To the best of our knowledge, the C-GALL trial is the largest multicentre, pragmatic trial to evaluate the clinical and cost-effectiveness of observation/conservative management compared with laparoscopic cholecystectomy to prevent recurrent symptoms and complications in adults presenting with uncomplicated symptomatic gallstones in a secondary care setting.
The primary outcome was QoL measured by AUC at up to 18 months using the SF-36 bodily pain domain. Secondary outcomes included the Otago gallstones CSQ, SF-36 domains (excluding bodily pain), AUC at up to 24 months for the SF-36 bodily pain domain, persistent symptoms (pain and dyspepsia) and complications.
Principal findings
Clinical effectiveness
The trial was conducted in the UK NHS setting, across 20 secondary care sites, and randomised 434 participants. There was no evidence of a difference in the primary outcome of bodily pain at 18 months and no evidence of differences in QoL, complications or in the need for further treatment between the strategies at up to 24 months follow-up. There was statistically significant evidence that gall bladder-specific measures of QoL improved in the cholecystectomy randomised group at 24 months.
Before the trial, it was envisaged that clinicians would be reluctant to recruit patients due to preference in favour of surgery. Moreover, it was thought that patients would be unwilling to consent to recruitment because it was likely that they would feel surgical options were needed after being referred to the hospital for that purpose. During the trial, it was noted that many patients opted for non-surgical treatment after being provided with detailed information about the alternative options available. Almost one-third of patients in the conservative management group subsequently received surgery and 30% of those randomised to surgery had not received surgery by 24 months.
Prespecified sensitivity analyses demonstrated clearly that compliance with treatment allocation, missing data and the impact of COVID-19 did not change the findings.
The profile of complications in the two groups was as expected in routine care. There was no evidence of any difference in total complications between the groups. In the observation/conservative management group, presurgical complications of cholecystitis/biliary colic were the most prevalent complications, and for the surgical management group, bile/stone spillage from gallbladder was the main complication.
Cost-effectiveness
Cost analysis shows that observation/conservative management group was less costly than the laparoscopic cholecystectomy group. The trial did not demonstrate a significant difference in QALYs between the groups. The ICER was found to be high, meaning significant potential savings to the NHS with limited QALY loss by following an observation/conservative management approach in the short term. Longer-term modelling suggested that following an observation/conservative management approach might be cost-effective but there was greater uncertainty due to limited information on subsequent surgeries in the randomised groups and differences in QoL beyond 24 months could reverse this finding. Sensitivity analysis incorporating longer-term QoL scores reduced the potential saving to just £14,700 per QALY lost. The current decision uncertainty could be reduced with a long-term follow-up of the C-GALL trial participants.
Process evaluation
The embedded process evaluation in C-GALL explored ways of improving recruitment and retention across the trial. A total of 16 sites provided 180 audio recordings of consultations for analysis. Analysis of the transcripts identified four core challenge areas for recruiters: (1) providing a balanced presentation about both treatments; (2) discussing and exploring preferences; (3) discussing uncertainty; and (4) discussing participants who did not receive their treatment allocation (crossovers in treatments). A subset of 38 audio recordings of consultations from 4 sites were included in the analysis of discussion of retention. Thirty (79%) of these consultations did not include any discussion of trial retention. Interviews with participants (n = 9) to explore challenges in returning postal questionnaires identified six themes influencing retention: unclear expectations of trial participation; personal attributes for questionnaire completion; significance of questionnaire non-return; commitment to returning questionnaires given other priorities; individual preferences for presentation mode and timing of the questionnaires; and internal and external strategies to encourage questionnaire return. The innovative adoption of a behavioural science approach to the process evaluation led to structured changes in written and verbal information across the trial including e-mail feedback, amendments to trial information leaflet and updates to cover letters and newsletters.
Core outcome set
The final COS for symptomatic uncomplicated gallstone disease included 11 critically important outcomes from both patients and healthcare professionals. These were QoL, overall health state, overall satisfaction, overall pain, common bile duct injury, biliary leak, haemorrhage, need for endoscopic retrograde cholangiopancreatography, intra-abdominal collections, admission/re-admission for problems and reoperation.
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.