Identification of Predictive Factors of Incidentally Detected Gallbladder Cancer and Prospective Validation of a Scoring System to Allow Selective Histological Analysis of the Gallbladder
Conditions: Gallbladder Cancer
Sponsor: University Hospital Plymouth NHS Trust

 
 
 
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SHORT TITLE 
P-iGBC 
(Predicting Incidental Gallbladder Cancer) 
 
 
 
FULL TITLE OF THE TRIAL 
Identifying predictive factors of incidentally detected gallbladder cancer and 
prospective validation of a scoring system to allow selective histological analysis of 
the gallbladder. 
 
Version 1.3: 04 November 2024 
 
 
IRAS Number: 
334671 
REC Reference: 
FREIC Reference: 
24/LO/0504 
5550 
SPONSORS Number: 
23SUR879 
FUNDERS Number: 
TBC 
 
 
This protocol describes the study and provides information about procedures for entering participants. Every care 
was taken in its drafting, but corrections or amendments may be necessary. These will be circulated to 
investigators in the study. Problems relating to this study should be referred, in the first instance, to the Chief 
Investigator.  
This study will adhere to the principles outlined in the NHS UK Policy Framework for Health and Social Care 
Research (2017). It will be conducted in compliance with the protocol, the Data Protection Act (2018) and other 
regulatory requirements as appropriate. 
 
 

 
 
 
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SIGNATURE PAGE 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the study in compliance with the approved protocol and will adhere to 
the principles outlined in the Declaration of Helsinki, the Sponsor’s SOPs, and other regulatory 
requirement. 
 
I agree to ensure that the confidential information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the investigation without the prior written consent 
of the Sponsor.   
 
I also confirm that I will make the findings of the study publicly available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent account 
of the study will be given; and that any discrepancies from the study as planned in this protocol will be 
explained. 
 
For and on behalf of the Study Sponsor: 
Signature:  
 
 
 
 
 
Date:  
 
 
Name (please print): 
 
 
 
 
 
 
Position: 
 
 
 
 
 
 
Chief Investigator: 
Signature:  
 
Date: 04/11/2024  
 
Name (please print): 
Mr Somaiah Aroori  
 
 
 
 
 
 

 
 
 
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KEY CONTACTS 
Chief Investigator: 
Mr Somaiah Aroori 
Co-investigators: 
Mr Oliver Brown 
Dr Lexy Sorrell 
Professor Jos Latour 
 
Sponsor: 
University Hospitals Plymouth NHS Trust 
Funder(s): 
Peninsula Medical Foundation 
Association of Upper Gastrointestinal Surgeons of Great Britain 
and Ireland 
University Hospitals Plymouth NHS Trust 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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TABLE OF CONTENTS 
 
GLOSSARY OF ABBREVIATIONS 
6 
KEY WORDS 
8 
STUDY SUMMARY 
8 
STUDY FLOW CHARTS 
10 
1. 
INTRODUCTION 
11 
1.1 
BACKGROUND 
11 
1.2 
RATIONALE FOR CURRENT STUDY 
13 
1.3 
PARTICIPANT AND PUBLIC INVOLVEMENT AND ENGAGEMENT 
13 
2. 
STUDY OBJECTIVES 
15 
2.1  
PRIMARY OBJECTIVES 
15 
2.2 
SECONDARY OBJECTIVES 
15 
2.3 
OUTCOME MEASURES 
15 
3. 
STUDY PARTICIPANTS 
15 
3.1 
SCREENING PROCEDURES 
16 
3.2 
INCLUSION CRITERIA 
16 
3.3 
EXCLUSION CRITERIA 
17 
4.  
STUDY DESIGN, PROCEDURES, AND INTERVENTIONS 
18 
4.1 
STUDY DESIGN 
18 
4.2 
RECRUITMENT 
18 
4.3 
CONSENT 
19 
4.4 
STUDY ASSESSMENTS/ INTERVENTIONS 
21 
4.5 
DEFINITION OF END OF STUDY 
22 
5. 
SAFETY REPORTING 
23 
6. 
STATISTICS 
23 
6.1 
THE NUMBER OF PARTICIPANTS 
23 
6.2 
SAMPLING 
23 
6.3 
ANALYSIS OF ENDPOINTS 
25 

 
 
 
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7. 
DATA MANAGEMENT AND DATA SHARING PLAN 
28 
7.1  
DATA FLOW DIAGRAM 
29 
7.2  
DESCRIPTION OF THE DATA 
30 
7.3  
COLLECTION OF DATA AND STUDY MATERIALS 
30 
7.4  
DATA STORAGE AND SECURITY 
32 
7.5  
ARCHIVING, PRESERVATION, AND CURATION 
32 
7.6  
DATA SHARING 
32 
8. 
ETHICAL AND REGULATORY COMPLIANCE 
33 
8.1 
ETHICS AND HRA APPROVAL 
33 
8.2 
INDEMNITY 
33 
8.3 
SPONSOR 
33 
8.4 
FUNDING 
34 
8.5 
MONITORING 
34 
9. 
STUDY MANAGEMENT 
35 
9.1  
STUDY SITES AND PERSONNEL 
35 
10. 
PUBLICATION POLICY 
37 
10.1  
AUTHORSHIP 
37 
11. 
REFERENCES 
39 
APPENDICIES 
43 
APPENDIX 1 – SCHEDULE OF EVENTS 
44 
APPENDIX 2 – AMENDMENT HISTORY 
46 
LINKED APPENDICES (APPENDIX 3-13) 
47 
 

 
 
 
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GLOSSARY OF ABBREVIATIONS 
AE 
Adverse event 
BHA 
Benign Histological Abnormalities 
BMI 
Body Mass Index 
CAG 
Confidentiality Advisory Group 
CI 
Chief Investigator 
CRF 
Clinical Research Fellow 
fP-iGBC 
Feasibility/Pilot phase of P-iGBC (qP-iGBC and pP-iGBC together) 
GBC 
Gallbladder Cancer 
GBD 
Gallbladder Dysplasia 
GPo 
Gallbladder Polyp(s) 
HRA 
Health Research Authority 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonisation 
ICJME 
International Committee of Medical Journal Editors 
iGBC 
Incidental Gallbladder Cancer 
NHS 
National Health Service 
NRES 
National Research Ethics Service 
PES 
Plain English Summary 
PI 
Principal Investigator 
P-iGBC 
Predicting Incidental Gallbladder Cancer (short title/acronym for full study) 
PIS 
Participant/ Patient Information Sheet 
PPIE 
Patient and Public Involvement and Engagement 
pP-iGBC 
Pilot P-iGBC Component 
qP-iGBC 
Qualitative P-iGBC Component 

 
 
 
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R&D 
NHS Trust R&D Department 
REC 
Research Ethics Committee 
RHA 
Routine Histological Analysis 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SHA 
Selective Histological Analysis 
SOP 
Standard Operating Procedure 
TBC 
To Be Confirmed 
UHP 
University Hospitals Plymouth NHS Trust 
UK 
United Kingdom 
XC 
Xanthogranulomatous Cholecystitis 
 
 
 

 
 
 
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KEY WORDS 
 
 
Incidental Gallbladder Cancer, Gallbladder Cancer, Cholecystectomy, Histology, Gallbladder, 
Selective Histological Analysis, Histopathology, Adaptive design 
STUDY SUMMARY 
 
Study Title 
Identification of Predictive factors of Incidentally detected Gallbladder 
Cancer and prospective validation of a scoring system to allow selective 
histological analysis of the gallbladder (P-iGBC). 
 
Study Design 
Prospective, Multi-centre, Observational & Modelling Study with an internal 
pilot and adaptive design. 
Parallel, embedded qualitative study 
 
 
Study Participants 
Adults undergoing cholecystectomy during the trial period, Biliary pathway 
patients and professionals involved in their care. 
 
Eligibility Criteria 
Inclusion Criteria: 
 
All adult patients (>=18 years of age) undergoing cholecystectomy 
(including subtotal and remnant cholecystectomy) for benign indications: 
1. Symptomatic Gallstone Disease  
2. Biliary dyskinesia 
 
Exclusion Criteria: 
 
1. Imaging suspicious for/confirming type III & IV Mirrizzi syndrome.  
2. Previous or current diagnosis of biliary tree malignancies 
3. Pre-operative concern or suspicion of Gallbladder or biliary tree 
malignancy 
4. Presence of gallbladder polyps ≥5mm 
5. Biliary tree abnormalities, including Primary Sclerosing Cholangitis 
and Choledochal Cysts 
6. Patients undergoing cholecystectomy as a part of, or incidental to, 
another procedure. 

 
 
 
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Planned Sample Size 
300-500 (internal pilot) up to 30,000 (TBC on the result of an internal pilot) 
 
Follow-up Duration 
Ends on report of histopathology result. No longitudinal follow-up.  
 
 
Planned Study Period 
June 2024-June 2029 
 
Primary Objective 
Development and validation of a diagnostic score for incidental gallbladder 
cancer 
 
Secondary Objectives 
Evaluation of willingness for and barriers to selective histological analysis 
of the gallbladder 
Incidence of incidental Gallbladder Cancer and associated benign 
abnormalities. 
Identification of the risk factors for incidental Gallbladder Cancer.  
 
 
 

 
 
 
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STUDY FLOW CHARTS 
Quantitative component 
 
Qualitative component 
 
 
 

 
 
 
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1. 
INTRODUCTION  
1.1 
BACKGROUND  
Incidental Gallbladder Cancer (iGBC) is a rare diagnosis following cholecystectomy, which is a 
common operation normally performed for symptomatic gallstone disease (1,2). Less common benign 
indications include gallbladder dyskinesia and gallbladder polyps. Overall, 67,819 cholecystectomies 
were performed in NHS England and Wales in the year to March 2022 and it is standard practice in 
the UK for cholecystectomy specimens to be sent for Routine Histological Analysis (RHA) to exclude 
underlying iGBC(1,3). The United Kingdom (UK) has a low incidence of iGBC of between 0.14-0.3%, 
which contrasts with high-incidence countries, for example in South America and South Asia, where it 
is as high as 1.18% (4–12). Other, non-cancerous abnormalities, termed Benign Histological Changes 
(BHC), such as Xanthogranulomatous Cholecystitis (XC) and Gallbladder Dysplasia (GBD), can be 
challenging to diagnose or differentiate from cancer macroscopically and therefore require histological 
examination. Combined, iGBC and BHC have an incidence in the UK of around 2% (4,6,13). 
 
RHA is not unique to the UK, and is practised in most high-income countries, however it is expensive 
and requires examination of thousands of unremarkable gallbladders to diagnose relatively few 
patients with iGBC(1,8,10,14). We conservatively estimate that the cost of RHA in routine 
cholecystectomy is at least £5,055,228.26 annually, based on an historic estimate of the cost of 
processing individual specimens multiplied by the volume of cholecystectomies quoted above (1,8). In 
addition to the financial costs incurred by RHA, processing so many gallbladder specimens puts 
enormous pressure on histopathology services who are acknowledged to be overburdened and under 
resourced(15,16). This volume of specimens is particularly significant at present, as subsequent 
delays in processing NHS cancer specimens can anecdotally reach 4- 6 weeks, potentially delaying 
decisions on adjuvant treatment (e.g. chemotherapy) which, in some cases, may affect overall 
survival(17). As the incidence of iGBC is so low, it has been argued that sending every gallbladder 
specimen for RHA is unnecessary and could be replaced with Selective Histological Analysis (SHA), 
whereby gallbladders with no significant risk of iGBC or BHC would not be sent for 
histopathology(3,5,8–11,18–20). 
 
Whilst SHA has the potential to significantly reduce costs and mitigate high pathological workloads, its 
safety is intrinsic to its success. Key to this is a good, clinically applicable method of risk-stratification, 
and current methods require improvement. Some centres in high-income countries already practice 
SHA, however the risk stratification methods and criteria by which gallbladders are selected for 
histopathology are not always clear (7,20). Proponents of SHA suggest that it is safe when specimen 

 
 
 
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selection is based on macroscopic inspection or uses a defined, algorithmic approach (5,9,11,14,21). 
However, review data suggests that macroscopic inspection misses between 23.1 and 33.3% of iGBC 
and that there are higher incidences of iGBC in RHA centres than in SHA centres. This implies that 
current selection methods lead to missed diagnoses(5,7,20). Although it is not clear why SHA has not 
been adopted in the UK, it has been suggested that UK surgeons are averse to taking responsibility 
for a missed diagnoses(21,22). Further, whether SHA is acceptable to patients in the UK is yet to be 
evaluated.  
 
The risk factors for GBC are well recognised. Cholelithiasis is a pre-disposing factor, and there is a 
strong association with chronic cholecystitis, while acute cholecystitis confers a poorer prognosis (23–
25). Other risk factors include age, ethnicity, female gender, jaundice, a raised alkaline phosphatase, 
certain intra-operative factors and findings (including macroscopic cholecystitis or a thick-walled 
gallbladder and a need for lengthy or open operations), a history of typhoid infection or pre-existing 
disorders of the biliary tree, such as Primary Sclerosing Cholangitis and Choledochal 
Cysts(7,10,13,14,19,26–28). Gallbladder polyps are also associated with GBC, with a well described 
relationship between the size of the polyp and likelihood of cancer. The risk is negligible in polyps 
under 5mm but rises above the 0.2% UK incidence of iGBC to a 1.2% risk of GBC when the polyp is 
between 5-10mm, and increases to 8.5% in polyps over 10mm(29). It is therefore recommended that 
patients with high-risk polyps over 5mm or any polyps over 10mm undergo prophylactic 
resection(30,31). In Mirrizzi Syndrome, in which impacted stones fistulate into the Common Hepatic 
Duct, the risk of GBC and cholangiocarcinoma occur is even higher, occurring in up to 28% of 
patients(32–34). 
 
Although these multiple risk factors for GBC are well recognised, there is no robust risk-stratification 
method which is suitable for use in routine cholecystectomy in the UK. If a clinically applicable 
diagnostic score was able to stratify patients by their risk of iGBC, it could facilitate SHA, but 
importantly may also enable early identification, intervention, or investigation in high risk patients. 
These two major benefits of a risk-stratification or diagnostic score have clear potential benefits for 
patients and the health service, so it is perhaps unsurprising that there are already two such 
diagnostic scores in existence. Both, however, are limited in their reliability by their methodology and 
in their generalisability to the UK because of the settings in which they were developed. The first 
study, from a Swedish group, developed a diagnostic score based on age, sex, presence of 
cholecystitis and jaundice(19). A Dutch group recently published a more methodologically sound, 
retrospective, multi-centre study (18). From a methodological viewpoint, the data from which both 
were derived were limited and poorly complete - the Dutch study was missing 30.9% of data - and 

 
 
 
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both resultant scores consequently failed to identify all patients with iGBC in validation. Furthermore, 
the studies relied on existing or prospectively collected registry variables and, as a result, neither 
captured or were able to utilise many of the multiple known pre- and intra-operative risk factors. 
Further, both studies were conducted in settings in which SHA is already sporadically practiced, which 
may have meant that iGBC diagnoses were missing from their datasets leading to skewed data.  
 
When comparing the populations in question, a further problem with the use of these scores arises. 
Compared to other European countries where patients are often operated within days of presentation, 
NHS patients wait longer for their cholecystectomies and therefore risk recurrent inflammation (35–
43). In this post-COVID-19 era, a higher proportion of UK cholecystectomies are being performed for 
inflammatory indications, and this may suggest that the UK prevalence of iGBC will increase or the 
prognosis be poorer(7,23,35). As a consequence, we are unable to generalise the findings of the 
Swedish and Dutch studies to our own population and there is, therefore, a need for a high quality and 
comprehensive diagnostic modelling study of UK patients, to accurately identify and stratify the risk of 
iGBC.  
 
This study aims to collect the data required to develop a high-fidelity, clinically applicable diagnostic 
score with a high negative predictive value, and has the potential to facilitate SHA and early 
identification of patients at high-risk of iGBC in this country. 
 
1.2 
RATIONALE FOR CURRENT STUDY 
Stratifying patients undergoing routine cholecystectomy by their risk of iGBC could facilitate SHA, 
enabling significant financial savings and reduced histopathological workloads, and allow identification 
of the highest-risk patients, meaning that their care could be prioritised appropriately. Published 
diagnostic scores and historical techniques, such as macroscopic inspection, either fail to identify all 
cases of iGBC or are poorly generalisable to our population and, as such, are inadequate for use in 
the UK. Multiple risk and predictive factors are well established, but no dataset adequately 
encompasses them to develop and validate such a robust, UK-based diagnostic score for iGBC.  
 
This study aims to build a dataset from which a validated diagnostic score could be developed.  
 
1.3 
PARTICIPANT AND PUBLIC INVOLVEMENT AND ENGAGEMENT 
Fortunately, we have had the support of a patient representative (AB) who has critically reviewed the 
study design and documents, and has provided valuable feedback. A second patient representative 

 
 
 
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(HW) has assisted in developing Plain English Summaries (PES) for formal PPIE consultation and 
grant applications.  
 
The overall hypotheses and aims of the study were discussed with the PENPeg PPIE group’s “Ideas 
Cafe” in its early development stages. The group unanimously supported the project, with several 
members expressing surprise at the current practice of routine histological analysis in 
cholecystectomy.  
 
A formal PPIE consultation has been undertaken, in which five patients agreed to participate. Patients 
were provided with pertinent study documents and a PES before one-to-one meetings were held. For 
full report on the PPIE consultation, including full methodology and detailed results, please see 
appendix 12.  
 
Overall, consultation participants were very supportive of the study, stating that they were, “so much in 
favour of what you’re doing,” and that the study would be, “helpful for patients and… the medical 
profession”. Most commented that they were surprised that gallbladders were routinely sent for 
analysis, and that they had not considered that cancer may, “complicate,” their procedure. There was 
a general consensus that non-consented data collection was both justified and acceptable, as it was 
felt that the research was, “for the greater good,” and that attempting to consent all patients would be, 
“impractical if [the protocol adopted] too formalised a route… [it] would cost too much and take a huge 
amount of time”. 
 
Some further changes to the protocol were made following PPIE consultation. One participant 
commented that the original initialism, PIGBC, and the associated logo read to them as “pig” and had 
a negative association with obesity as their perceived cause of gallstone disease. They suggested that 
the revised acronym P-iGBC held a much weaker association, and subsequently approved this and a 
revised logo. The opinion was supported by subsequent consultees. The original arrangements for 
non-consented data collection and informing patients of the study have also been revised. Although 
there was unanimous support for non-consented data collection, consultees felt that the wording of the 
protocol needed to be changed to encourage active informing of patients by clinicians in participating 
units. Consultees understood that this was different from informed consent but were satisfied that 
clinicians would be encouraged to draw patients’ attentions to public notices of the study during the 
process of normal consultation and consent. Other minor changes to study documents resulting from 
the PPIE consultation include revisions to the PIS for the qualitative study and re-wording of public 
facing documents to improve clarity. 

 
 
 
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Given that this project affects histopathological services in that hypothesised changes to histological 
analysis protocols may affect their workload, we have sought and have been granted the support of 
our local histopathology department. 
 
 
2. 
STUDY OBJECTIVES 
2.1  
PRIMARY OBJECTIVES 
• 
To develop and validate a diagnostic score for iGBC in patients undergoing cholecystectomy 
for benign indications.  
2.2 
SECONDARY OBJECTIVES 
• 
To establish the pre- and peri-operative risk factors for iGBC and BHC in a UK population 
• 
To define the incidence of iGBC and BHC in a UK population 
• 
To explore the views of patients and healthcare professionals regarding the risk of iGBC in 
routine cholecystectomy and their acceptance of selective histological analysis of the 
gallbladder 
 
 
2.3 
OUTCOME MEASURES 
• 
Rates of iGBC 
• 
Rates of BHC 
• 
Internal pilot: Feasibility of conducting a large multi-centre prospective study. 
• 
Internal pilot: Feasibility of developing a diagnostic scoring system for the diagnosis of 
incidental gallbladder cancer based on pre- and intra-operative factors. 
• 
Completed study: Validation of a diagnostic score for incidental gallbladder cancer. 
 
3. 
STUDY PARTICIPANTS  
Cross sectional study: All adult patients undergoing routine cholecystectomy within the study period 
at participating sites (subject to inclusion and exclusion criteria below). 
 
Qualitative study: Participants will be recruited from patient lists at study sites, from within the NHS 
and through specialty association mailing lists. Each group will consist of participants who have been 

 
 
 
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purposively selected to represent a cross section of the population. For example, by incorporating a 
range of ages or career stages, rural and urban settings, and from primary, secondary, and tertiary 
care settings. Contingency arrangements, including convenience sampling and snowballing, are 
outlined in section 6.2. 
 
 
Participant groupings will include:  
1. Patients with a history of benign gallbladder disease, either pre- or post-cholecystectomy 
including, if possible, at least one post-operative patient with an iGBC diagnosis (5-7 pre-
operative and 5-7 post-operative)  
2. Surgeons who undertake adult cholecystectomy as part of their routine practice, including, if 
possible, at least two who have experience with patients with iGBC (8-10 participants)   
3. Healthcare staff involved in non-clinical management and decision-making (3-5 participants)  
a. Clinical Commissioners  
b. Managers  
 
 
3.1 
SCREENING PROCEDURES 
Cross-sectional study:  
All patients aged 18 and over who are being considered for cholecystectomy at participating sites 
during the study period should be screened. 
 
Qualitative study: 
Participants will be purposively selected to represent a cross-section of the relevant populations, for 
example, by incorporating a range of ages or career stages, rural and urban settings, and primary, 
secondary, and tertiary care settings.  
 
3.2 
INCLUSION CRITERIA 
Cross-sectional Study: 
All adult patients (>=18 years of age) undergoing cholecystectomy (including subtotal and remnant 
cholecystectomy) for benign indications: 
• 
Symptomatic Gallstone Disease (includes Gallstone Pancreatitis) 
• 
Biliary Dyskinesia 
 

 
 
 
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Embedded Qualitative Study 
 
Consenting adult participants (>=18 years of age) will be purposively selected into groupings, which 
will include, 
• 
Patients with a history of gallbladder disease, either pre- or post-cholecystectomy, including, if 
possible, at least one post-operative patient with an iGBC diagnosis (10-15 participants)  
• 
Surgeons who undertake adult cholecystectomy as part of their routine practice, including, if 
possible, at least two who have experience with patients with iGBC (8-10 participants)   
• 
Healthcare staff involved in non-clinical management and decision-making (5-8 participants)  
o Examples include, 
▪ 
Clinical Commissioners  
▪ 
Managers  
▪ 
Histopathologists 
 
3.3 
EXCLUSION CRITERIA 
 
Cross-Sectional Study: 
Participants may not enter the study if ANY of the following apply: 
• 
Imaging suspicious for/confirming type III/IV Mirrizzi syndrome.  
• 
History of gallbladder or biliary tree malignancies 
• 
Any pre-operative clinical suspicion of Gallbladder or biliary tree malignancy, (even if 
subsequently dismissed or disproven) 
• 
Presence of Gallbladder polyps ≥5mm 
• 
Biliary tree abnormalities, including Primary Sclerosing Cholangitis and Choledochal Cysts 
• 
Patients undergoing cholecystectomy as a part of, or incidental to, another procedure. 
 
Embedded Qualitative Study: 
Participants may not participate in interviews if ANY of the following apply: 
• 
Unable to consent, or to communicate consent. 
• 
Unable to undertake interview in English, despite reasonable support measures. 
 

 
 
 
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4.  
STUDY DESIGN, PROCEDURES, AND INTERVENTIONS 
4.1 
STUDY DESIGN 
Multi-centre, cross-sectional study for diagnostic modelling with an integrated internal pilot, an 
embedded, parallel, interview-based, qualitative study, and an adaptive design. 
 
The internal pilot and parallel qualitative workstreams will form a feasibility phase of this study (fP-
iGBC). Following this feasibility phase, data collection will pause for 18 to 24 months to allow time for 
analysis of the feasibility phase, additional funding to be secured, expansion of the study team and for 
centres to be recruited and registered. 
 
4.2 
RECRUITMENT 
Cross-Sectional Study 
Patients will be identified from waiting lists and emergency admissions within the relevant departments 
of participating centres during the study period by clinicians undertaking cholecystectomy and those 
participating in the research (all of whom will be members of the direct care team). As data collection 
is non-consented, all patients who pass screening against the inclusion and exclusion criteria may be 
recruited, however patients will be able to opt-out of inclusion in the study as detailed in section 4.3, 
below. 
 
Qualitative Study 
Patients will be recruited from existing patient waiting and clinic lists and historical patient lists at 
participating sites. Professional participants will be recruited through speciality association mailing 
lists, direct approach and those who have expressed an interest in participation in the recruitment 
stages of the cross-sectional study. 
 
Where potential participants are identified by a collaborator at a participating site, the collaborator will 
make initial contact with the potential participant to inform them about the study and to invite them to 
take part in an initial conversation with the central research team. If they are willing to receive more 
information, the collaborator will ask the potential participant to contact the central research team 
either by telephone or email, on receipt of which the central research team will take over contact with 
potential participants to undertake a formal invitation to participate and the informed consent process, 
as laid out below. Collaborators may alternatively offer to share a contact detail (e.g. an email address 
or a telephone number) with the central study team, using the encrypted NHS.net email, with the 
express consent of the potential participant. 

 
 
 
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4.3 
CONSENT  
Cross-sectional Study 
Data will be collected from patients and patient records without their consent. Patients will be informed 
about the study and provided with an opt-out mechanism as outlined below. 
 
Rationale for non-consented data collection. 
The cross-sectional component of this study exclusively requires the collection of de-identified 
information which would normally be recorded during patient care. This will be extracted from the 
patient’s record by members of the direct care team. The volume of patients required is felt to make 
individual consent impractical and prohibitively expensive, and would therefore prevent sufficient 
recruitment. It is subsequently felt to be both justified and necessary to collect the de-identified data 
without individual patient consent, as per the Confidentiality Advisory Group pre-application checklist, 
and guidance received in communication with them.  
 
Local arrangements for informing patients about the study. 
When data is collected without informed consent, is good practice to publicise the study and provide a 
mechanism for patients to opt-out. Participating units will be required to display notifications (see 
example in appendices) in appropriate areas, such as outpatient, inpatient, and pre-operative areas. 
These notifications must include the contact details of the local study team and must expressly state 
the right to opt-out. Following feedback from our PPIE consultation, we recommend that consenting 
clinicians inform patients of their eligibility for inclusion, and right to opt-out of the study. This is 
especially important in the event that a patient does not speak English and is being consented for 
surgery with the help of a translator (see below). Clinicians in participating units should direct patients 
to further information, such as the website, a poster, or the PIS if asked. Whilst it will not be 
mandatory, clinicians may wish to record that the patient has been informed, for example by noting the 
conversation in the patient’s record, on a clinic letter or other clinical documents related to the episode 
of care.  
 
Patients who do not speak English. 
Patients who do not speak English should be informed of the study during the operative consent 
conversation, which is normally with a translator. Within the feasibility phase, there is no specific 
information available in languages other than English. If and where there is any doubt over the 
participant’s understanding, the participant should be recorded on RedCAP as having opted out, given 

 
 
 
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that other opportunities for that patient to opt out may be more limited than for those who speak 
English. Provision will be made to ensure that this reason can be specifically identified, to inform 
whether multi-lingual participant information sheets should be funded and developed following the 
feasibility phase. Welsh Language information will be developed following the feasibility phase, if and 
where centres in Wales participate. 
 
National arrangements for informing patients about the study. 
During periods of recruitment and data collection, the central study team will post monthly notices of 
the study to Twitter/X (see example in appendices), and maintain notifications on the website. 
Collaborating units, are advised to share these notifications, which will include a link to the study 
website where the PIS, and information about opting-out of the study, will be posted. Following PPIE 
consultation, notifications will make a distinction between the pilot phase and the full national study. 
 
Arrangements for patient opt-out. 
Patients have a right to opt-out of the study. As the central research team will not have access to 
identifiable patient information, it will not be possible for the opt-out mechanism to be centrally 
administered. Instead, local study teams will be required to field requests for study opt-out. The 
contact details for the study team at each unit will be made available on local notifications, and on the 
study website. On receiving a study opt-out request from a patient, units are required to respond and 
confirm the request within ten working days. In case of a non-response from the local unit, patients will 
be able to contact the central study team via the study website. This will require the patient to share a 
single contact address (such as a telephone number or email address) with the central study team, 
which will in turn be shared with the local unit. The central study team will contact the local team by 
any or all additional means at their disposal and will require the local team to confirm the opt-out 
directly with the patient, and then confirm with the central team. As a contingency, and to safeguard 
patients, in the event that contact cannot be established with the local team, data entry by 
collaborators in that unit will be paused and data from that unit will not be included in export, until the 
opt-out request has been satisfactorily fulfilled. 
 
If an eligible patient exercises their right to opt-out before they are identified for inclusion in the study, 
or before any data is collected, units should still allocate a study ID in REDCap. After screening for 
inclusion, the CRF will ask, “has the patient opted out?”, which will both allow monitoring of opt-out 
rates and act as a barrier to further data entry in the event of an affirmative response. When data has 
already been collected, any locally held information, except for the study ID and cross-referenced 
identifiers, should be deleted and/or destroyed in line with local policy. Changing the response to the 

 
 
 
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opt-out question will automatically prompt the deletion of any remaining data associated with that 
study-ID. As an additional safeguard, alongside checks for outlying data points, the central study team 
will regularly check the database for opt-outs and manually remove any remaining data held against 
the study-ID. 
 
It will not be possible for patient data to be removed once the data collection period for each phase of 
the study has ended (i.e. six to eight  weeks after the end of the recruitment period in each unit).  
 
Qualitative study 
Consent to enter the study must be sought from each participant only after a full explanation has been 
given, a participant information sheet offered, and time allowed for consideration.  Signed participant 
consent should be obtained and, to minimise hard-copy and to facilitate remote consent, eConsent will 
be obtained using the relevant REDCap modules*. The right of the participant to refuse to participate 
without giving reasons must be respected.  All participants are free to withdraw at any time from the 
interview, without giving reasons and without prejudicing their clinical treatment or professional 
situation. 
4.4 
STUDY ASSESSMENTS/ INTERVENTIONS 
Cross-sectional study: 
No deviation from routine patient care is required. The cross-sectional study will collect baseline 
information about the patient's background, including age, ethnicity, co-morbidity, BMI, pre-operative 
investigations and intra-operative findings, which will largely be available from the patient’s written and 
digital records.  The diagnosis/diagnoses of the postoperative histopathology report will be collected 
once available and is considered a result from the event of interest (the cholecystectomy). 
Consequently, there is no longitudinal follow-up required. 
 
Qualitative Study: 
The embedded qualitative study consists of carefully designed, semi-structured interviews which 
follow an interview guide, and can be found in the appendices. The analysis will occur 
contemporaneously, and the interview guide may be adjusted where appropriate, to maximise data 
richness, as the study progresses. 
 
The fundamental questions to be answered are:  
 
* eConsent forms will exactly match the wording of approved paper consent forms. 

 
 
 
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• 
What are the participant’s attitudes, experiences, and beliefs towards the risk of GBC?  
• 
How supportive are participants of the concept of SHA in routine cholecystectomy?  
• 
What perceived problems and barriers exist around introducing SHA in the UK?   
 
Participants will undergo contact by the research team or by collaborators at the following time points. 
All events may be either face-to-face, or remotely. 
1. Identification 
Participants will be contacted either by a member of the research team at University Hospitals 
Plymouth NHS Trust, or by a collaborator at a participating unit, as previously described. At 
this stage, they will be informed of the study and invited to make contact with the central 
research team to obtain more information. 
2. Initial information, including provision of PIS 
Participants will be contacted by an appropriate researcher from the central team, and 
provided with an explanation of the study, a copy of the PIS and an opportunity to ask any 
questions pertinent to their decision to participate. A minimum of 24 hours for the participant to 
consider their decision is required and the participant should indicate their agreement in 
principle before an interview is arranged. 
3. Possible further liaison regarding logistics of interview arrangements 
Further contact may be necessary, to make suitable arrangements for an interview to take 
place, or to answer any supplementary questions. 
4. Interview 
A qualitative researcher will meet with participants, either face to face or via MS Teams, as 
outlined elsewhere. At this contact, a final opportunity to ask questions will be offered, the 
consent form will be completed and the interview will be conducted. 
5. Member checking (optional) 
As outlined elsewhere, participants will be emailed transcripts and reports and invited to 
comment on them. This activity is strictly optional. 
 
4.5 
DEFINITION OF END OF STUDY 
This is defined as the date of the last visit of the last participant undergoing the study. The Sponsor 
will notify the REC, in writing, within 90 days of the end of the study. 
 

 
 
 
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5. 
SAFETY REPORTING 
Given the purely observational nature of this study, safety reporting is not applicable and there are no 
defined or undefined Serious Adverse Events. 
 
6. 
STATISTICS  
6.1 
THE NUMBER OF PARTICIPANTS 
Cross-sectional study: 
The required power to develop a diagnostic score for iGBC, assuming a 0.2% prevalence, 
Nagelkerke's R2 of 0.3 and 20 diagnostic parameters, is 20,996. Allowing for a 20% rate of incomplete 
data, 26,245 participants would be required. It is possible that, following the feasibility study, it will be 
clear that more than 20 diagnostic parameters are required. The study will, therefore, aim to recruit up 
to 30,000 participants to ensure adequate power. 
 
An internal pilot study will be undertaken between 8 participating units to ensure the feasibility of 
recruiting so many participants and calibrating the final recruitment target. Data collection will be 
paused at the first of 500 participants between all participating units or six months of completed data 
collection in each participating unit, allowing for the internal pilot to be evaluated. For a sample size of 
500, an iGBC incidence of 0.2% will be estimated with a margin of error of +/- 0.39%. Rates of 
recruitment, completeness of data, and events will be evaluated. The assumptions above will be 
adjusted, and the corrected data will be used to re-calculate the final recruitment target before data 
collection for the complete cross-sectional study begins. 
 
Qualitative Study: 
Saturation is typically considered to occur after 20 interviews, however multiple participant groups are 
being included in this analysis. The total number of purposely selected participants will therefore be 
between 23 and 33, as outlined in the group descriptions in section 3.2. If data saturation is felt to 
have occurred, participants will only be interviewed if the minimum group size has not been met. If a 
participant withdraws and the minimum number for any group falls below the sample sizes described 
in section 3.2, participants will be replaced. If, however, the minimum numbers are maintained the 
participant will not be replaced. 
 
6.2 
SAMPLING 
Cross-sectional study:  

 
 
 
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Trainee collaboratives are a well-proven data collection method which limits the patient burden and 
encourages broad participation, as well as ensures that only the direct care team accesses identifiable 
information. A trainee collaborative model will be used, with a Lead Trainee or Associate PI† and a 
Principal Investigator or Co-Investigator responsible for data collection in each unit (see section 9).  
 
Local clinicians will identify patients from elective and emergency general surgical operating lists 
occurring during the study period. All patients undergoing cholecystectomy during the study period 
should be screened for inclusion by any clinical team member. 
 
Data will be prospectively collated in a Microsoft Excel Spreadsheet, and de-identified information will 
be entered directly into REDCap at each study site. A minimum dataset cross-referencing a study ID 
and patient identifiers will be kept locally. The local investigators will be responsible for ensuring that 
the spreadsheet is kept and maintained according to local data security guidelines, and, as a bare 
minimum, the spreadsheet should be held on a secure, institution-approved drive location and 
password protected. Patient identifiers held locally will be excluded from transfer to the main trust 
undertaking analysis, and sites will be encouraged to keep a secure cross-referencing database so 
that patients can be locally identified for internal validation or obtaining missing data. Data will be 
submitted to the primary investigating team centrally at UHP using REDCap to facilitate secure 
transfer and assess the dataset's completeness. Individual surgeons will not be centrally identified and 
will strictly remain anonymous. 
 
Qualitative study: 
Participants will be selected from patient lists at study sites, from public support groups, from within 
the NHS and through specialty association mailing lists. Each group will consist of participants who 
have been purposively selected to represent a cross-section of the relevant population. 
 
As a contingency, in the event of either an un-representative mixture of participants, or the minimum 
number for any group not being achieved, convenience sampling will be used to identify and recruit 
participants from the relevant staff and patient groups at UHP. If required, snowballing will be used to 
aid recruitment.  
 
 
† This definition is dependent on whether the study is adopted by the NIHR and accepted to the Associate 
Principal Investigator scheme. 

 
 
 
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6.3 
ANALYSIS OF ENDPOINTS 
Cross-sectional Study 
a. Internal pilot analysis 
Descriptive statistics (including means, standard deviations, medians, inter-quartile ranges and 
ranges, as appropriate for continuous variables and frequency and percentage for categorical 
variables) will be summarised for all demographics and potential predictive factors of iGBC collected.    
The prevalence of iGBC and BHC will be presented as a percentage with confidence intervals. 
 
The number of patients undergoing cholecystectomy, the number of patients eligible, the number of 
patients (and percentage) recruited, and the number of patients (and percentage) undergoing the 
procedure will be summarised overall and by site.  
The level of data completeness (demographics, potential risk factors and outcomes) will be 
summarised by frequency and percentages overall and by site. 
Descriptive statistics will be used for 
• 
rates of iGBC and BHC in the pilot population 
• 
rates of recruitment of patients to the study 
• 
data completeness 
The dataset will be evaluated to identify commonly incomplete data points (core data points for which 
completeness is <80%). Units and collaborators will then be surveyed to evaluate the challenges 
associated with these areas. Following the result of this survey, the study team will discuss each 
incomplete data point and make suitable adjustments to the power calculation and data points for 
collection according to the figure below.  
 
 

 
 
 
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Variable with large effect size 
or significance for iGBC in pilot, 
or in previous studies 
Variable with low or uncertain 
effect size or significance for 
iGBC 
Completeness likely to improve 
to >80% following intervention 
(e.g. change in the phrasing of 
a question or definition, change 
to patient record sheet) 
Retain data point for full study 
Retain data point for full study 
Completeness unlikely to 
improve following intervention 
Retain data point for full study, 
consider adjusting power 
calculations to accommodate 
level of completeness achieved 
in pilot 
Consider whether omitting data 
point from full study is justified 
 
Rates of recruitment will be considered in the context of the power calculation and the time initially 
allocated to complete data collection. Where necessary, proposed timeframes will be adjusted in the 
context of the power calculation and with details of potential participating units, prior to data collection 
for the full study beginning. 
Feasibility of the study may be hypothetically established, however adequate funding and sufficient 
participating centres with at least firm expressions of interest are required for actual progression. A 
final analysis and assessment against the following criteria (see table) will inform whether it is 
considered practically feasible to progress and therefore seek funding to continue the study. 
 
 

 
 
 
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Green 
(Progress to full trial) 
Amber 
(May progress, 
subject to revision 
and review) 
Red 
(Not to progress 
without further 
evaluation and/or 
development) 
Variables 
Sufficient variables 
completed >80% for 
meaningful 
diagnostic score 
development 
Insufficient variables 
completed >80% for 
meaningful 
diagnostic score 
development, likely 
to resolve with 
adaptations (e.g. 
changes to CRF) 
Insufficient variables 
completed >80% for 
meaningful 
diagnostic score 
development, and 
unlikely to improve 
with adaptations 
Centres 
 
*Time to meet 
recruitment target 
based on mean per-
centre recruitment 
rate in fP-iGBC. 
Sufficient centres to 
meet recruitment 
target* within two 
years 
Sufficient centres to 
meet recruitment 
target* within three 
years 
(aim to recruit 
centres to shorten 
data collection 
period) 
Insufficient centres 
to meet recruitment 
target* within three 
years. 
 
b. Full prospective study analysis 
A summary of the demographics, potential predictive factors and outcomes will be presented.  
A multivariable predictive model will be developed using potential risk factors available before the 
decision to send cholecystectomy specimens for RHA to identify patients with iGBC. The predictive 
model will be in the form of a logistic regression model and, therefore, will be interpreted using odds 
ratios. A post-estimation method to reduce the possibility of overfitting will be implemented.   
Internal validation of the predictive model will be performed using a method of resampling from the 
original data (e.g. cross-validation or bootstrapping). Measures of model performance, including 
discrimination, calibration statistics and clinical usefulness (e.g. net benefit), will be presented. 

 
 
 
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A complete, detailed statistical analysis plan (SAP) for each of the pilot and the complete study will be 
available at a later date. 
Qualitative Study: 
Thematic analysis of interview transcripts will be performed using dedicated qualitative analysis 
software and data-driven to reduce the potential for interviewer bias. The analysis will start after the 
first 3-4 interviews to inform subsequent interviews and actively assess data saturation. Where 
appropriate, the interview guide may be adjusted to maximise the richness of the data. Data extracts 
will be coded and categorised into themes, following proper guidance. Coded data will be reviewed 
and agreed upon by at least two researchers. A provisional summary will be sent to 3 patient 
participants and to 3 professional participants, for member checking. Outcomes of interest will be 
aligned with the aims of the qualitative study as defined previously. 
 
7. 
DATA MANAGEMENT AND DATA SHARING PLAN 
To comply with the Data Protection legislation, information will be collected and used fairly, stored 
safely and not disclosed to any unauthorised person. This applies to both manual and electronically 
held data. 
 
The Chief Investigator will preserve the confidentiality of participants taking part in the study and 
ensure the EU General Data Protection Regulation (GDPR), in conjunction with the UK Data 
Protection Act 2018, which sets out the statutory requirements for processing personal data, is 
adhered to. 
 
 
 
 

 
 
 
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7.1  
DATA FLOW DIAGRAM  
 
 

 
 
 
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7.2  
DESCRIPTION OF THE DATA 
The following discrete data points will be collected. Data points will be re-evaluated following the pilot, 
and the feasibility of collection of each data point will be considered.  
A summary of these data points is presented in the table below, and a fully exploded list of variables is 
available in the appendices. Not all data points will be applicable to all patients, for example where 
variation in practice exists. These dependent data points, and their sub-points are marked with an 
asterisk (*).  
 
Core data points (all patients) 
Study ID 
Patient Factors 
Referral Pathway 
Indication for Surgery 
Laboratory findings 
Intra-operative Findings 
Histology 
Semi-dependent data points (minimum dataset 
required per patient) 
Imaging findings (minimum one modality, include 
all directly relevant to patient’s cholecystectomy 
pathway). 
Dependent data points (applicable patients) * 
Pre-operative interventions  
Intra-operative imaging  
Progression to CBD exploration 
 
7.3  
COLLECTION OF DATA AND STUDY MATERIALS  
Cross-sectional Study: 
Trainee collaboratives are a well-proven data collection method that limits the patient burden and 
encourages wide participation. A trainee collaborative model will be used, with a Lead Trainee or 
Associate Principal Investigator (PI)‡ responsible for data collection in each unit under the supervision 
of a formal PI. Each unit will be asked to recruit as many patients as possible, and will be provisionally 
asked to target a minimum of 10 recruited patients per month of inclusion. 
 
 
‡ This definition is dependent on whether the study is adopted by the NIHR and accepted to the Associate 
Principal Investigator scheme. 

 
 
 
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Data will be prospectively collected on a digital Case Report Form (CRF), and may either be initially 
collated in a Microsoft Excel Spreadsheet, or entered directly onto REDCap at each study site. A 
separate, minimum dataset cross-referencing a study ID and patient identifiers must be kept locally to 
allow data validation and identification and/or recovery of missing variables. The local investigators will 
be responsible for ensuring that the spreadsheet is kept and maintained according to local data 
security guidelines, and, as a bare minimum, the spreadsheet should be held on a secure, institution-
approved drive location and password protected. Only de-identified information will be exported to the 
central team at UHP using REDCap. This tool facilitates secure data transfer, can help to ensure de-
identification and has the facility to assess the dataset's completeness. Individual surgeons will not be 
centrally identified and will strictly remain anonymous. 
 
In order to ensure the integrity of the data, the dataset will be subject to a regular review process 
during data collection periods to identify outliers, which may be the result of typographic errors. This 
will allow timely feedback to the collaborating researchers and ensure that the final datasets are of 
high quality.  
 
To further validate the dataset, units will be asked to perform an internal validation exercise. As 
outlined in section 9, this will be conducted in each participating unit by a collaborator who is not 
otherwise involved in data collection and will act independently from the other collaborators at the site. 
For the feasibility phase, 10% of patients will undergo this exercise. For a unit achieving the 
provisional target of 10 patients each month, this will equate to six records. The data validator will be 
asked to review the clinical record of the recruited patient and re-enter data from several core data 
points on a new CRF. This duplication of data entry will allow an assessment of concordance and give 
an idea of the quality of the dataset. The need for ongoing internal validation, and the proportion of 
patients required to validate the dataset will be reviewed following the feasibility phase. 
 
Qualitative Study: 
Semi-structured interviews will be conducted in a private setting, either face-to-face in a suitable, 
mutually convenient location, which might be, for example, the participant’s home (subject to the 
relevant sections of the University of Plymouth’s Guidance for Assessor/Supervisors and learners 
when carrying out unaccompanied home visits and for the use of learners’ vehicle for placement 
activity), a room in a hospital or academic setting, or remotely over Microsoft Teams. Settings for 
interviews must be private, quiet, and comfortable, and measures must be in place to limit interruption, 
such as switching off telephones. In each instance, the interview will be recorded using an audio 

 
 
 
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recording device or the built-in recording function of MS Teams. Where appropriate, the researcher(s) 
will collect observational field notes. 
 
The interviews will be transcribed into a pseudonymised Microsoft Word document, with each 
individual identified by a study ID. Auto-transcription software may be used to assist transcription, 
subject to manual checking and correction against the original recording. A separate Microsoft Excel 
spreadsheet will be maintained, cross-referencing the study ID and patient identifiers. All recordings 
and documents will be digitised, kept and maintained according to local data security guidelines and 
will be held on a secure, institution-approved drive location and password protected. 
 
7.4  
DATA STORAGE AND SECURITY 
Electronic data captured in the Trust’s web-based system, REDCap Community, will be stored on Microsoft 
Azure servers in the UK South and uses Locally Redundant Storage, meaning that the data is stored in 
three separate locations within this data centre. All electronic data are regularly backed up and retained for 
30 days.   
 
7.5  
ARCHIVING, PRESERVATION, AND CURATION 
Archiving will be authorised by the Sponsor following the submission of the end-of-study declaration. 
Upon completion of the study, study documents will be digitised (Hard Copies will be destroyed) and 
archived for a minimum of 10 years, and as per the participating Trust’s Research Archiving SOP. 
Once the archiving retention period has been reached, the Sponsor will liaise with the sites regarding 
destruction.   
 
7.6  
DATA SHARING 
Requests for data sharing can be made after the publication of the primary results papers. Requests 
should be made to the Chief Investigator in the first instance. Requesters will be asked to complete an 
application form detailing specific requirements, rationale, and proposed usage. The CI and study 
sponsor (including the Sponsor's Research Governance Manager (or deputy), the Information 
Governance Team, Caldicott Guardian, IM&T Security Officer and the researcher funder, as 
appropriate) will review all requests. 
 
Consideration will be given to: 
• 
The viability and suitability of the request 
• 
Appropriate steps have been taken to minimise the risk of identifying participants 

 
 
 
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• 
Data security policies and procedures of recipient organisation (including country if aboard) 
and other regulatory requirements are applicable 
• 
The credentials of the requestor 
 
Where access to requested data is granted, requester's organisations must sign a data sharing 
agreement before accessing any data. 
 
Subject to appropriate data sharing agreements, individual participants' data that underlie the results 
will be made available (after de-identification) on a controlled access basis. Requested data will be 
made available, along with supporting documentation (e.g., data dictionary), on a secure server or 
through other secure data transfer methods.  
 
8. 
ETHICAL AND REGULATORY COMPLIANCE 
8.1 
ETHICS AND HRA APPROVAL 
The Chief Investigator has obtained approval from the Health Research Authority (HRA) and 
Research Ethics Committee (REC). The Investigator will ensure that this study is conducted in full 
conformity with relevant regulations and with the UK Policy Framework for Health and Social Care 
Research (2017), which have their basis in the Declaration of Helsinki. 
 
8.2 
INDEMNITY 
This is an NHS-sponsored research study. If an individual suffers negligent harm as a result of 
participating in the study, NHS indemnity covers NHS staff and those responsible for the trial who 
have honorary contracts with the relevant NHS Trust. In the case of non-negligent harm, the NHS 
cannot agree in advance to pay compensation, but an ex-gratia payment may be considered in the 
event of a claim. 
 
8.3 
SPONSOR 
UHP will act as the main Sponsor for this study, assuming overall responsibility for the initiation and 
management of the trial. Delegated responsibilities may be assigned to other relevant parties taking 
part in this study and appropriately documented. 
 

 
 
 
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8.4 
FUNDING 
Funding and costing will be considered in two stages – feasibility and full study. At this point, funding 
and costing has been performed for the feasibility phase only. If the feasibility phase of the study is a 
success, and meets criteria for progression, additional funding and costing will be required to continue 
the study.  
 
Arrangements, as they stand at present, are outlined below. 
 
University Hospitals Plymouth NHS Trust are funding fP-iGBC (the pilot and qualitative studies) as 
detailed below.  
 
• 
The salary of a Clinical Research Fellow (CRF) is being provided by the Trust, the CRF’s 
responsibilities predominantly include the delivery of the internal pilot and qualitative study, 
which will be conducted as part of their Medical Doctorate at the University of Plymouth. 
• 
UHP are providing the use of REDCap and oversight of f-P-iGBC free of charge for the 
feasibility phase. 
 
The Peninsula Medical Foundation and the Association of Upper Gastrointestinal Surgeons are 
supporting the research associated costs of the feasibility phase. Further funding will be sought 
following the feasibility phase. 
 
There will be no per-participant payments for the qualitative study. 
 
8.5 
MONITORING 
The study will be subject to monitoring by UHP under their remit as Sponsor to ensure adherence to 
the UK Policy Framework for Health and Social Care Research (2017). All UHP studies will be initially 
monitored approximately 25 days after local R&D Confirmation of Capability and Capacity has been 
given. The subsequent level of monitoring will be determined by a risk assessment, or on a for-cause 
basis. The study may also be audited/ inspected by regulatory bodies to ensure compliance with 
national regulations. 
 

 
 
 
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9. 
STUDY MANAGEMENT 
The day-to-day management of fP-iGBC (the pilot and qualitative study) will be co-ordinated through a 
UHP Clinical Research Fellow. A Clinical Trials Unit will be engaged to assist with completion of the 
quantitative study once feasibility has been established. 
 
9.1  
STUDY SITES AND PERSONNEL 
Study sites for the will be recruited based on a number required to meet patient recruitment targets. 8 
units, including University Hospitals Plymouth NHS Trust, will be recruited from within England for the 
feasibility phase. Each study site requires at least 3 collaborators adopting  
 
Principal Investigators and Co-Investigators 
Each organisation will require a Principal Investigator (PI). When an organisation has more than one 
study site, a single principal investigator will oversee study activities across the organisation. However, 
a Co-Investigator or, if possible, a Co-PI may be registered in the event that more than one surgical 
department operates across the organisation, but will not be required if a single team operates across 
multiple locations. This is likely to occur when NHS Hospital Trusts merge for organisational reasons, 
for example.  
 
Lead Trainees 
Each PI, Co-PI or Co-Investigator will be required to identify and recruit a Lead Trainee for their unit, 
who will be put forward for an Associate PI scheme if the study is adopted by the NIHR. The Lead 
Trainee should be a trainee, or locally employed doctor in an equivalent non-training grade, in an 
appropriate specialty. The study team recognises that trainees join and leave units frequently because 
of their rotational or contractual commitments, and therefore acknowledges that Lead Trainees may 
have a time-limited involvement with the study. There may, therefore, be more than one Lead Trainee 
over the course of a site’s involvement with the study. However, There should only be one Lead 
Trainee at any given point in time. A Lead Trainee should remain in that role for a minimum of six 
months, but ideally a minimum of a year, except when a data collection period starts or ends part way 
through a rotation. It is the responsibility of the PI to decide on the suitability of the Lead Trainees, 
however they should be in a position to recruit and lead their trainee peers, and consideration should 
be given to their seniority, ability to deliver the project and other commitments. Lead Trainees are not 
required during quiescent periods of the project. 
Roles of the Lead Trainee include 
1. Identification, recruitment and management of collaborators. 

 
 
 
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2. Active involvement in identification, recruitment and data collection of patient participants. 
3. Oversight and management of the locally delivered opt-out process (with support form the PI 
as required). 
4. Increasing awareness of the project within the organisation, particularly with regards to 
ensuring that relevant clinicians are aware of the project and inform patients about it as outline 
in the relevant section above. 
5. Liaison with the central research team. 
6. Confirmation of collaborators’ contribution to the project (in association with the PI). 
 
Collaborators – Data Collection 
Lead Trainees and PIs are required to recruit sufficient (trainee) collaborators to monitor operating lists 
and to identify, recruit and collect data from patients for each component of the study. Collaborators 
include the Lead Trainee and PI, and can be recruited from any grade of doctor or the allied health 
professions, including Physician Associates, Nurses etc, however must: 
1. Be drawn from members of the direct care team for patients undergoing cholecystectomy. 
2. Ordinarily have access to review necessary results. 
3. Have sufficient training and/or experience to provide the knowledge and understanding of 
common terminology found in reports and letters, which may need to be interpreted before 
input to the data collection tool. 
4. Meet any generic organisational requirements for involvement in research within the 
participating organisation. 
There is no centrally defined maximum number of collaborators per organisation, as in common with 
Lead Trainees it is recognised that many collaborators will be rotational, and that organisations will 
vary in their surgical volumes. However, to be considered for authorship each collaborator should be 
able to identify and collect data from 2 patients each month. For example, in a unit meeting the initial 
feasibility target of 10 cholecystectomies each month, 5 local collaborators (including the PI and Lead 
Trainee) would be suggested as an appropriate maximum. Data collectors should remain actively 
involved with the study for a minimum of one rotation (but not less than four months, as applicable to 
their job role, unless data collection starts or finishes mid-rotation), or one year for permanent staff. 
Collaborators are not required to remain involved outside of data collection periods. 
 
Collaborators – Data Validation 
Lead Trainees and PIs will also be required to recruit a data validator. These collaborators will 
undertake the data validation exercise described in the relevant sections above. Data validators 

 
 
 
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should meet the same requirements as data collectors however should not otherwise be involved in 
the identification or data collection processes, in order that their independence may be maintained. 
 
Collaborators – Limited role 
Where it may assist local teams to utilise other members of the direct care team to identify and screen 
patients, or to permit “live” operative data entry by the performing team, a limited access role will be 
available in REDCap in order for accurate, prospective recording of intraoperative events. These 
collaborators will be able to access the screening and operative findings sections of the eCRF. The 
Lead Trainee and PI are responsible for determining whether their contribution is sufficient to qualify 
for authorship, through comparison to those collaborators undertaking data collection and validation. 
 
10. 
PUBLICATION POLICY 
It is proposed that the study team will prepare a Plain English Summary of the study results, which will 
be sent to interested study participants as soon as possible after the end of the study. The study's final 
results will be disseminated via presentations at appropriate scientific meetings and conferences and 
publication in appropriate peer-reviewed journals. 
 
10.1  AUTHORSHIP 
This is a collaborative project. In all cases, collaborators will be considered for authorship if they meet 
the requirements of the International Committee of Medical Journal Editors’ (ICJME) statement on 
defining the role of authors and contributors. Briefly, the requirements are that an author should have 
made a “substantial contribution” to the work, which may include acquisition of data, have drafted, or 
critically reviewed the work, have approved the final version and agree to be accountable for it. In light 
of the design of the study, it is likely that all Principle Investigators and Trainee Collaborators will be 
able to meet the requirements§. Where they do not but have nonetheless been significant 
collaborators in the presented work, they will be listed as Contributors. Collaborators will only be 
considered for authorship if they have contributed to the segment of work being presented. For 
example, if a further analysis is performed on feasibility data after the full study is completed, only 
collaborators who contributed to the feasibility stage will be eligible for authorship. 
 
 
§ To facilitate compliance with these requirements, collaborators will be asked to review and approve drafts, and 
to agree to accountability statements. 

 
 
 
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How collaborators are listed as co-authors will depend on the rules and requirements of specific 
journals. Where only a limited number of individuals will be listed as authors by the journal, 
collaborators will be grouped as below. Whenever possible, the members of each group will be 
individually named, but will otherwise be known as the “writing group” or the “collaborative”. In 
MEDLINE, facility exists for collaborators to be individually associated with group, or collaborative 
authorship and, where this is acceptable, the group names below may be used. Individual listing of 
members of the Writing Group will take precedent over individual listing of members of the 
Collaborative. 
 
1. P-iGBC Writing Group 
Authors in this category are those who have contributed significantly to the writing of the paper.  
These authors will typically be part of the central research team or major collaborators from 
other participating units or universities and will meet ICJME authorship requirements by having 
made significant contributions to the conception and design, or analysis and interpretation of 
the presented work. Collaborators who have solely been involved in data collection or internal 
validation are unlikely to meet the requirements of this group. 
2. P-iGBC Collaborative 
Authors in this category are either central research team members who meet authorship 
requirements but do not meet writing group requirements, or those who have otherwise 
collaborated. They will typically meet ICMJE authorship requirements by virtue of significant 
contribution to the acquisition of data for the presented work. Where appropriate or required, 
their roles will be further defined as below. 
a. Members of the central research team 
b. Principle Investigators and Lead Trainees/Associate Principal Investigators** 
c. Trainee Collaborators††  
i. Data collection  
ii. Data validation 
d. Other collaborators, including limited role for identification, screening, recruitment and 
“live” operative data entry. 
 
 
** This definition is dependent on whether the study is adopted by the NIHR and accepted to the Associate 
Principal Investigator scheme.  
†† NB This “trainee” collaborative allows for non-training grade and non-medical grade collaborators. 

 
 
 
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28. 
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29. 
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30. 
Wiles R, Thoeni RF, Barbu ST, Vashist YK, Rafaelsen SR, Dewhurst C, et al. Management and 
follow-up of gallbladder polyps. Eur Radiol. 2017;27(9).  
31. 
Foley KG, Lahaye MJ, Thoeni RF, Soltes M, Dewhurst C, Barbu ST, et al. Management and 
follow-up of gallbladder polyps: updated joint guidelines between the ESGAR, EAES, EFISDS 
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32. 
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33. 
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coincidence of Mirizzi syndrome and gallbladder carcinoma. Surgery. 1997;121(1).  
34. 
Mirizzi PL. [Syndrome of spontaneous hepatic duct]. Dia Med. 1958 Aug;30:30 passim.  
35. 
Demetriou G, Wanigasooriya K, Elmaradny A, Al-Najjar A, Rauf M, Martin-Jones A, et al. The 
impact of the COVID-19 pandemic on elective laparoscopic cholecystectomy: A retrospective 
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36. 
Latenstein CSS, Wennmacker SZ, Groenewoud S, Noordenbos MW, Atsma F, De Reuver PR. 
Hospital Variation in Cholecystectomies in the Netherlands: A Nationwide Observational Study. 
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37. 
Rossi BWP, Bassett E, Martin M, Andrews S, Wajed S. Prompt laparoscopic cholecystectomy 
would reduce morbidity and save hospital resources. Ann R Coll Surg Engl. 2014;96(4).  
38. 
Lyu YX, Cheng YX, Jin HF, Jin X, Cheng B, Lu D. Same-admission versus delayed 
cholecystectomy for mild acute biliary pancreatitis: A systematic review and meta-analysis. Vol. 
18, BMC Surgery. 2018.  
39. 
Yuval JB, Mizrahi I, Mazeh H, Weiss DJ, Almogy G, Bala M, et al. Delayed Laparoscopic 
Cholecystectomy for Acute Calculous Cholecystitis: Is it Time for a Change? World J Surg. 
2017;41(7).  
40. 
Lucocq J, Patil P, Scollay J. Acute cholecystitis: Delayed cholecystectomy has lesser 
perioperative morbidity compared to emergency cholecystectomy. Surgery (United States). 
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41. 
Lawrentschuk N, Hewitt PM, Pritchard MG. Elective laparoscopic cholecystectomy: Implications 
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42. 
Gurusamy KS, Koti R, Fusai G, Davidson BR. Early versus delayed laparoscopic 
cholecystectomy for uncomplicated biliary colic. Cochrane Database of Systematic Reviews. 
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43. 
Tozlu M, Karaca B, Acar S, Toka B, Karacaer C, Eminler AT, et al. Higher Complications during 
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APPENDICIES 
Pease see Links to other appendices for hyperlinks to the most recent versions of the documents 
below. 
 
Appendix 1. 
Schedule of Events 
Appendix 2. 
Amendment History 
Appendix 3. 
P-iGBC Participant Information Sheet 
Appendix 4. 
P-iGBC Consent Form (redundant) 
Appendix 5. 
 
a. qP-iGBC Participant Information Sheet 
b. qP-iGBC Participant Information Sheet (Print Format, hyperlinks removed) 
Appendix 6. 
qP-iGBC Consent Form 
Appendix 7. 
qP-iGBC Patient Participant Interview Guide 
Appendix 8. 
qP-iGBC Professional Participant Interview Guide 
Appendix 9. 
Public Notification Poster (Example) 
Appendix 10. 
Public Notification Social Media Announcement (Example) 
Appendix 11. 
Plain English Summary for PPIE 
Appendix 12. 
Report on PPIE Consultation  
Appendix 13. 
Full list of variables 
 
 
 

 
 
 
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APPENDIX 1 – SCHEDULE OF EVENTS  
 
Quantitative Component 
 
Procedures 
 
 
 
- 2 
weeks 
Start of 
recruitment 
period 
Operating 
List 
Planned 
Day of 
operation 
End of 
recruitment 
period 
Histology 
+ 8 
weeks 
Public 
Announcements 
X 
X 
X 
X 
X 
 
 
PIS available 
online + paper 
X 
X 
X 
X 
X 
 
 
Start of data 
collection 
 
X 
 
 
 
 
 
Demographics, 
Imaging, Bloods 
 
 
X 
X 
 
 
 
Intra-operative 
findings 
 
 
 
X 
 
 
 
Histology 
 
 
 
 
 
X 
 
Monthly local 
performance 
updates 
 
X 
X 
X 
 
 
 
Fortnightly data 
upload 
reminders 
 
 
 
 
X 
 
 
Data upload 
ended (locked) 
 
 
 
 
 
 
X 
 
 
 
 
 
Qualitative Component 
 

 
 
 
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Procedures 
Screening Initial Contact Interview Week 2 
Basic Demographics 
X 
 
 
 
PIS Provided 
 
X 
 
 
Informed Consent 
 
 
X 
 
Interview Undertaken 
 
 
X 
 
Transcript Provided 
 
 
 
X 
 
 
 

 
 
 
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APPENDIX 2 – AMENDMENT HISTORY  
 
List details of all protocol amendments here whenever a new version of the protocol is produced. 
 
Amendment 
No. 
Protocol 
Version 
No. 
Date 
issued 
Author(s) 
of changes 
Details of changes made 
1 
1.1 
19/07/2024 
O Brown 
• 
Addition of REC reference number 
• 
Updated hyperlinks to 
Supplementary Participant 
Information Sheet, Participant 
Information Sheet for the qualitative 
workstream and Poster 
• 
Addition of print-format (hyperlink 
free) version of Supplementary 
Participant Information Sheet 
(Appendix 5b) 
2 
1.2 
06/09/2024 
O Brown 
• 
Addition of University of Plymouth 
Faculty Research Ethics and 
Integrity Committee reference 
number. 
• 
Addition of the Association of Upper 
Gastrointestinal Surgeons of Great 
Britain and Ireland as funders for the 
feasibility phase. 
• 
Clarification on the separation of 
funding arrangements between the 
feasibility phase and main study. 
 

 
 
 
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LINKS TO OTHER APPENDICES (APPENDIX 3-13) 
 
Appendix 1. 
See above. 
Appendix 2. 
See above. 
Appendix 3. 
 
a. P-iGBC Participant Information Sheet 
b. P-iGBC Participant Information Sheet (Print Format, hyperlinks removed) 
Appendix 4. 
P-iGBC Consent Form (redundant) 
Appendix 5. 
qP-iGBC Participant Information Sheet 
Appendix 6. 
qP-iGBC Consent Form 
Appendix 7. 
qP-iGBC Patient Participant Interview Guide 
Appendix 8. 
qP-iGBC Professional Participant Interview Guide 
Appendix 9. 
Public Notification Poster (Example) 
Appendix 10. 
Public Notification Social Media Announcement (Example) 
Appendix 11. 
Plain English Summary for PPIE 
Appendix 12. 
Report on PPIE Consultation  
Appendix 13. 
Full list of variables