Trial design and methods

Parts of this chapter are reproduced with permission from Ahmed et al.1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text.

The study was prospectively registered on a publicly available website on 27 May 2016 as International Standard Randomised Controlled Trial Number (ISRCTN) 55215960.

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. (Figure not reproduced here; see the original article.)

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.

Inclusion criteria

All adult patients with confirmed symptomatic gallstones electively referred to a secondary care setting for consultation. Clinical diagnosis of gallstone disease was confirmed by imaging. Transabdominal ultrasonography was the standard imaging technique for the diagnosis of gallbladder stones, but diagnosis by any imaging technique was acceptable.

Exclusion criteria

• Unable to consent.
• Medically unfit for surgery.
• Current pregnancy.
• Previous open major upper abdominal surgery.
• Gallstones in common bile duct or evidence of previous choledocholithiasis.
• A history of acute pancreatitis.
• Evidence of obstructive jaundice.
• Evidence of empyema of the gallbladder with sepsis.
• Suspicion of gallbladder cancer.
• Perforated gallbladder (recent or old perforation detected on imaging).
• Haemolytic disease.

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

Primary outcome

The primary patient outcome measure was QoL. This was measured by area under the curve (AUC) at up to 18 months post randomisation using the SF-36 bodily pain domain (AUC measures at 3, 9, 12 and 18 months).

Secondary outcomes

The secondary outcomes were measured at both 18 and 24 months post randomisation. These were:

• AUC up to 24 months post randomisation for SF-36 bodily pain
• CSQ
• SF-36 domains (excluding bodily pain domain)
• complications (defined as any presurgery, intraoperative or postoperative complications)
• need for further treatment (patient reported)
• persistent symptoms [patient reported and consisted of two sections (pain and dyspepsia) of the CSQ]
• HCRU
• costs.

Safety and breaches

Adverse events

An adverse event (AE) is defined as any untoward medical event affecting a clinical trial participant. Each AE will be considered for severity, causality and expectedness and may be reclassified as a serious event based on prevailing circumstances.

In the C-GALL trial, AEs were anticipated to occur during or after any type of surgery and while in observation/conservative management. In this trial, the following events were expected.

Adverse events during or after laparoscopic cholecystectomy

Intraoperative complications:

• bleeding > 500 millilitres (ml)
• injury to abdominal viscera, including liver tear or laceration
• anaesthetic complications (including hypersensitivity to the general anaesthesia and/or any of the medications or material used)
• injury to the bile duct
• bile leak from the bile duct, hepatic duct or ducts at the base of the liver or bile spillage from the gallbladder
• bile/stone spillage from the gallbladder.

Immediate postoperative complications:

• postoperative bleeding > 500 ml
• injury to the abdominal viscera, including liver tear or laceration
• injury to bile duct
• bowel obstruction
• wound infection
• pain requiring additional analgesia
• bile leak
• thrombosis (deep vein thrombosis/pulmonary embolism)
• urinary retention
• infection (sepsis, septicaemia, abscess)
• retained/missed common bile duct stone.

Late postoperative complications:

• incisional/port site hernia
• chronic wound pain
• infection (sepsis, septicaemia, abscess)
• biliary pain (right upper quadrant pain)
• non-specific abdominal pain
• post cholecystectomy jaundice.

Potential adverse events during observation/conservative management/presurgery

The anticipated risk of developing a potential AE in the conservative management group that might require further surgery or endoscopic treatment was 0.7%/year.35 The following were expected:

• acute cholecystitis
• empyema/mucocele
• gallbladder perforation
• acute pancreatitis
• common bile duct stone
• obstructive jaundice
• gallstone ileus.

Adverse events that met the criteria for ‘serious’ were reviewed in order to determine whether or not the event was ‘related’. Within C-GALL, ‘related’ was defined as an event that occurred as a result of a procedure required by the protocol, whether or not it was either (1) the specific intervention allocated at randomisation or (2) it was administered as an additional intervention as part of normal care.

All serious adverse events (SAEs) that were considered to be ‘related’ were recorded on a trial-specific SAE form. SAEs are described as complications or need for further treatment in Chapter 3. SAEs that were not related were not recorded. Deaths were also recorded on this SAE form.

A SAE is any AE that:

• results in death
• is life-threatening (i.e. the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe)
• requires hospitalisation or prolongation of existing hospitalisation
• results in persistent or significant disability or incapacity
• is a congenital anomaly or birth defect
• is otherwise considered medically significant by the investigator.

All AEs and SAEs that met the criteria for recording within C-GALL were recorded from the time a participant consented to join the trial until the end of the trial.

Breaches

Sites were asked to report potential breaches of trial protocol or GCP to the trial office. Trial office staff could also report potential breaches. There were two breaches recorded within the study and these are summarised in Appendix 1, Table 36. Both breaches were assessed by the Chief Investigator and the Sponsor as non-serious.

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

Sample size

The primary outcome was AUC measured from SF-36 bodily pain up to 18 months. To detect a 0.33 standard deviation (SD) difference, with 90% power and alpha at 5%, 194 participants per group (388 in total) were required. A 0.33 difference in generic health status is considered clinically relevant and in terms of treatment effect size, in the small to medium ranges as observed in other clinical studies. We allowed for 10% of participants to have completely missing outcome data, with no AUC calculable, inflating the sample size to 430 participants in total.

Primary outcome analysis

The primary outcome, AUC SF-36 bodily pain up to 18 months, was analysed using a mixed effects regression model with adjustment for the minimisation covariates gender (male, female), age (< 35; 35–64; ≥ 65 years) and including centre as a random effect. The AUC for each participant was generated by the trapezium rule using baseline, 3-, 9-, 12- and 18-month time points. Missing SF-36 bodily pain baseline values were imputed using centre-specific baseline mean. Our primary analysis included all participants who had at least one time point up to 30 months post randomisation. For participants with missing data at 18 months, multiple imputation (MI) using Rubin’s rule under a missing at random assumption was used to impute their SF-36 bodily pain score at 18 months only. Variables included in the imputation model were SF-36 bodily pain at follow-up time points up to 30 months as well as baseline characteristics. The number of imputations used was the proportion of missing data. If participants were missing SF-36 bodily pain at other time points (apart from 18 months), then the AUC was calculated using the time points available only. Secondary analysis of the primary outcome was performed for participants who had an 18-month score. A sensitivity analysis was performed including all participants who had at least one time point up to 18 months with MI being used for missing 18 months’ data.

Secondary outcome analysis

Short Form-36 bodily pain AUC up to 24 months post randomisation was analysed in a similar way to the primary outcome analysis. CSQ, SF-36 (excluding bodily pain) and persistent symptoms were analysed using repeated-measures mixed-effects regression model correcting for baseline score, minimisation covariates gender (male, female), age (< 35; 35–64; ≥ 65 years) and time as a fixed effect. The repeated measures were assessed at 3, 9, 12, 18 and 24 months with treatment effects estimates from time-by-treatment interactions at each time point. This approach uses participant data from all time points and incorporates a random effect for centre and participant. Data missing at baseline were reported as such. For the analysis, missing baseline data were imputed using the centre-specific mean of that variable. Complications and need for further treatment were analysed using a Poisson model adjusting for minimisation covariates gender (male, female), age (< 35; 35–64; ≥ 65 years) and including a random effect for centre using robust error variance.37 This allows results to efficiently calculate adjusted relative risk. Analysis was performed separately for data up to 18 months and data up to 24 months.

Subgroup analysis

Planned subgroup analyses explored the potential treatment effect moderation of gender (male, female), age (< 35; 35–64; ≥ 65 years) and ethnicity on the primary outcome. For ethnicity, we planned to use the UK census ethnic groupings; however, due to limited numbers in certain categories we categorised ethnicity as white or other than white. The subgroup-by-treatment interaction was assessed by including interaction terms in the models outlined above. We used a stricter level of significance (two-sided 1% significance level) and 99% CIs to reflect the exploratory nature of these analyses.

Compliance analysis

We explored the influence of compliance by undertaking a complier-adjusted causal estimation analysis. Compliance was defined as participants who received their allocated treatment within 24 months. For the laparoscopic cholecystectomy group, participants who received emergency cholecystectomy were defined as non-compliant. For the complier-adjusted causal estimation analysis, an instrumental variable two-stage least squares regression model with compliance instrumented by random allocation was used adjusting for baseline score, minimisation covariates gender (male, female), age (< 35; 35–64; ≥ 65 years) and adjusting for centre using cluster robust variance.

Coronavirus disease 2019

The impact of coronavirus disease 2019 (COVID-19) was assessed by looking at the AUC for the subset of data pre-COVID-19 defined as before 11 March 202038 using the same analysis as described in the primary outcome analysis.

Criteria for the termination of the trial

Due to the staggered nature of recruitment and, therefore, the measurement of the primary outcome at 18 months, there were no planned interim analyses for futility or benefit. We proposed one main effectiveness analysis at the end of the trial. During the trial, safety and other data were monitored by reports prepared for the Data Monitoring Committee (DMC).

Differences between the statistical analysis plan and the published protocol

In the published protocol,1 we did not include ethnicity in the subgroup analysis. This was because when writing the SAP, we highlighted the need to look at the effect of different ethnic groups on the primary outcome. Also, we stated we would look at a per-protocol analysis; however, we decided to do a compliance analysis as it does not exclude participants who did not receive their allocated intervention.

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

Project Management Group

The PMG was responsible for overseeing the management of the trial. This group consisted of the representatives from the study office, and grant holders which included a grant holder who was the patient and public involvement (PPI) representative and a senior programmer. Members of the PMG are listed in the Acknowledgements.

Trial Steering Committee

The TSC was responsible for monitoring and supervising the progress of the C-GALL study. The committee met nine times between August 2016 and September 2021 at agreed intervals. The TSC consisted of independent experts, patient representative, the Co-Chief Investigators and key members of the PMG. Members of the TSC are listed in the Acknowledgements.

One of the independent members of the TSC was a patient representative who contributed their individual perspectives of gallstone disease and the perspectives of gallstone disease of the wider community. Our grant holder PPI representative also provided us with perspectives of gallstone disease from the wider community. The TSC reviewed and commented on the study design, protocol and all study documentation, including patient-facing documents that were sent to potential and recruited participants in the C-GALL study. In addition, the PPI partners (grant holder PPI representative and TSC patient representative) also contributed to regular funder progress reports.

Patient and public involvement

The PPI partners were actively involved in discussions of the study results with the TSC and the trial investigators and contributed to the preparation of the plain language summary. They continue to be involved in developing dissemination materials for participants and contribute to academic papers. The PPI partner on the TSC will comment on the participant results letter. At the end of the study, the PPI partners reflected on their input and made suggestions for future research, which is included in the discussion.

Participants who took part in the focus group for the core outcome set (COS), described in Chapter 7, have remained involved with the C-GALL study as members of the C-GALL PPI group. The PPI group were actively involved in discussions of the study results with the PPI partners and contributed to the review of the Plain language summary. They continue to be involved in the review of dissemination materials for participants.

Data Monitoring Committee

The DMC was independent of the trial and was responsible for monitoring safety and data integrity. The DMC met nine times between October 2016 and November 2021 at agreed intervals. The trial statistician provided the data and analyses requested by the DMC prior to each meeting. The committee consisted of three independent experts. Members of the DMC are listed in the Acknowledgements.

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

Extension to recruitment

Slower than anticipated recruitment and longer than anticipated waiting lists for surgery meant an 18-month recruitment extension was required to achieve full sample size and the opportunity for more participants to receive surgery. The 24-month time point, as an outcome, was added as part of this extension. Due to the staggered recruitment of participants, when the later randomised participants reached 24 months, earlier participants would have reached a longer follow-up time point. Therefore, it was decided to carry on collecting data, as it was deemed this would be useful in the analysis and any long-term follow-up plans.

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.