a member of the NIHR HTA CET Committee since 2020; Jane Blazeby reports grants from NIHR Bristol Biomedical Research Centre and being a member of the NIHR Clinical Trials Unit Standing Advisory Committee 2015–9; Seonaidh Cotton is a coinvestigator on unrelated grants from NIHR (HTA and EME programmes: NIHR129819, 15/130/95, 15/130/20) for which her institution has received payment; Bernard Croal reports a Leadership or fiduciary role in the Association of Clinical Biochemistry and Laboratory medicine as president 2021–2023 and Royal College of Pathologists as Trustee and Scottish Chair; Craig Ramsay reports no financial interest as a member of the NIHR HTA General Committee 2017–22.

Additional funding

Chapter 7 – Core Outcome Set: This work was also supported by NHS Grampian Endowment (project grant no. 16/11/006). KG held a Medical Research Council UK Methodology Fellowship during the delivery of this project (MR/L01193X/1).

Publications

Tunji-Ajayi P, Duncan EM, Gillies K. An embedded mixed-methods study highlighted a lack of discussions on retention in clinical trial consultations. J Clin Epidemiol. 2020;123:49–58. https://doi.org/10.1016/j.jclinepi.2020.03.011

Ahmed A, Innes K, Brazzelli M, et al. Protocol for a randomised controlled trial comparing laparoscopic cholecystectomy with observation/conservative management for preventing recurrent symptoms and complications in adults with uncomplicated symptomatic gallstones (C-GALL trial). BMJ Open 2021;11:e039781.

Cruickshank M, Newlands R, Blazeby J, et al. Identification and categorisation of relevant outcomes for symptomatic uncomplicated gallstone disease: in-depth analysis to inform the development of a core outcome set. BMJ Open 2021;11:e045568.

Lawrie L, Duncan EM, Dunsmore J, et al. Using a behavioural approach to explore the factors that affect questionnaire return within a clinical trial: a qualitative study based on the theoretical domains framework. BMJ Open 2021;11:e048128. https://doi.org/10.1136/bmjopen-2020-048128

Innes K, Hudson J, Banister K, et al. Core outcome set for symptomatic uncomplicated gallstone disease. Br J Surg 2022;109:539–44. https://doi.org/10.1093/bjs/znac095

Disclaimers

This article presents independent research funded by the National Institute for Health and Care Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, the HTA programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, the HTA programme or the Department of Health and Social Care.