Gastric Bypass, Adjustable Gastric Banding or Sleeve Gastrectomy Surgery to Treat Severe and Complex Obesity: a Multi-centre Randomised Controlled Trial
Phase: NA
Conditions: Obesity, Surgery, Quality of Life, Weight Loss
Sponsor: University of Bristol

 
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Gastric Bypass, adjustable gastric Banding or Sleeve gastrectomy 
surgery to treat severe and complex obesity: a multi-centre 
randomised controlled trial   
  
 
 
The By-Band-Sleeve Study 
 
REC No: 11/SW/0248 
 
ISRCTN No: 00786323 
 
HTA No: 09/127/53  
 
 
Sponsor 
Dr Birgit Whitman 
Head of Research Governance 
University of Bristol, Senate House,  
Tyndall Avenue,  
Bristol, BS8 1TH 
 
Tel:  0117 331 7130 
Fax: 0117 929 8383 
 
Chief Investigators & Research Team Contact Details 
 
Chief Investigator 
Professor Jane M Blazeby  
Professor of Surgery, Honorary Consultant 
Surgeon, Bristol Medical School (PHS), 
Canynge Hall, 39 Whatley Road, Clifton, 
Bristol BS8 2PS  
 
Tel: 0117 928 7332 
Fax: 0117 925 2736 
Email: j.m.blazeby@bris.ac.uk 
 
Methodological Lead 
Professor Barney Reeves 
Professorial Research Fellow in Health 
Services Research, Bristol Medical School 
(THS), Level 7, Bristol Royal Infirmary 
Marlborough Street, Bristol, BS2 8HW 
 
Tel: 0117 342 3143 
Fax: 0117 342 3288 
Email: Barney.Reeves@bristol.ac.uk 
 
Surgical Lead 
Mr Richard Welbourn 
Consultant Upper GI & Bariatric Surgeon 
Taunton and Somerset NHS Trust, 
Musgrove Park Hospital, 
Taunton, TA1 5DA 
 
Tel: 01823 250611 
Fax: 01823 250610 
Email: richardwelbourn@gmail.com 
 
Qualitative Research Lead 
Professor Jenny Donovan  
Professor of Social Medicine & Head of 
School, Bristol Medical School (PHS), 
Canynge Hall, 39 Whatley Road 
Bristol, BS8 2PS 
 
Tel: 0117 9287214 
Fax: 0117 925 2736 
Email: jenny.donovan@bris.ac.uk 
 
 
 
 

 
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CTEU and Statistical Lead 
Professor Chris Rogers 
Professor of Medical Statistics and Clinical 
Trials, Bristol Medical School (THS), Level 7, 
Bristol Royal Infirmary, Marlborough Street,  
Bristol, BS2 8HW 
 
 
Tel: 0117 342 2507 
Fax: 0117 342 3288 
Email: chris.rogers@bris.ac.uk 
 
Endocrinology Lead 
Dr Robert Andrews 
Consultant Senior Lecturer in Diabetes & 
Endocrinology, Department of Diabetes & 
Endocrinology, Taunton & Somerset 
Hospital, Musgrove Park, Taunton 
Somerset, TA1 5DA 
 
Tel: 01823 344988 
Fax: 01823 344542 
Email: Rob.Andrews@bristol.ac.uk 
 
Health Economics Lead 
Dr Sarah Wordsworth 
Senior Research Fellow in Health 
Economics, Health Economic Research 
Centre 
Old Road Campus, Old Road, Headington 
Oxford 
 
Tel: 01865 289268 
Fax: 01865 226842 
Email: sarah.wordsworth@dphpc.ox.ac.uk 
 
Surgical Expertise 
Mr James Byrne  
Consultant Surgeon and Honorary Senior 
Lecturer, Department of Surgery, 
Southampton University Hospitals NHS 
Trust, Tremona Road, Southampton, SO16 
6YD 
 
Tel: 02380 798 535 
Fax: 02380 795 215 
Email: jamespbyrne@aol.com 
 
Nutritional Lead 
Professor Janice Thompson 
Professor of Public Health Nutrition and 
Exercise 
The University of Birmingham 
School of Sport and Exercise Sciences 
Edgbaston, Birmingham, B15 2TT 
 
Tel: 0121 414 4119 
Fax:  
Email: j.thompson.1@bham.ac.uk 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Table of contents 
 
Glossary / abbreviations .................................................................................................... 5 
1. 
Trial summary ............................................................................................................ 6 
2. 
Background ................................................................................................................ 8 
2.1 
Existing research evidence ................................................................................. 8 
2.2 
Surgery for severe and complex obesity ............................................................. 8 
2.2.1 Laparoscopic gastric bypass (Bypass) .................................................... 8 
2.2.2 Laparoscopic adjustable gastric banding (Band) ..................................... 9 
2.2.3 Laparoscopic sleeve Gastrectomy (Sleeve) ............................................ 9 
2.3 
Systematic review evidence ............................................................................... 9 
3. 
Aims and objectives ................................................................................................ 11 
4. 
Plan of Investigation ................................................................................................ 12 
4.1 
Study design ..................................................................................................... 12 
4.2 
Trial schema ..................................................................................................... 13 
4.3 
Trial population ................................................................................................. 14 
4.3.1 Eligibility criteria - participating centres .................................................. 14 
4.3.2 Eligibility criteria - participating surgeons ............................................... 14 
4.3.3 Eligibility criteria – patients .................................................................... 14 
4.4 
Trial interventions ............................................................................................. 15 
4.4.1 All three operations ............................................................................... 15 
4.4.2 Laparoscopic adjustable gastric banding (Band surgery) ...................... 15 
4.4.3 Laparoscopic gastric bypass surgery (Bypass surgery) ......................... 16 
4.4.4 Laparoscopic sleeve gastrectomy surgery (Sleeve surgery) .................. 16 
4.4.5 Concomitant interventions ..................................................................... 16 
4.5 
Primary and secondary outcomes .................................................................... 16 
4.5.1 Primary outcome ................................................................................... 16 
4.5.2 Secondary outcomes............................................................................. 16 
4.6 
Sample size calculation .................................................................................... 17 
5. 
Trial methods ........................................................................................................... 20 
5.1 
Description of randomisation ............................................................................ 20 
5.2 
Research procedures ....................................................................................... 20 
5.2.1 Measurement of weight and height ........................................................ 20 
5.2.2 Assessment of patient reported outcomes ............................................. 21 
5.2.3 Assessment of co-morbidities ................................................................ 22 
5.2.4 Measurement of waist circumference .................................................... 23 
5.2.5 Metabolomic profiling ............................................................................ 23 
5.3 
Integrated qualitative research: recruitment ...................................................... 23 
5.3.1 Phase I .................................................................................................. 23 
5.3.2 Phases II and III: Feedback to TMG ...................................................... 26 
5.4 
Integrated qualitative research: process evaluation .......................................... 27 
5.4.1 Phases I and II ...................................................................................... 27 
5.4.2 Phases II and III .................................................................................... 28 
5.5 
Development of a core clinical outcome set for obesity surgery ........................ 28 
5.6 
Duration of treatment period ............................................................................. 29 
5.7 
Definition of end of trial ..................................................................................... 29 
5.8 
Data collection .................................................................................................. 29 
5.9 
Source data ...................................................................................................... 30 
5.10 Planned recruitment rate .................................................................................. 31 
5.11 Participant recruitment ...................................................................................... 31 
5.12 Discontinuation/withdrawal of participants ........................................................ 32 
5.13 Frequency and duration of follow up ................................................................. 32 
5.13.1 Band consultations ................................................................................ 33 
5.14 Likely rate of loss to follow-up ........................................................................... 33 

 
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5.15 Expenses ......................................................................................................... 33 
5.16 Measures taken to avoid bias ........................................................................... 33 
5.17 Criteria for the termination of the trial ................................................................ 34 
5.18 Economic issues............................................................................................... 34 
6. 
Statistical analyses .................................................................................................. 36 
6.1 
Analyses of quantitative data ............................................................................ 36 
6.2 
Analyses of qualitative data .............................................................................. 36 
6.3 
Subgroup analyses ........................................................................................... 37 
6.4 
Frequency of analyses...................................................................................... 37 
6.5 
“Metabolomics sub-study” ................................................................................. 37 
7. 
Trial management .................................................................................................... 38 
7.1 
Day-to-day management .................................................................................. 38 
7.2 
Monitoring of sites ............................................................................................ 38 
7.2.1 Initiation visit ......................................................................................... 38 
7.2.2 Site monitoring ...................................................................................... 38 
7.3 
Trial Steering Committee and Data Monitoring and Safety Committee ............. 38 
8. 
Safety reporting ....................................................................................................... 39 
8.1 
Expected adverse events ................................................................................. 39 
8.2 
Period for recording serious adverse events ..................................................... 43 
9. 
Ethical considerations ............................................................................................. 44 
9.1 
Review by an NHS Research Ethics Committee ............................................... 44 
9.2 
Risks and anticipated benefits for trial participants and society ......................... 44 
9.3 
Information to potential trial participants of possible benefits and known risks .. 44 
9.4 
Obtaining informed consent from participants ................................................... 44 
10. 
Research governance .............................................................................................. 45 
10.1 Sponsor approval ............................................................................................. 45 
10.2 NHS approval ................................................................................................... 45 
10.3 Investigators' responsibilities ............................................................................ 45 
10.4 Monitoring by sponsor ...................................................................................... 45 
10.5 Indemnity .......................................................................................................... 45 
10.6 Clinical Trial Authorisation ................................................................................ 45 
11. 
Data protection and participant confidentiality ..................................................... 46 
11.1 Data protection ................................................................................................. 46 
11.2 Data handling, storage and sharing .................................................................. 46 
11.2.1 Data handling ........................................................................................ 46 
11.2.2 Data storage ......................................................................................... 46 
11.2.3 Data sharing .......................................................................................... 46 
12. 
Dissemination of findings ....................................................................................... 47 
13. 
References ............................................................................................................... 47 
14. 
Amendments to protocol......................................................................................... 50 
 
 
 
 

 
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Glossary / abbreviations 
 
AE 
Adverse event - any undesirable event in a subject receiving treatment 
according to the protocol, including occurrences which are not necessarily 
caused by or related to administration of the research procedures. 
Band 
Bypass 
Laparoscopic adjustable gastric banding surgery 
Laparoscopic gastric bypass surgery  
BMI 
Body mass index 
CA 
Conversation analysis 
CI 
Confidence interval 
CRF 
Case report form 
CPAP 
Continuous positive airways pressure 
CTEU 
Clinical Trials and Evaluation Unit 
DMSC 
Data monitoring and safety committee 
DVT 
EQ-5D-5L 
Deep vein thrombosis 
EuroQol health status questionnaire (5 level version) 
ELF 
Enhanced liver fibrosis test 
GI 
Gastro-intestinal 
GIQLI 
Gastro-intestinal quality of life index 
GP 
General practitioner 
HA 
Hyaluronic acid 
HADS 
Hospital anxiety and depression scale 
HRQOL 
Health related quality of life 
HTA 
ICH-GCP 
Health Technology Assessment 
International conference for harmonisation of good clinical practice 
IQS 
Integrated qualitative study  
IWQOL-Lite 
Impact of weight of quality of life-Lite 
MRC 
Medical Research Council 
NICE 
NIHR 
National Institute for Health and Care Excellence 
National Institute for Health Research 
PIIINP 
Aminoterminal peptide of procollagen type III 
PCT 
Primary care trust 
PI 
Principal investigator 
PIL 
Patient information leaflet 
QALY 
Quality adjusted life years 
RCT 
Randomised controlled trial 
REC 
Research ethics committee 
SAE 
Serious adverse event - events which result in death, are life threatening, 
require hospitalisation or prolongation of hospitalisation, result in persistent 
or significant disability or incapacity.   
SAR 
Serious adverse reaction 
SF-12 
Sleeve 
Short-form 12 question HRQOL questionnaire 
Sleeve gastrectomy surgery 
SMS 
Standard message service 
SOP 
Standard operating procedure 
SSAR 
Suspected serious adverse reaction 
SUSAR 
Suspected unexpected serious adverse reaction - an untoward medical 
occurrence suspected to be related to a medicinal product that is not 
consistent with the applicable product information and is serious. 
TIMP-1 
Tissue inhibitor of matrix metalloproteinase 
TMG 
Trial management group 
TPN 
Total parenteral nutrition 
TSC 
Trial steering committee 

 
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1. 
Trial summary 
 
Obesity is an increasing health problem in the UK and is predicted to worsen. There are 
many health problems associated with obesity including risk of diabetes, gallbladder 
disease, sleep problems, heart disease and arthritis. These health issues can shorten a 
person’s life expectancy, impair quality of life and increase the use of expensive health 
services. Current national guidelines to treat obesity recommend management of life-style 
changes as the initial treatment for people who are overweight. However, surgery is 
considered for the very overweight (severe and complex obesity) or for those remaining 
obese after trying other options. The three recognised operations in bariatric surgery are 
laparoscopic adjustable gastric banding (’Band’), laparoscopic gastric bypass (’Bypass’) and 
Sleeve gastrectomy (‘Sleeve’).  When By-Band was conceived, the two most commonly 
performed operations in the UK and worldwide were laparoscopic adjustable gastric banding 
(’Band surgery’) and laparoscopic gastric bypass (’Bypass surgery’). Together these 
accounted for over 80% of all operations carried out to treat severe and complex obesity. At 
that time Sleeve gastrectomy (‘Sleeve surgery’) accounted for 8% of procedures and was 
considered to be insufficiently established to warrant full evaluation in a pragmatic 
randomised controlled trial (RCT).  However, over the past five years the number of Sleeve 
gastrectomies undertaken in the UK has increased from 8% to 29% and this pattern is 
mirrored worldwide. At the same time there has been a gradual decrease in gastric Band 
surgery, although it still accounts for over 40% of operations carried out in the private sector.   
 
Bypass surgery alters the food passage so food spends less time in the stomach and avoids 
some of the small bowel.  Band surgery involves inserting an adjustable plastic band around 
the top of the stomach to reduce its capacity, and Sleeve gastrectomy involves removing a 
large part of the stomach to reduce it to about 25% of its original size.  All three operations 
lead to weight loss by reducing appetite and inducing satiety, but they are associated with 
different problems. In the short term there are varying complications and inconvenience 
relating to the operation. In the longer term there are different outcomes relating to weight 
regain, symptoms and side effects of the gastric Bypass, Sleeve gastrectomy or problems 
with the band. Estimates of initial surgical costs of Band is about 3K, Sleeve about 5K and  
more complex Bypass procedure (about 6K), however Band surgery requires more intensive 
follow-up clinic visits with adjustment of fluid in the band. At present only rough estimates of 
overall costs can be therefore given because of the variation between tariffs for the 
procedures in the NHS and variable provision of follow up visits. The tariffs may also change 
over the next few years due to changes in the commissioning of bariatric surgery in the UK. 
 
There is a lack of well-designed research comparing Band, Bypass and Sleeve and current 
decisions in the UK to undergo one of the three operations rely upon guidance from general 
practitioners (GPs), or local surgeons (not informed by good evidence) and patients’ 
preferences. Head to head comparisons of the three surgical procedures has previously 
been considered too difficult to undertake because surgeons have tended to favour one type 
of procedure more than another. However, it is widely acknowledged that studies are 
urgently required to compare the effectiveness, cost effectiveness and acceptability of Band, 
Bypass and Sleeve. The most suitable study design is a trial in which patients could be 
allocated to one of the three procedures by a process of randomisation. This means they 
have an equal chance of having one of the procedures and so a fair comparison of the 
outcomes of each of them can be made.  
 
We propose a three phase study in twelve hospitals. The first phase (in two hospitals) will 
test the feasibility of recruitment, randomisation and develop ways to optimise information for 
patients to maximise trial recruitment to either Band or Bypass.  Phase 1 will also establish a 
core set of clinical outcomes to use to evaluate the surgery for severe and complex obesity. 
The second phase (in all 12 hospitals) will be adapted to include Sleeve. The third phase will 

 
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complete the recruitment and follow-up. The three group trial will recruit a total of 1341 
patients and will follow-up all participants for at least three years after randomisation.  
 
We will compare the effects of Band, Bypass and Sleeve surgery three years after 
randomisation on weight loss, a wide range of symptoms and aspects of quality of life. We 
will also examine patients’ experiences during follow-up, nutritional outcomes, short and long 
term surgical complications and NHS value for money. 
 
In addition, once recruitment to the trial is complete and all participants are in follow-up (or 
earlier if recruitment is going well and the study management group agree) we are inviting 
eligible patients who do not join the trial to join a sub-study which will focus on the impact of 
weight change and bariatric surgery on the metabolome (“metabolomics sub-study”).  
Patients who join this sub-study will be followed for one year.   The participation of any study 
centre in the sub-study will be optional.  
 
 
 
 
 

 
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2. 
Background 
 
2.1 
Existing research evidence 
 
Adult obesity prevalence is increasing around the world, and in the UK rates have trebled 
during the past 25 years to around 24% [1].  If trends persist, 36% of men and 28% of 
women aged 21 to 60 will be obese in 2015, and worldwide approximately 700 million adults 
will be living with the condition [1, 2]. The prevalence of severe and complex obesity 
(clinically defined as a body mass index (BMI) ≥ 35kg/m2 with co-morbidity or a BMI > 40 
kg/m2 without co-morbidity) is also on the increase, and UK prevalence has been estimated 
at around 2.1% [3, 4]. 
 
Obesity is associated with a number of health problems, including type 2 diabetes, 
cardiovascular disease, musculoskeletal disorders, infertility, and psychiatric disorders. The 
mortality rate for those with severe and complex obesity is approximately double that for the 
general population. Additionally, obesity is a major contributor to social inequalities in health 
[5] and places a huge financial burden on the NHS. The direct costs of treating diseases 
associated with overweight and obesity were estimated at £3.2 billion in 2002, or nearly 5% 
of total NHS expenditure [6]. On an individual level, living with obesity has been associated 
with psychological distress and social stigma, both of which may have a significant impact on 
individuals’ quality of life [7, 8]. The prevention and treatment of obesity is thus a key priority 
for the NHS, and the provision of weight management services for adults is now firmly 
established as a core policy objective.  
 
Reversal of obesity is uncommon without intervention [9], and National Institute for Health 
and Care Excellence (NICE) guidance states that health authorities should establish 
comprehensive care pathways for addressing overweight and obesity within their 
populations, which should include access to diet and exercise interventions, anti-obesity 
drugs, and, in some circumstances, weight reduction surgery [10]. However, it is known that 
many interventions for obesity fail, and bariatric surgery is increasingly being viewed as a 
solution to weight loss, particularly for those who have severe and complex obesity. 
Although surgery is usually considered after patients have attempted other forms of weight 
loss without success, the exception to this is for adults with a BMI > 50. NICE guidelines 
recommend surgery as a first-line option for this group of patients (instead of lifestyle 
interventions or drug treatment) if surgical intervention is considered appropriate.  
 
2.2 
 Surgery for severe and complex obesity 
 
Surgical procedures for those with obesity aim to reduce weight and maintain weight loss 
through restriction of intake and/or malabsorption of food.  There are several different 
operations in use including laparoscopic gastric bypass (Bypass), laparoscopic adjustable 
gastric band (Band), biliopancreatic diversion and its duodenal switch variant, vertical 
banded gastroplasty and sleeve gastrectomy (Sleeve). Despite the variety of different 
surgical procedures available, the three most commonly performed operations worldwide are 
Bypass, Band and Sleeve. Together these account for about 80% of all obesity operations in 
the UK and the USA [11-13].  
 
2.2.1 Laparoscopic gastric bypass (Bypass)  
 
Bypass achieves weight loss by altering the flow of food through the gut and combining 
restrictive, hormonal and some malabsorptive principles. The surgical procedure alters 
physiology and anatomy in such a way as to achieve rapid weight loss, although it is not 
adjustable. Observational studies show that significant early weight loss occurs within 12 
months of Bypass and this is associated with improvements in generic aspects of health 
related quality of life (HRQOL) (physical, social and role function) [5, 14]. There is a lack of 

 
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medium or longer term outcome data after Bypass and studies suffer from loss to follow up 
and lack of generic and disease specific long term HRQOL data [15]. Surgical risks of 
Bypass include serious morbidity and death. In a study of 2975 patients undergoing Bypass 
the risk of death at 30 days was 0.2% (6 deaths), and 94 patients (3.2%) required re-
operation [16, 17]. Longer term complications of Bypass may include the need for re-
operation because of internal hernias or intestinal obstruction, symptoms of flatulence and 
regurgitation and nutritional deficiencies. Long term follow up is therefore required and may 
also provide an opportunity for dietary education and support. 
 
2.2.2 Laparoscopic adjustable gastric banding (Band) 
 
Band achieves weight loss by three processes, (i) placement of a band surgically around the 
top of the stomach to restrict the stomach, (ii) post-operative adjustment of the band (at out-
patient visits) to regulate the degree of gastric restriction (by injection or removal of fluid from 
the band via a subcutaneous access port) and to help control the appetite and iii) education 
and support of patients at band adjustment appointments. Observational studies show that 
after Band patients experience gradual weight loss and that it may take 12 to 24 months to 
achieve optimal weight loss [17]. The number and nature of visits for band adjustment are 
important [18, 19], however there are currently no UK nationally agreed standards for post-
operative visits after Band to assist either service providers or commissioners. The literature 
suggests that up to 7 visits are required in the first year and that three monthly visits are 
required in the second year to achieve and maintain optimal weight loss. There is also 
evidence that on-going visits (six monthly thereafter) are needed [18, 19]. Centres which 
achieve the greatest weight loss with Band ensure that the follow up care is at least three 
monthly at first and that it is maintained [3, 18, 19]. After Band patients may have symptoms 
of dysphagia and regurgitation and, although weight loss after Band is associated with 
improvements in HRQOL [20], medium and long term HRQOL data are lacking. Short term 
surgical risks of Band are uncommon; in a prospective cohort of 1198 patients undergoing 
Band, there were no deaths and 9 re-operations [16]. Longer term complications of Band 
include band erosion or migration, pouch dilatation, leakage from the circuit or infection 
which may require revision surgery or band removal [17, 21]. 
 
2.2.3 Laparoscopic sleeve Gastrectomy (Sleeve) 
 
Sleeve gastrectomy achieves weight loss by reducing the stomach to about 25% of its 
original size.  A large portion of the stomach is removed along the greater curvature. The 
result is a sleeve or tube like structure. The pyloric valve at the bottom of the stomach is left 
intact which means that the stomach function and digestion are unaltered.  Surgical risks of 
Sleeve include leakage and vomiting due to damage to the vagus nerve.  Registry data to 2 
years shows that after Sleeve patients experience gradual weight loss over the first 12 
months, which tends to plateau thereafter [12]. Weight loss in the first year after Sleeve is 
associated with improvements in HRQOL [22], but medium and long term HRQOL data are 
lacking. 
 
2.3 
Systematic review evidence  
 
Evidence for the different types of surgery for severe and complex obesity (and comparison 
with non-surgical treatment) was summarised in an HTA systematic review [9], which has 
recently been updated [23]. Of the 22 randomised controlled trials (RCTs) in the updated 
review, fifteen compared different types of bariatric surgery, three comparing Band with 
Bypass, six comparing Bypass with Sleeve, and one is comparing Band with Sleeve.  
 
The three trials comparing Band and Bypass were all single centre studies conducted 
outside the UK.  The Italian trial included 51 participants, excluded some after 

 
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randomisation, did not perform analyses by ‘intention- to treat’, did not blind outcome 
assessors and did not assess HRQOL [24]. The second US-based study randomised 250 
patients [25]. Patients, however, were differentially excluded after randomisation creating 
imbalance in the numbers in each group and an imbalance in key patient characteristics at 
baseline (age and BMI) and the analysis was not by ‘intention-to-treat’. The generation of the 
allocation sequence was unclear; there was incomplete outcome data in the two groups at 
follow up and no details of the number of participants completing HRQOL questionnaires 
were presented. The third trial, conducted in Egypt, randomised 34 patients and did not 
assess HRQOL [26]. The evidence of the effectiveness of Band and Bypass is therefore 
inadequate with just three single centre trials that have an uncertain risk of bias and an 
inadequate HRQOL analysis.  
 
The six trials comparing Bypass and Sleeve were all conducted outside the UK and had 
relatively small sample sizes ranging from 15 to 217 patients.  Except for the largest trial 
conducted in four centres in Switzerland, all were single centre studies.  The Swiss trial was 
at high risk of bias as the outcomes reported were from an interim analysis that did not 
include all patients randomised [27]. The other trials also have methodological weaknesses 
due to risk of bias, they are underpowered with optimistic effect sizes and many have short 
term primary outcomes (12 months). 
 
The one trial to compare Band and Sleeve was conducted in a single centre in Belgium.  
Eighty patients were recruited and at 3-years there was a significantly greater weight loss 
with Sleeve compared to Band (mean 29.5kg vs. 17kg).  However, the study has uncertain 
risk of bias and HRQOL was not assessed.  
 
Bariatric surgical practice continues to be based on the preferences of local commissioners, 
surgeons and patients. The need for a well-designed RCT of Band, Bypass and Sleeve, with 
clinically relevant comparisons, measures of generic and disease specific HRQOL, cost 
effectiveness evaluations and at least medium term follow up and documentation of longer 
term adverse events remains. 
 
This need was highlighted in both the original and updated HTA systematic reviews, but it 
was also stated in the original review that a trial may be too difficult to conduct and recruit 
into because of strong preferences amongst surgeons that influence patient selection for 
surgery [9]. This RCT will therefore compare Band versus Bypass versus Sleeve in three 
phases; the first phase (Band versus Bypass only) will establish optimal methods to recruit 
into the trial and ensure that the main trial is feasible. The second and third phases, which 
will include Sleeve as a third group, will continue recruitment in multiple centres.  
 
 

 
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3. 
Aims and objectives 
 
The By-Band-Sleeve study will compare the effectiveness, cost-effectiveness and 
acceptability of Band versus Bypass versus Sleeve surgery for treatment of severe and 
complex obesity.  
 
We will test the following joint hypotheses: 
 
i) Bypass is non-inferior to Band with respect to excess weight loss of more than 50% at 
three years and that Bypass is superior to Band with respect to HRQOL at three years.  
 
ii) Sleeve is non-inferior to Band with respect to excess weight loss of more than 50% at 
three years and that Sleeve is superior to Band with respect to HRQOL at three years.  
 
iii) Sleeve is non-inferior to Bypass with respect to excess weight loss of more than 50% at 
three years and that Sleeve is superior to Bypass with respect to HRQOL at three years.  
 
In the primary analysis both outcomes will be considered collectively, i.e. both hypotheses 
must be supported to conclude that Bypass is more effective than Band, or that Sleeve is 
more effective than Band or Sleeve is more effective than Bypass.  
 
Specific objectives are to estimate: 
 
A. The difference between groups in the proportion of patients achieving >50% excess 
weight loss at three years; 
 
B. The difference between groups in their average EQ-5D-5L health state score at three 
years;  
 
C. The difference between groups with respect to a range of secondary outcomes including 
generic, disease specific and gastro-intestinal symptom specific measures of HRQOL, 
adverse events, and resolution of co-morbidities; to explore, in a sub-sample, patients’ 
experiences of management, outcome and eating behaviour change. 
 
D. The cost effectiveness of Band, Bypass and Sleeve. 
 
The objective of the “metabolomics sub-study” is to assess the impact of weight loss and 
weight loss surgery on the metabolome.  
 
 
 
 

 
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4. 
Plan of Investigation 
 
4.1 
 Study design 
 
By-Band-Sleeve is a pragmatic RCT with three phases. Phase 1 will establish the feasibility 
of the trial by undertaking the RCT of Band versus Bypass (By-Band) in two centres. During 
this time a core outcome set for bariatric surgery will be developed. At the end of phase 1, 
the progression criteria for undertaking a main trial will be reviewed and discussed with the 
Trial Steering Committee (TSC) and the funder, NIHR-HTA. This will include a review of the 
current practice and evidence for sleeve gastrectomy to determine whether in phase 2 the 
trial should be adapted to include Sleeve. If appropriate and there is agreement the full trial 
will proceed. Phase 2 is a multi-centre RCT. At the end of phase 2, progression criteria for 
continuing with a three-group trial will be reviewed and discussed with the TSC and the 
NIHR-HTA. If appropriate and there is agreement phase 3 will proceed unchanged,  
 
Phase 1:  This will take place in two centres, integrating qualitative research to establish 
optimum methods of recruitment and informed consent. A core outcome set for measuring 
adverse outcomes and benefits of severe and complex obesity surgery will be developed.  
 
Phase 2:  This will extend recruitment to ten additional centres, using the optimum methods 
of recruitment established in phase 1. Participants will be followed up for at least three years. 
 
Phase 3:  This will continue recruitment in the twelve centres. Participants will be followed 
up for at least three years. 
 
“Metabolomics sub-study”: once recruitment to the trial is complete and all trial participants 
are in follow-up (or earlier if recruitment is going well and the study management group 
agree), eligible patients referred for surgery who do not join the trial will be invited to join the 
“metabolomics sub-study”. These participants will be offered the usual treatment at their 
hospital with follow up care as standard. In addition, as part of the “metabolomics sub-study” 
these participants will be followed up for one year after their operation.  
 
The overall schema for the trial is detailed overleaf.  
 
 

 
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4.2 
Trial schema 
 
In Phase 1 a core set of adverse and beneficial outcomes of obesity surgery will be 
developed. 
Eligible for By-Band (60%) 
Randomised to: 
63 Bypass 
63 Band 
All patients referred for bariatric surgery (100%) 
Eligible for By-Band-Sleeve (60%) 
Not eligible, 40%, 
n=248 
Randomised to: 
384 Bypass 
All patients referred for bariatric surgery (100%) 
Phase 1, 2 and 3 participants (126 + 1215) 
followed up after surgery, n= 1341 
85% followed to primary outcome, 
n=1140 in primary analyses at 3 
years 
384 Band 
n= 620 
Phase 1: By-Band, in 2 centres (24 months) 
Phases 2 and 3: By-Band-Sleeve, in 12 centres (48 months) 
447 Sleeve 
n= 372 
Not recruited; 70% in 
first 18 months, 50% 
thereafter, n=246 
n= 126 (80 +46) 
n= 5727 (staggered 
start of recruitment of 
new centres)   
Not eligible, 40%, 
n=2291 
Not recruited:  
50% in Phase 1 centres,  
80% in new centres for 
12 months and 55% 
thereafter, n=2087  
n= 3436 
 
Potential n= 1349 
n= 1262 needed  

 
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4.3 
Trial population 
 
4.3.1 Eligibility criteria - participating centres  
 
All centres will be NHS Trusts, with surgical units carrying out at least 50 bariatric surgery 
operations per year. Participating surgeons will work within a specialist multi-disciplinary 
bariatric team with at least two surgeons. All centres will have carried out a minimum of 200 
Band, 250 Bypass and 200 Sleeve procedures before entering patients into the trial. Phase 
1 will take place in two UK centres (Taunton and Southampton). In Phase 2 recruitment will 
be extended to include a further ten centres (total twelve centres).  
 
4.3.2 Eligibility criteria - participating surgeons 
 
Participating surgeons will have performed more than 100 laparoscopic Bypass procedures,  
more than 50 laparoscopic Band procedures and more than 50 laparoscopic Sleeve 
procedures for severe and complex obesity. With the agreement of the Chief Investigator 
and study team, a surgeon with experience in some but not all three procedures may be 
permitted to participate, but the number of operations this surgeon may contribute will be 
capped and closely monitored.  All other participating surgeons at the centre must have the 
pre-requisite experience in all three surgical procedures and be willing to carry out all three 
procedures within the trial according to the randomised allocation.  
 
4.3.3 Eligibility criteria – patients 
 
All patients referred for bariatric surgery will form the target population. Each site will 
maintain a trial screening log. This will record the details of patients who are or are not 
screened for trial entry, reasons for ineligibility and it will record details of eligible participants 
who do not consent for participation (and reasons for this choice). 
 
This information will be reviewed on a monthly basis to provide feedback to recruiters and it 
will help in understanding surgeons’ and patients’ preferences for types of surgery. It will 
also allow the trial results to be reported in accordance with CONSORT guidelines.  
 
Eligible patients will be informed about the trial and given the patient information leaflet (PIL) 
and an appointment for a ‘recruitment consultation.’  At that consultation they will be given 
the opportunity to ask questions about the trial and treatments, and asked to give written 
informed consent to the trial.  These consultations will be routinely audio-recorded and 
available for qualitative investigation. 
 
Inclusion criteria 
 
Participants may enter study if ALL of the following apply 
 
1. Male or female patients 
2. Over 18 years of age 
3. Referred for bariatric surgery according to NICE guidelines - BMI of 40kg/m2  or more, 
OR BMI of 35 kg/m2 to 40 kg/m2 and other significant disease (e.g. type 2 diabetes or 
high blood pressure) OR BMI of 30 kg/m2 or more and recent onset diabetes OR 
Asian family origin with lower BMI and recent onset diabetes, that could improve with 
weight loss 
4. Has been or is willing to receive intensive management in a specialist tier 3 obesity 
service 
5. Fit for anaesthesia and surgery 
6. Committed to follow-up and able to complete quality of life questionnaires 
7. Able to provide written informed consent. 

 
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Exclusion criteria 
 
Participants may not enter study if ANY of the following apply (assessed by patient history 
and clinical examination) 
 
1. Previous gastric surgery or surgery for severe and complex obesity 
2. Previous abdominal surgery or gastro-intestinal (GI) condition that precludes one or 
more of Band, Bypass or Sleeve  
3. Large abdominal ventral hernia 
4. Pregnancy (women who have given birth and women planning pregnancy will NOT 
be excluded) 
5. Crohn’s disease 
6. Liver cirrhosis and portal hypertension 
7. Systemic lupus erythematosis 
8. Known silicone allergy 
9. Hiatus hernia >5cm 
10. Other clinical/psychological reason, to be specified 
11. Active participation in another interventional research study which might interfere with 
By-Band-Sleeve 
 
4.4 
Trial interventions  
 
Participants will be listed for surgery optimally within 2 weeks. The time between 
randomisation and surgery will be recorded and it is recommended that this is less than 10 
weeks. 
 
For the purposes of this pragmatic trial the operations are to be carried out in accordance 
with the protocol. This protocol classifies each component of the surgery, and the 
concomitant interventions as mandatory, optional or prohibited. Where surgeons do not 
undertake mandated components of the surgery or the concomitant interventions, and, when 
they perform prohibited ones it will form a protocol deviation. Annual review of the individual 
surgeon adherence to these criteria will be conducted and confidential and team meetings 
will be organised to provide feedback. Fidelity to the mandated components of the surgical 
interventions (and prohibited components) will be monitored by completion of the operative 
case report forms.  
 
4.4.1 All three operations 
 
All three surgical procedures (Band, Bypass and Sleeve) will be carried out laparoscopically.   
The methods used to create a pneumoperitoneum, the placement of the laparoscopic ports, 
and retractors are at the discretion of the surgeon. The type of instruments used is also at 
the surgeon’s discretion. Undertaking a hiatal hernia (<5cm) repair and cholecystectomy are 
permitted but not compulsory. An apronectomy is prohibited at the time of surgery. 
Placement of drains is optional.   
 
4.4.2 Laparoscopic adjustable gastric banding (Band surgery) 
 
The type and size of adjustable gastric band is at the discretion of the surgeon. It is 
mandatory to i) dissect the lesser curve using the ‘Pars flaccida’ technique, ii) to fix the Band 
(any fixation method is allowed) and iii) to fix the adjustable port to the anterior abdominal 
wall.  
 

 
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4.4.3 Laparoscopic gastric bypass surgery (Bypass surgery) 
 
Methods used to create the biliary and gastric limbs are flexible, although upper limits of 
75cm and 150 cm are recommended for the biliary and gastric limbs respectively. Routing of 
the Roux limb (antecolic or retrocolic) is flexible. The pouch can be created according to the 
surgeon’s usual practice, except that a horizontal gastric pouch that includes fundus is 
prohibited. Use of a bougie is optional.  Anastomoses can be performed as the surgeon 
chooses (e.g. stapled or sutured, single or double layer).  Closure of iatrogenic mesenteric 
defects is mandatory. Testing integrity of the anastomoses is optional. 
 
4.4.4 Laparoscopic sleeve gastrectomy surgery (Sleeve surgery) 
 
It is mandated to visualise the left crus after dissection of the fundus. The type of bougie 
used is flexible although should be between 30 and 40Fr. The type of stapler used is flexible 
and the use of additional sutures, clips, reinforcement of the staple line is at the discretion of 
the surgeon. Testing the integrity of the staple line is optional. 
 
4.4.5 Concomitant interventions 
 
Procedures will be carried out under general anaesthesia. All patients will receive peri-
operative antibiotics and thromboprophylaxis in accordance with local policy. The use of 
nasogastric tubes, central and arterial lines, and urinary catheters is optional. After surgery,  
oral intake will be commenced according to local policy. The day of discharge will be chosen 
at the surgeon’s discretion. The use of post-operative contrast swallows is optional. 
 
4.5 
Primary and secondary outcomes 
 
4.5.1 Primary outcome 
 
There are two primary endpoints:  
 
i) 
the proportion achieving loss of greater than 50% of excess weight at three years 
(calculated as 100×[BMI at 3 years – BMI at randomisation1] / [BMI at randomisation 
– 25]) 
ii) 
HRQOL at three years (EQ-5D-5Lhealth state score) 
 
1 Calculated using the participant weight recorded at baseline, after consent and before randomisation  
 
Procedures for measuring height and weight are described in section 5.2 
 
4.5.2 Secondary outcomes 
 
These will include: 
 
• 
Change in BMI over time adjusted for BMI at randomisation 
 
• 
% weight loss at 3 years  
 
• 
Waist circumference at 3 years 
 
• 
Time taken from randomisation to reach first loss of at least 50% of excess BMI 
 
• 
Time taken from first losing 50% excess BMI to first relapse (defined as weight re-
gain such that the target of at least 50% of excess weight loss is no longer met) 

 
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• 
Generic and symptom specific (i.e. obesity and GI specific) HRQOL: SF12, EQ5D, 
IWQOL-Lite, and GIQLI to three years 
 
• 
Resource use to three years 
 
• 
Standard NHS nutritional blood tests will be performed at each assessment including; 
full blood count, electrolytes, creatinine, glucose, HbA1c, liver function tests, iron, 
ferritin, vitamin B12, folate/red cell folate, lipid profile, 25-hydroxyvitamin D, calcium, 
parathyroid hormone 
 
• 
Measures of 24 hour recall eating using a standardised and validated interview 
process 
 
• 
Binge eating behaviour using a validated questionnaire 
 
• 
Adverse health events including the need for re-operation and cross over between 
interventions 
• 
 
• 
Resolution of co-morbidities at 3 years, including sleep apnoea, non alcoholic fatty 
liver disease, type-2 diabetes, hypertension and hyperlipidaemia 
 
• 
Time to resolution of sleep apnoea, type-2 diabetes, hypertension and 
hyperlipidaemia 
 
Details of methods used to define the above are described below (section 5.2). 
 
A fasting 20ml blood sample will also be taken at baseline and at 3 years post randomisation 
for future investigations.   
 
In the case of (non-randomised) bariatric patients taking part in the “metabolomics sub-
study”, a fasting 4ml blood sample will be taken at pre-surgery and at 1-year post surgery 
(and used to derive serum).  
 
These blood samples (serum/plasma/whole blood) will be transferred from each recruiting 
site to the University of Bristol for long-term storage and subsequent analysis (any useable 
sample not used for the “metabolomics sub-study” will be stored for future investigations). 
The trial manager/coordinator will organise an approved courier and liaise with the By-Band-
Sleeve lead research nurse from each centre to ensure that the samples are ready for 
collection on dry ice. Once the samples arrive at the University an email will be sent to the 
recruiting site confirming receipt. Sample logs will be kept at each recruiting site, and copies 
of these sample logs will be kept in Bristol. 
 
All samples will be used, stored and disposed of in accordance with the Human Tissue Act 
2004. 
 
4.6 
Sample size calculation  
 
We hypothesise that (a) Bypass/Sleeve/Sleeve will be non-inferior to Band/Band/Bypass in 
terms of the proportion of participants achieving an excess weight loss of at least 50% at 
three years, and that (b) the HRQOL at three years for participants receiving a 
Bypass/Sleeve/Sleeve will be superior to the HRQOL for participants with a 
Band/Band/Bypass, as measured using the EQ-5D-5L health state score. The sample size 
has been chosen to test both these hypotheses. Data from the literature [28, 29] and from a 

 
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registry of patients treated with Bypass or Band at the Taunton centre were used to inform 
the power calculation.  These estimates are unchanged for the adaptation to a three group 
trial.   
 
The expected proportion of participants losing at least 50% of their excess weight at three 
years was estimated from the Taunton registry; for the sub-group with a BMI at surgery of 
between 40 and 60 (the target weight range for trial participants), 73% of Band and 75% of 
Bypass patients had lost at least 50% of their excess weight at three years. The non-
inferiority margin was chosen on the basis of the opinions of the clinical applicants and 
patient representatives. The power calculation for hypothesis (a) requires the estimation of 
two parameters, i.e. the total proportion of participants that are expected to have lost at least 
50% of their excess weight at three years and the difference in proportions achieving this 
target that would be considered clinically important (the non-inferiority margin).  Table 1 
shows the sample size needed for a one-sided test of non-inferiority at the 2.5% level, for 
different parameter estimates and power. 
 
The power calculation for hypothesis (b) requires the estimation of six parameters, i.e. the 
within group standard deviation, the difference in mean HRQOL that would be considered 
clinically important, the number of pre and post randomisation measures, and the 
correlations between pre and post randomisation scores and between repeated post 
randomisation scores.  The estimates used were chosen on the basis of the published 
literature [30, 31] and, in order to estimate correlations between different time points, on data 
from a surgical trial in spine injury. Table 2 shows the sample size needed for a 2-sided test 
of superiority at the 5% level, for different parameter estimates and power. 
 
 
Table 1  
Proportion achieving 50% excess weight loss   
 
Overall, proportion achieving 
50% excess weight loss 
Smallest difference considered 
clinically important (margin) 
Sample size (total) 
90% power 
80% power 
0.75 
0.12 
548 
410 
0.70 
0.15 
394 
294 
0.70 
0.12 
614 
458 
0.70 
0.10 
884 
660 
0.65 
0.12 
666 
498 
 
 
Table 2  
EQ-5D score 
 
Correlation 
between pre & 
post-surgery 
measures 
Correlation 
between post-
surgery repeated 
measures 
No. of post 
surgery 
measures 
Effect 
size 
Mean 
difference in 
EQ5D state 
score 
SD 
Sample size (total) 
Power 
90% 
80% 
0.5 
0.65 
3 
0.2 
0.06 
0.3 
544 
406 
0.5 
0.70 
3 
0.2 
0.06 
0.3 
578 
432 
0.5 
0.75 
3 
0.2 
0.06 
0.3 
614 
458 
0.5 
n/a 
1 
0.2 
0.06 
0.3 
790 
590 
 
 
The study size for a two group trial (Band versus Bypass) has been set at 614; which 
allowing for a 15% dropout at three years gives a target sample size of 724.  Adapting the 
trial to include a third group, Sleeve, increases the sample size to 1140 (adjusting the 
significance levels from the conventional 2.5% and 5% levels for non-inferiority and 
superiority to 1% and 2% respectively to account for the three hypotheses); which allowing 
for a 15% dropout at three years gives a target sample size of 1341 patients (447 per group). 
This will provide 90% power to test both hypotheses, assuming that 70% of patients will 

 
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have lost ≥50% of their excess weight at three years, that a difference of ≥12% between the 
groups would be clinically important and that a small effect size of 0.2 standard deviations in 
HRQOL would be clinically important. For the HRQOL score, a conservative estimate of the 
correlation between repeated measures has been assumed. The calculation based on three 
post-surgery measures assumes the treatment difference is similar at the three time points.  
However, it is anticipated that the difference in HRQOL may change over time. The 
calculation based on a single measure shows that the study will have 80% power to detect 
differences at individual time points. 
 
Metabolomics sub-study 
The target sample size for the “metabolomics sub-study” has been set at 500 (non-
randomised) patients receiving Band, Bypass or Sleeve surgery  The most recent analysis of 
the impact of bariatric surgery (specifically gastric bypass) on the metabolome was able to 
show changes in lipid, fatty acids and amino acids profiles after surgery in a study involving 
only 10 patients [32]. This study was not powered to comprehensively characterise the 
metabolomic consequences of bariatric surgery and weight loss but does serve to illustrate 
the scale of effects we expect to see.  Similarly, a range of small studies (10-100 
subjects) applying metabolomics to examine alterations in the metabolic profile according to 
weight gain/obesity have found evidence for alterations in amino acid and branched chain 
amino acid profiles associated with obesity [33].  Complementary analyses carried out in 
population cohorts have shown that even relatively subtle shifts in BMI over time are 
reflected in metabolic profile (<1500 individuals) [34].  
 
 

 
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5. 
Trial methods 
 
5.1 
Description of randomisation  
 
Randomisation will be carried out after trial eligibility has been confirmed and consent given, 
usually within 2 weeks of recruitment. Patients will be informed about their randomisation 
arm after they have agreed and consented to participate in the trial. This will allow patients 
time to make arrangements for support at home after discharge from hospital (which is 
different between the three procedures) and it will allow surgeons time to efficiently plan an 
operating list (because of the time difference required in theatre for each procedure). 
Randomisation will be performed by an authorised member of the local research team using 
a secure internet-based randomisation system ensuring allocation concealment. Patients will 
be allocated 1:1 to Band or Bypass in phase 1.  In phases 2 and 3 patients will be allocated 
1:1:1.16 (adjusted to give a 1:1:1 allocation ratio at the end of the trial) into the following 
treatment strategies:  
 
i) 
adjustable gastric banding (Band surgery) with follow up appointments (in the first 
24 post-surgical months) to include follow up at 4 weeks, 3, 6, 9, 12 and 24 months 
(expected to be up to 10 appointments) and annual follow up thereafter.  Research 
data collection will not be required at the 3 and 9 months visit. 
 
ii) 
gastric bypass (Bypass surgery) with standard 4 week, 3, 6, 9 and 12 month follow 
up and annual follow up thereafter.  Research data collection will not be required at 
the 3 and 9 month visits. 
 
iii) 
sleeve gastrectomy (Sleeve surgery) with standard 4 week, 3, 6, 9 and 12 month 
follow up and annual follow up thereafter.  Research data collection will not be 
required at the 3 and 9 month visits. 
 
Allocation will be computer-generated. Cohort minimisation (with a random element 
incorporated) will be used to ensure balance across the groups, by diabetes status (any 
type/none), and BMI more than 50 (yes/no). Allocation will also be stratified by centre. Other 
baseline data to be assessed will include socio-demographic information and prior weight 
loss methods attempted. 
 
5.2 
Research procedures 
 
5.2.1 Measurement of weight and height 
 
At randomisation, on the day of surgery and at each study visit, participants’ weight in 
kilograms (kg) will be measured on calibrated electronic clinic scales.  Participants will be 
weighed fully clothed after removal of shoes. Participants will stand with weight evenly 
balanced on both feet and they will be asked to remove jackets and heavy items from 
pockets. The arms should hang loosely at the sides. Participants’ heaviest weight ever (both 
self-reported and heaviest recorded in the participants’ medical records) will also be 
collected.  
 
At randomisation participants’ height in centimetres (cm) will be measured after removal of 
shoes with a calibrated stadiometer.  
 
In the case of the “metabolomics sub-study”, participant weight and height will be measured 
at consent, and weight will be measured pre-surgery (pre-operative assessment or on the 
day of surgery and one year after surgery. 
 

 
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5.2.2 Assessment of patient reported outcomes 
 
Questionnaires administered at baseline before randomisation will be given to patients to 
complete themselves when they attend hospital (see Table 3 for details). Participants may 
elect to complete the questionnaires at home and return them by post in a stamp-addressed 
envelope which will be provided. Questionnaires completed after randomisation will be 
posted to participants by the coordinating centre (Bristol Clinical Trials and Evaluation Unit, 
CTEU) to ensure that the follow-up time points are met. If the questionnaires are not 
returned within 3 weeks, participants will be contacted by letter, telephone, email or standard 
message service (SMS) text as preferred (if appropriate the questionnaires can be read to 
the participant over the telephone or a second set posted for completion). Recruiting sites 
can also administer questionnaires during a follow up visit if the participant has not already 
completed and returned their questionnaires. An option to log in to a secure web-site and 
complete the questionnaires on-line will also be provided. A 24 hour recall eating 
assessment will be measured by the research nurses (trained by JT) using repeat 24-hour 
recalls at baseline and single 24-hour recalls at the 6, 12, 24 and 36 month follow-up 
assessments.  
 
Reasons for the non-completion of questionnaires will be recorded. Missing or erroneous 
items on questionnaire measures will be handled according to the questionnaire developers’ 
scoring manuals. Reasons for withdrawal from the study, loss to follow up or death (and 
cause of death) will be recorded.  
 
Patient reported outcome measures 
 
The SF12 and the EQ-5D-5L will assess generic aspects of health and the EQ-5D-5L data 
will be used in the analysis of QALYs [35]. A validated obesity specific measure, the Impact 
of Weight of Quality of Life-Lite (IWQOL-Lite) will assess HRQOL issues perceived by 
patients that are related to their weight including physical function, self-esteem, sexual life, 
public distress and work [36, 37]. The IWQOL-Lite is a 31 item self-completed questionnaire 
developed directly from commonly expressed concerns of obese patients as well as from 
clinicians’ experience.  It has five quality of life scales: physical function (11 items), self-
esteem (7 items), sexual life (4 items), public distress (5 items) and work (4 items).  
Respondents are asked to rate their experiences for the previous week.  Each item has five 
options for response and is scored from 1 (“never true”) to 5 (“always true”), hence a higher 
score is less favourable.  An increase in score of 8 to 12 points has been shown to indicate a 
meaningful change in score using anchor-based and distribution-based methods from weight 
loss studies that have employed the questionnaire [36, 37].  
 
A gastro intestinal specific measure, the GIQLI (Gastrointestinal Quality of Life Index, 36 
items), will assess the impact of specific symptoms associated with bariatric surgery and 
obesity [38]. This measure captures the impact of symptom-specific gastrointestinal 
disorders on a patient’s quality of life. There are four gastrointestinal symptom scales and 
three generic scales (physical, social and emotional function).  Each item is scored on a five 
point scale (0-4) to denote the burden of the specific symptom; a lower score indicates more 
burden (less favourable).  The majority of items ask about frequency of occurrences from the 
previous two weeks.  
 
The Hospital Anxiety and Depression Scale (HADS) will be used to assess the participant’s 
levels of anxiety and depression [39]. The HADS is a 14 item scale; 7 of the items relate to 
anxiety and 7 relate to depression.  Each item on the questionnaire is scored from 0-3 giving 
a total score between 0 and 21 for either anxiety or depression. A score of 8/21 or more 
indicates anxiety or depression [40]. 
 
 

 
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5.2.3 Assessment of co-morbidities 
 
Sleep apnoea 
 
The STOPBANG questionnaire and Epworth Sleepiness Scale will be completed at baseline. 
The Epworth Sleepiness Scale, but not STOPBANG, will be completed at each research 
follow-up appointment (see Table 3) [41].  Patients will be selected for sleep studies on the 
basis of history or a score of 5 or more using the STOPBANG questionnaire [41]. A variety of 
techniques for further investigating sleep apnoea are currently available and used in clinical 
and research practice, although there is no gold standard clinical modality. 
Polysomnography is the gold standard for research purposes, and currently used techniques 
range from video plus pulse oximetry plus recording snoring, which generally requires an 
overnight stay in hospital, to simple pulse oximetry alone that can be performed at home. 
  
Overnight pulse oximetry, where a pulse oximeter and recorder are attached during a period 
of sleep is the minimum investigation required for patients in the By-Band-Sleeve study 
being investigated for sleep apnoea. However, if patients are symptomatic for sleep apnoea 
and pulse oximetry is negative, then further specialist assessment in a sleep clinic is 
required. 
 
Resolution of obstructive sleep apnoea: remission will be confirmed after repetition of sleep 
studies. Participants with sleep apnoea at recruitment will be invited to undergo a repeat 
sleep study at 3 years. The standard definition is less than 5 apnoea episodes per hour as 
assessed by polysomnography (sleep study). 
 
Non-alcoholic fatty liver disease 
 
A non-invasive assessment will be performed at baseline and at three years (timing of the 
primary end point) with the enhanced liver fibrosis test (ELF). This is an algorithm that 
combines age, hyaluronic acid (HA), amino terminal peptide of procollagen type III (PIIINP) 
and tissue inhibitor of matrix metalloproteinase (TIMP-1) [42].   
 
Type-2 diabetes 
 
Remission of diabetes will be defined by criteria set out from a consensus meeting in 
Diabetes Care for remission after surgery [43] and HbA1c, fasting glucose and number of 
diabetes medications taken will be recorded at follow up appointments. Remission is defined 
as achieving glycaemia below the diabetic range in the absence of active pharmacologic 
(anti-hyperglycaemic medications, immunosuppressive medications) or surgical (ongoing 
procedures such as repeated replacements of endoluminal devices) therapy.  A remission 
can be characterized as partial or complete.  Partial remission is sub-diabetic 
hyperglycaemia (A1c not diagnostic of diabetes [<6.5%], fasting glucose 100–125 mg/dl 
[5.6–6.9 mmol/l]) of at least 1 year's duration in the absence of active pharmacologic therapy 
or ongoing procedures.  Complete remission is a return to “normal” measures of glucose 
metabolism (A1c) in the normal range, fasting glucose<100 mg/dl [5.6 > mmol/l]) of at least 1 
year's duration in the absence of active pharmacologic therapy or ongoing procedures. 
 
Hypertension 
 
Remission will be based on the international definition described in the metabolic syndrome, 
systolic blood pressure < 130mmHg and diastolic < 85 mmHg without treatment. 
 
 
 

 
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Hyperlipidaemia 
 
Standard remission of hyperlipidaemia will be defined as total cholesterol ≤5.0 mmol without 
cholesterol lowering treatments.  
 
5.2.4 Measurement of waist circumference 
 
This will be performed with outer layers of clothing removed. The researcher will be 
positioned to the right of the participant and will locate the right ilium. Just above the 
uppermost lateral border of the right ilium, a piece of tape1 is placed and then crossed with a 
vertical mark on the mid-axillary line. The researcher places the measuring tape around the 
trunk at the level of the mark on the right side, and then inspects all sides to make sure the 
measuring tape is at a level horizontal plane. The tape is then tightened slightly, but without 
compressing the skin and underlying subcutaneous tissues. The measure is made at 
minimal respiration and is recorded to the nearest millimetre (0.1cm) asking the participant to 
look straight ahead, be relaxed, and not to pull the tummy in. 
 
The waist circumference (to the nearest 0.1 cm) will be recorded twice. If the measures differ 
by more than 0.5 cm, the technique will be checked and a third and fourth measurement 
taken. All readings will be recorded. 
 
5.2.5 Metabolomic profiling  
 
Serum derived from blood samples collected at baseline and three-years (a sample of the 
By-Band-Sleeve randomised cohort) or pre-surgery and at one-year (the “metabolomics sub 
study” cohort) will be used to assess changes in the metabolome. Metabolite data will be 
collected using two complementary approaches: (i) Quantitative 1H-NMR analysis delivered 
via the Brainshake platform delivered by the University of Bristol in collaboration with 
Professor Mika Ala-Korpela, Univeristy of Oulu, Finland; (ii) The mass spectrometry-based 
Discovery HD4TM platform delivered by Metabolon, North Carolina, US.  
 
5.3 
Integrated qualitative research: recruitment 
 
The By-Band-Sleeve trial compares three different surgical procedures that are in common 
use, and is likely to face a number of recruitment challenges. Based on previous work by 
Donovan et al [44], By-Band-Sleeve will include an integrated qualitative study (IQS) in two 
phases: 
 
5.3.1 Phase I 
 
The aim of the IQS is to work with RCT staff to understand the recruitment process in the 
early stages, so that any difficulties related to design or conduct can be raised and changes 
put in place.  The IQS will also be used to determine any staff training that needs to be 
developed or feedback given to staff.  There are several distinct parts to Phase I that are 
intended to provide information about recruitment as it happens, and to provide the basis for 
the plan of action to improve it.  The parts listed below are not necessarily employed 
sequentially and some may not be required.  The ethnographic nature of the IQS means that 
the research moulds itself around the needs of the research and is completed when 
theoretical saturation is reached (that is, new data collection does not materially add to the 
findings). 
 
 
 

 
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Patient pathway through eligibility and recruitment 
 
A comprehensive process of logging of potential RCT participants through screening and 
eligibility phases will be used to monitor recruitment (see section 5.3 for further details).  The 
screening logs and flow charts will be assessed for complexity and compliance with the 
protocol as well as variation between centres.  They will provide data on the numbers of 
eligible patients and particular points where patients are ‘lost’ from the RCT.  They will also 
indicate levels of equipoise – as evidenced by the numbers rejecting participation in the RCT 
and the selection of particular treatments. Flow charts will indicate the degree of complexity 
of participation and any variations between centres.  
 
In-depth interviews and investigator meetings 
 
In-depth, semi-structured interviews will be conducted with three groups:  
 
(a) Members of the trial management group (TMG), including the chief investigator and 
those most closely involved in the design, management, leadership and coordination of 
the trial 
 
(b) Clinical and recruitment staff at the centres involved in the RCT 
 
(c) Participants eligible for recruitment to the RCT, including those who agree or decline to 
take part   
 
Interview topic guides will be used to ensure similar areas are covered in each interview 
within each group, based on those used in previous studies, but also encouraging the 
informants to express their own views about the RCT and any recruitment challenges 
expected or experienced. 
 
Informants in group (a) will be asked about the background, development and purpose of the 
RCT, including their knowledge of the evidence and equipoise; their role in the trial and 
recruitment, including their expectation of the pathway through eligibility and recruitment. 
They will also be asked to provide a short verbal summary of the RCT for the interviewer, as 
if s/he were a patient.   
 
Informants in group (b) who directly recruit to the trial will also be asked the questions about 
their knowledge of the evidence and personal views about equipoise; the recruitment 
pathway, how they feel the protocol fits their clinical setting and any adjustments they think 
are needed.  They will also be asked how they explain the RCT, the two interventions to 
patients, and the randomisation process. They will be asked to audio-record their 
appointments with patients, with a view to discussing any discomfort or perceived difficulty 
with this.   
 
Informants in group (c) will include those who have agreed to randomisation and those who 
have rejected it but are willing to discuss their views. The following will be explored: 
perspectives of living with severe and complex obesity, previous experiences with 
treatments, views about surgery, and the acceptability of randomisation between the 
procedures. Attempts will be made to obtain a variation sample that includes those who are 
male and female, younger/older, choosing band or bypass, and employed/unemployed.   
 
In the early stages of the feasibility/pilot phase 1 of the RCT the TMG and clinical 
investigators will meet several times.  The IQS team will ask to observe these meetings and 
to audio-record them with permission.  The IQS researchers will discuss the agenda with the 
chief investigator, with the aim of fostering discussion, particularly about issues of eligibility 

 
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and equipoise if these have emerged from the early findings.  The meetings will also be a 
forum to discuss the findings of the IQS, and to deliver training or advice about recruitment. 
 
Interviews and meetings will be audio-recorded and transcribed with consent.  Recordings 
may be transcribed verbatim whole or in selected parts, as necessary for comprehensive or 
targeted analysis.  Transcripts and notes will be analysed thematically by the IQS 
researcher, using techniques of constant comparison and case-study approaches. 
Interviews and meetings will provide data about: the perspectives of eligible patients, the 
evidence underlying the RCT, including the importance of the question and the commitment 
of staff to it, as well as individual clinical equipoise; the application of the protocol in clinical 
centres and any logistical issues; and suggestions about reasons for recruitment difficulties 
and potential solutions from those working closely within the RCT.   
 
Audio-recording of recruitment appointments 
 
The importance of audio recording discussions about RCT recruitment will be emphasised to 
the TMG, and methods of communicating this with recruiters will be explored.  It has been 
shown previously that recruiters tend to be unfamiliar with audio-recording and, even if they 
agree to it, often resist making successful recordings.  It will be emphasised that the 
feedback to them will be confidential and positive (not critical).  The TMG will be asked to 
discuss this with recruiters and attempt to identify a ‘recruitment appointment’ suitable for 
recording.   
 
One main point of contact (usually the lead research nurse) will be identified at each centre 
and digital audio-recorders will be provided; the number of recorders required for the RCT 
will depend on the number of actively recruiting staff in the centre and the logistics and 
geographic location of recruiters.  Recruitment staff will be requested to audio-record all 
appointments where they provide information to patients and attempt to recruit them to the 
RCT.  Documents explaining the ethical requirements of audio-recording of patient 
appointments (Patient and Recruiter Information Sheets and consent forms for audio-
recording) and Standard Operating Procedures (SOPs) to help with the operation of the 
recorder, dictation of patient/recruiter /recording identifiers, naming and transferring of the 
recording to the computer and then to the IQS team will be provided to centres in ‘Recruiter 
Packs’.   
 
Audio-recordings of appointments will be analysed as described above for interviews, with 
the addition of some of the techniques of focussed conversation analysis (CA) – pioneered 
in previous studies. CA techniques will be used to identify and document aspects of informed 
consent and information provision that is unclear, disrupted or hinders recruitment.  
Recordings will be listened to by the researcher and notes made about the content of the 
appointment.  An assessment will be made as to whether the appointment is recruiter- or 
participant-led, and also the degree to which there is evidence that the participant has 
understood the key issues of equipoise, randomisation, participation in the RCT, the option 
to choose their treatment, and the option to withdraw from the research at any time.  
 
The IQS researcher will document these details. When at least three recordings have been 
analysed, the IQS researcher and Principal Investigator (PI) will decide what confidential 
feedback will be given to the recruiter. Issues to be fed back to the RCT TMG, or to be used 
anonymously in training programmes will be discussed and defined. 
 
These data will form the basis for feedback to individuals and to determine the content of the 
information, and training programmes to be implemented in Phase II of the RCT.   
 
 
 

 
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Non-participant observation of staff-patient interactions 
 
While the routine audio-recording of all discussions about the trial will be promoted, non-
participant observation of a selection of these discussions will be carried out.  Appointments 
to be observed will be purposively selected to include a) discussions by recruiting staff such 
as surgeons and b) discussions by staff members such as dieticians, nurses and 
anaesthetists, who may not actively recruit patients to By-Band but whose roles involve 
providing important information about the two operations.  This will mean that some 
discussions may only be audio-recorded, some audio-recorded and observed and others 
only observed.  Observations of clinics such as the “one-stop” and pre-assessment clinics 
will be performed.  Non-participant observation will involve the qualitative researcher sitting 
in the room that the discussions take place and taking notes on the interaction without 
contributing to the discussion.  Prior to undertaking any observation, informed consent will 
be obtained from the patient and staff member involved.  The aim of the observations is to 
provide data in the form of extensive field notes that can be qualitatively analysed to inform 
the recruitment process. 
 
Evidence base 
 
The TMG will be asked for the main systematic reviews or published research evidence 
justifying the need for the RCT (this is also likely to be contained within the protocol and 
original research proposal).  They will be asked about any recent evidence that supports or 
threatens the RCT.  If, during the interviews and recorded appointments, it becomes clear 
that equipoise is an issue in the RCT or clinicians report other evidence as influential, this 
will be fed back to the TMG and it may be necessary to undertake a new literature review or 
to discuss the quality and reliability of the evidence identified.     
 
5.3.2 Phases II and III: Feedback to TMG  
 
The QRS researcher and PI will present summaries of anonymised findings emerging from 
phase I of the IQS to the RCT TMG, identifying any aspects of RCT design and conduct that 
could be hindering recruitment with the supporting evidence.  A plan of action to try to 
improve recruitment, if this proves necessary, will be agreed by the RCT TMG and IQS PI 
and team.  No activities will be undertaken by the IQS team without the prior approval of, 
and collaboration with, the RCT TMG.  
 
The plan for phases 2 and 3 of the RCT will be focussed on the issues emerging from the 
IQS of phase 1 of the RCT and how it has been applied in the two centres.  It is likely that 
some aspects will be generic, such as difficulties with the application of eligibility criteria or 
explaining randomisation.  The plan is likely to include some or all of: reconsideration of 
study information, advice about presenting the study, discussions about equipoise or 
evidence, issues with patient pathways, and logistical issues in particular centres.  These 
may be addressed by a new PIL, documents, changes to the protocol, or training for 
recruiters in the presentation of RCTs in general or the By-Band-Sleeve RCT.   
 
Numbers of eligible patients, and the percentages of these that are approached about the 
RCT, consent to be randomised and immediately accept or reject the allocation will be 
assessed before the plan of action is implemented, and regularly afterwards to check 
whether rates are improving.  Interviews with recruiters will ask about the acceptability of the 
IQS and any changes that occur. 
 
It is expected that the qualitative research will permit between 40% and 60% of eligible 
patients to be enrolled into the trial. See section 5.10 for projected recruitment figures with 
the integrated qualitative research. 

 
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5.4 
Integrated qualitative research: process evaluation 
 
The aims of the process evaluation are as follows: 
 
1. 
To describe and refine the intervention (if required), identify key components (of the 
surgical intervention and concomitant components) and context  
 
2. 
To establish which components (and/or their individual steps) are a) mandatory, b) 
optional and c) prohibited  
 
3. 
To establish the level of standardisation required for each component and set limits 
concerning fidelity and quality control.  
 
5.4.1 Phases I and II 
 
The process evaluation to be performed in the phase 1 (Band and Bypass) and phase 2 
(Band, Bypass and Sleeve) of the trial will be a mixed methods study comprising three parts: 
 
Non-participant observation in the operating theatre 
 
Non-participant observation of a purposively selected sample (n=10-20) of operations will be 
performed by one or two researchers to supplement and triangulate information obtained 
from a) video and audio recordings and b) interviews of surgeons and team members 
(below). Observations will focus on the surgical interventions, concomitant interventions 
occurring in the operating theatre, and also contextual factors (e.g. noise, interruptions, team 
working and communication). Observations will either be recorded by hand or using the 
Observer XT 10.5 PDA. Dual observation will increase the study validity and ensure that 
both clinical and non-clinical interactions will be recorded. Patients will provide written 
consent for the recording of their surgery. 
 
Video and audio recording of surgical procedures 
 
Digital video recordings of the operations will be performed using standard techniques. Data 
will be collected directly from the laparoscopy 'stack' already in routine use for the 
procedures. Recording will start from when the surgeon has placed the camera port and will 
end when the camera is removed after the procedure. Recordings will be stored in a secure 
USB hard drive and then transferred to a secure server held at the University of Bristol. 
These will be anonymised with study ID, patient initials and date of birth. Audio recordings 
will be made using a digital recorder and start at the beginning of the procedure (where the 
patient is anaesthetised and the equipment prepared and checked), continuing through all of 
the operation itself, including the end of the procedure, patient recovery and clearing up of 
the theatre and equipment, when the patient has left the operating theatre. 
 
Interviews with surgeons, anaesthetists and nurses 
 
A purposefully selected sample of surgeons and other team members (n=20-30) will be 
interviewed after the operation (within 3 days) and also 1-2 weeks later.  Interviews will be 
guided by a topic guide which will be a list of open-ended questions to ensure that all topics 
are covered in each interview but will be sufficiently flexible to enable topics of importance to 
the informant to emerge. The topic guide is likely to be adapted as interviews and analyses 
proceed but proposed topics include: 
 

 
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• 
Exploration of knowledge of the trial and trial protocol, the intervention and if/how 
they plan to modify it for the particular patient/disease state 
 
• 
Views of the impact of variations from the surgical (or anaesthetic) protocol 
 
• 
Reasons for advocating or not advocating surgery and any particular surgical 
approach 
 
• 
Questions about which parts of the operation and protocol are considered to be 
difficult and how patient factors influence this 
 
• 
Hospital, team or equipment factors that influence carrying out surgery and in what 
ways this may differ if they are training others to do the procedure 
 
• 
What advice surgeons give to patients about the surgical intervention in a trial (if any) 
 
• 
What they think are the most important elements of the surgical (or anaesthetic or 
nursing) intervention that influence outcomes (and how these might change in light of 
complications) 
 
• 
Self-reported expertise 
 
It is anticipated that the process evaluation will result in development of a manual, which will 
provide details of the surgical interventions, concomitant components and context as well as 
defining the mandatory, flexible and prohibited aspects of each of the components and/or 
steps.  The manual will be developed and designed in conjunction with the surgeons 
participating in By-Band-Sleeve. 
 
5.4.2 Phases II and III 
 
During Phases 2 and 3 of the trial, fidelity to the surgical interventions will be monitored by 
completion of the operative case report forms (see section 4.4).  
 
5.5 
Development of a core clinical outcome set for obesity surgery 
 
Systematic literature reviews will identify all the current reported clinical and patient reported 
outcomes of bariatric surgery (and their definitions) and the National Bariatric Surgery 
Registry will be included. Data from the qualitative interviews performed in this trial will 
identify additional potential outcomes of importance to surgeons and patients that are not 
identified from literature searches.  Delphi methodology surveying relevant health care 
professionals and patients will reduce the potential list to a shorter list of outcomes to be 
discussed at the consensus meetings. In the Delphi survey, stakeholders (professionals and 
patients) will be asked to rate the importance of inclusion of each potential outcome in the 
core outcome set and three rounds will be undertaken to reduce the list according to pre-
specified criteria. Each Delphi round will be analysed to identify key or redundant items from 
the list.  Two consensus meetings will be convened with key stakeholders. One will be with 
health professionals. The meeting will discuss the survey results and further anonymised 
rating of the importance of retained items. The other will be with patients. It is anticipated 
that 100 health professionals and 100 patients will participate in the Delphi survey.  
Participants will be asked if they wish to attend the meeting.  We anticipate that up to 30 
participants will attend the meeting, which will last between two and three hours and be held 
at the University of Bristol. This work will link with ‘COMET’ (http://www.comet-initiative.org/), 
funded by the MRC ConDuCT and North West Hubs for trials methodology research. The 
final core set of outcomes of bariatric surgery is expected to be less than 10 items.  

 
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5.6 
Duration of treatment period  
 
The surgical procedures last between 45 and 120 minutes. The hospital stay varies between 
one and three days, on average. The on-going band fills for patients randomised to Band 
surgery take place on 10 follow up visits in the first two years. 
 
5.7 
Definition of end of trial 
 
Each participant will have completed detailed follow up at the 36 months post randomisation 
assessment. The whole trial will have completed detailed follow up when the final 
randomised participant has reached the 36 months post randomisation assessment.  
Limited annual telephone follow-up (for weight and quality of life (EQ-5D) only) will continue 
to 96 months.  
 
Patients who consent to the “metabolomics sub-study”, will have completed follow up at 12 
months post-surgery.  The whole sub-study will have completed follow up when the final 
sub-study participant has reached the 12 months post-surgery assessment. 
 
5.8 
Data collection  
 
A unique file identified by the study number will be maintained for participants.  All data 
recorded on paper relating to the participant will be located in these files. A list will be 
maintained at each centre of staff with authorisation to make alteration to the study records, 
including the study database (see section 11.2 for information on the database architecture 
and data handling).  Data collection will include the following elements: 
 
(a) A screening log of all patients referred for bariatric surgery and those who are 
approached for the trial (including the date when they are given the PIL). 
  
(b) Patients approached and assessed against the eligibility criteria and, if ineligible, 
reasons for ineligibility. 
 
(c) Eligible patients approached and refused randomisation and reasons for this. 
 
(d) Consent and baseline information (e.g. history and planned operation and response 
to health status questionnaires) collected prior to randomisation in participating 
patients. 
 
(e) Anthropometric and nutritional data, participant responses to health status 
questionnaires, and co-morbidity assessment collected at follow-up as indicated in 
Table 3. 
 
(f) Audio-recording of consultations and interviews as outlined in section 5.3. 
   
 
 
 

 
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Table 3  
Data collection at the standard assessments (randomised participants) 
 
Measurement 
Pre          
randomisation 
         
Day of 
surgery 
4 
weeks 
post 
surgery 
Post randomisation 
Months 
6 
12 
24 
36 
Weight 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
Blood pressure 
X 
 
X 
X 
X 
X 
X 
Co-morbidities 
X 
 
 
 
 
 
 
Waist circumference 
X 
 
X 
X 
X 
X 
X 
Patient questionnaires 
 
 
 
 
 
 
 
    SF12 
X 
 
X 
X 
X 
X 
X 
    EQ-5D-5L 
X 
X+ 
X 
X 
X 
X 
X 
    IWQOL-Lite 
X 
 
X 
X 
X 
X 
X 
    GIQLI 
X 
 
X 
X 
X 
X 
X 
    HADS 
X 
 
X 
X 
X 
X 
X 
    Eating Habits 
X 
 
 
X 
X 
X 
X 
Resource use (including 
medications, use of medical services 
and other economic information)  
X 
 
X 
X 
X 
X 
X 
Nutritional blood tests *** 
   Full blood count 
   Electrolytes  
   Creatinine 
   Fasting glucose 
   Lipids 
   HbA1c 
   Liver function tests      
   Iron, ferritin, vitamin B12  
   Folate/red cell folate 
   Lipid profile  
   25-hydroxyvitamin D   
   Calcium  
   Parathyroid hormone  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
Blood sample for future research 
X 
 
 
 
 
 
X 
24 hour recall eating questionnaire 
X 
 
 
X 
X 
X 
X 
Other co-morbidity 
Sleep apnoea    
   STOPBANG 
Epworth sleepiness scale 
Non-alcoholic fatty liver disease**     
 
 
X 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
In-depth interviews* 
X 
 
X 
X 
X 
X 
X 
 
*undertaken in a purposeful sample of participants, **enhanced liver fibrosis test 
***for the assessment of co-morbidities, + posted to participants 2 weeks before surgery 
 
Table 4  
Data collection (metabolomics sub-study participants) 
 
Measurement 
Consent 
Day of 
surgery 
12 months post-
surgery 
 
Weight 
X 
X 
X 
 
Height 
X 
 
 
 
Co-morbidity (diabetes) 
X 
 
 
 
Blood sample  
 
X 
X 
 
 
 
5.9 
Source data 
 
The primary data source will be the participant’s medical notes. The laboratory reports will 
be the primary data source for the results of the blood analyses. The CRFs will be the 
source data for the resource use data and the completed patient questionnaires will be the 

 
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primary data source for these measures. The audio and video recordings will be the primary 
data source for the qualitative aspects of the study. 
 
5.10 
Planned recruitment rate 
 
Recruitment will be closely monitored throughout the trial. Expected numbers are shown in 
Table 5 below.   Recruitment of patients to the “metabolomics sub-study” will take place in 
those centres that decide to take part. 
 
 
Table 5  
Estimated recruitment rates, assuming 60% of patients undergoing 
bariatric surgery are eligible for the trial 
 
Phase 1 sites (PI) 
No. of 
referrals/yr 
No./yr if 
30% 
recruited 
No./yr if 
50% 
recruited 
No./yr if 
60% 
recruited 
Total no. if 30% of 
eligible patients 
recruited up to 18 
months & 50% 
thereafter 
Taunton (Welbourn) 
250 
45 
75 
90 
105 
Southampton (Byrne) 
60 
10 
18 
22 
25 
Phase 1 (2 yrs) 
620 
110 
186 
224 
130 
Phase 2 (2 yrs) 
620 
110 
186 
224 
186 
Phase 3 (2 yrs) 
620 
110 
186 
224 
186 
Phase 2 sites (PI) 
No. of 
referrals/yr 
No./yr if 
20% 
recruited 
No./yr if 
45% 
recruited 
No./yr if 
50% 
recruited 
Total no. if 20% of 
eligible patients 
recruited up to 12 
months & 45% 
thereafter 
Sunderland (Jennings) 
180 
21 
48 
54 
165 
Imperial (Ahmed) 
180 
21 
48 
54 
165 
Homerton (Agrawal) 
180 
21 
48 
54 
165 
Derby (Leeder) 
160 
19 
43 
48 
148 
Leeds (Hayden) 
130 
15 
35 
39 
120 
Birmingham (Singhal) 
130 
15 
35 
39 
120 
Truro (Finlay) 
80 
9 
21 
24 
72 
Bournemouth (Davies) 
80 
9 
21 
24 
72 
Portsmouth (Carter) 
120 
14 
32 
36 
110 
North Bristol Trust 
200 
24 
54 
60 
186 
10 new centres  
1440 
168 
385 
432 
 
Phase 2 (2 yrs) 
2880 
336 
770 
864 
553 
Phase 3 (2 yrs) 
2880 
336 
770 
864 
770 
Total in all centres in 
6 yrs 
7620 
 
 
 
 1825* 
 
 
* if recruiting for 4 years (target will be adjusted based on when a centre actually opens) 
 
 
5.11 
Participant recruitment 
 
Eligible patients referred for bariatric surgery will be invited to participate in By-Band-Sleeve.  
Potential trial participants will be identified from the multi-disciplinary team meetings and all 
surgical clinics.  All potential participants will be sent or given an invitation letter and PIL 
(approved by the local Research Ethics Committee (REC)) describing the study.  The patient 
will have time to read the PIL and to discuss their participation with others outside the 
research team (e.g. relatives or friends) if they wish.  Most patients will have at least 48 
hours to consider whether to participate.  Following a consultation with the surgical team, 

 
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patients will be asked if they wish to participate in the trial. If they remain uncertain they will 
be telephoned the following week to find out their decision and answer further questions that 
may have arisen. 
 
Patients who consent to the “metabolomics sub-study” will be asked to provide a blood 
sample before and one year after surgery.  
 
The baseline data will be collected at the pre-operative assessment clinic where consenting 
patients will be seen by an authorised member of the local research team (study 
clinician/research nurse/trial co-ordinator) who will answer any questions, confirm the 
patient’s eligibility and take written informed consent if the patient decides to participate.  
 
5.12 
Discontinuation/withdrawal of participants  
 
Each participant has the right to withdraw at any time.  In addition, the investigator may 
withdraw the participant from their allocated treatment arm if subsequent to randomisation a 
clinical reason for not performing the surgical intervention is discovered. If this occurs this 
will be documented.  
 
If a participant wishes to withdraw, data collected up until this point will be included in the 
analyses, unless the participant expresses a wish for their data to be destroyed. Withdrawing 
patients will be asked at this point if they can be contacted for an assessment of weight and 
HRQOL three years after surgery (the timing of the primary end point). 
 
5.13 
Frequency and duration of follow up 
 
Band patients will have band visits and adjustments in the first two years (expected to be up 
to 10 visits) and annual visits thereafter. Initial visits will be held at 4 weeks post-surgery, 
and follow up visits at 6, 12, 24 and 36 months post-randomisation will be standard. 
Additional visits will be scheduled to the participants’ requirements.   
 
Bypass and Sleeve patients will be seen at 4 weeks post-surgery, and at 6, 12, 24 and 36 
months post-randomisation and annually thereafter. At each visit the patients will be seen by 
the standard NHS bariatric team (depending upon the local centre practice).  
 
It is expected that follow-up visits will take place at the hospital.  However, if hospital visits 
are not practical either because the participant is unable/unwilling to attend hospital or the 
hospital policy is to limit hospital visits to essential visits for clinical care only (e.g. to 
minimise the risk of COVID-19 transmission) then visits may be conducted in the 
participant’s home (subject to appropriate risk assessment and local site approval).  Face-to-
face visits allow for the accurate collection of secondary outcomes (e.g. physical 
measurements, taking of blood samples), which are difficult to obtain remotely.   
Detailed data collection and active follow-up will continue to 36 months post-randomisation.  
Thereafter patients will be followed through the NHS Information Centre’s ‘Medical Research 
Information Service’ for mortality and patients will be contacted annually to 96 months post-
randomisation for information on their weight and quality of life. 
 
Active participation in the trial ends at 96 months post-randomisation  
 
For patients who take part in the “metabolomics sub-study” there will be one follow-up at 12 
months post-surgery. 
 
Funding to support follow-up beyond 3 years is being sought. 

 
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In light of the temporary pause in face to face patient consultations due to the Covid-19 
pandemic, and the uncertainty of when hospital visits might resume, we are giving centres 
the option of conducting home visits. Throughout the pandemic sites have continued to 
collect follow up data over the ‘phone. However, some of the outcomes cannot be collected 
as desired because nurses cannot take physical measurements such as weight, blood 
pressure, or blood samples for the assessment of key secondary outcomes and for future 
research. The pause in face to face hospital visits took effect in March 2020 and sites are uncertain 
when patients will be allowed to attend hospital appointments, and in some cases patients may not 
have the confidence to attend their appointment.  Having the option of carrying out home visits, 
sites will be able to collect our primary outcomes and the physical measurements which can only be 
taken in person. 
 
 
5.13.1 Band consultations 
 
Participants in the Band arm will undergo follow-up consultations according to a specific 
Band protocol. This will be performed by the trained research nurse or surgeon.  
 
The patient will be interviewed by the research nurse to assess the amount of food they are 
able to eat, their appetite and whether they feel satisfied between meals. If a fill is indicated, 
it will be carried out according the local protocol and the patient will be tested for restriction. 
If there is too much restriction, fluid is withdrawn. 
 
The band is filled progressively to reach the so-called 'sweet spot' of optimal restriction. Care 
is taken to try to avoid over-filling the band at any one time to avoid the disappointment of 
needing urgent band defill.  Occasionally the port may not be accessible in the clinic and the 
band fill may need to be done under X-Ray control, and where this occurs it will be 
separately documented.  However, fixing the port to the rectus sheath usually avoids this.   
 
5.14 
Likely rate of loss to follow-up 
 
Until discharge from hospital, the only losses to follow-up will be due to death or participant 
withdrawal; these losses are expected to be very few.  We expect loss to follow-up after 
discharge over the first three years to be less than 15%. 
 
5.15 
Expenses  
 
Participant travel expenses will not be reimbursed for the follow up visits which would be 
expected to occur as part of normal surgical follow up. Exceptions to these can be 
considered on a case by case basis.  Expenses will be available for research-specific visits 
that would not be expected to occur as part of normal surgical follow up. 
 
Trial participants will be sent or given a shopping voucher (maximum value £10) as a “thank 
you” for continuing to participate in follow-up. A voucher will be sent for the questionnaire 
booklet completed during follow-up at 12 and 36 months post randomisation. Funding for this 
has been sought separately.   
 
5.16 
Measures taken to avoid bias  
 
Concealed randomisation will protect against selection bias. Participants, clinicians and 
other hospital staff caring for participants and participants themselves will not be ‘blind’ to 
their allocation, because of the need for adjustment of gastric bands with injection of saline 
into the subcutaneous port after discharge for participants given Band.  

 
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Standard protocols for follow-up after all procedures will be used to minimise the risk of 
performance bias arising from carers differentially providing co-interventions. We will monitor 
adherence to protocols and explore views of staff and participants with in-depth interviews 
about the follow up.  We cannot prevent participants taking up co-interventions or adopting 
differential eating or other health behaviours contingent on their knowledge of their 
allocation. Indeed, such behaviours represent pragmatic aspects of the respective 
interventions since in routine practice patients will always know what operation they have 
had (although the uptake of various behaviours after completion of the trial might be 
modified by the findings of the trial). 
 
Self-completion HRQOL measures will inevitably be susceptible to bias although we believe 
that expectations about the effects of the different procedures prior to surgery are likely to 
wane with follow-up, so participants will not have strong differential expectations of the 
treatments after three years.  
 
We estimate up to 15% loss to follow-up. However, we aim to keep in touch with participants 
(through annual assessment; checking on change of address etc.), especially if a participant 
misses an annual follow-up assessment and we will investigate the sensitivity of the primary 
analyses to attrition bias. 
 
To further minimise bias, outcome measures are defined as far as possible on the basis of 
objective criteria. Biochemical markers will be measured by an independent laboratory 
technician at the local hospital, without knowledge of treatment allocation.  
 
The trial will be analysed on an intention-to-treat basis, i.e. outcomes will be analysed 
according to the treatment allocation, irrespective of future management and events, and 
every effort will be made to include all randomised participants.  Follow-up for the outcome 
measures during the participant’s stay in hospital should be complete for all participants.   
 
5.17 
Criteria for the termination of the trial 
 
The trial may be terminated early on the instruction of the DMSC or if the results of another 
study supersede the necessity for completion of this study. 
 
5.18 
Economic issues 
 
The economic evaluation will follow established guidelines [45, 46].  The main outcome 
measure will be quality adjusted life years (QALYs) using EQ-5D-5L[43], to be administered 
at baseline, before surgery, 4 weeks after surgery, 6,12, 24 and 36 months post-
randomisation.  Respondents will be assigned valuations derived from published UK 
population tariffs [47] and the mean number of QALYs per trial arm and incremental QALYs 
will be calculated.  Data on percentage weight loss will act as an additional outcome 
measure. Data will be collected from the trial centres on health care resource use for 
surgery, follow-up appointments and treatments for any side effects. The costs for short term 
surgical complications such as peri-operative injury to adjacent organs and early post-
operative morbidities such as staple leak or bleed will be estimated.  Longer term 
complications such as wound hernias, or the need for re-intervention or for cosmetic plastic 
surgery will also be costed.   
 
Resource use will be measured in naturally occurring units; for example, staff time will be 
measured in terms of length of times for treatments and unit costs will be derived from 
nationally published sources where available and from trial centres.  Collection of these 
details will allow micro-costing of the two surgical strategies. This is important information 
that we have identified as lacking, which can feed into NHS tariffs. Costs for contact with 

 
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additional health care professionals as a result of surgery such as GP visits will be 
estimated.  
 
The analysis will calculate the average cost and outcome on a per patient basis and, from 
this the incremental cost-effectiveness ratios for the different trial arms will be derived, 
producing an incremental cost per QALY and cost per % weight loss achieved. Probabilistic 
sensitivity analysis will be used to demonstrate the impact of the variation around the key 
parameters in the analysis on the baseline cost-effectiveness results.  Results will be 
expressed in terms of a cost-effectiveness acceptability curve, which indicates the likelihood 
that the results fall below a given cost-effectiveness ceiling.   
 
Decision modelling will be used to explore longer terms costs and effects for at least 20 
years post-surgery. This will enable us to consider for instance longer term costs such as 
vitamin B12 replacement, calcium and vitamin D replacement for Bypass and follow-up for 
post gastric surgery bone disease. Also cost savings as a result of a potential reduction or 
resolution in co-morbidities (e.g. diabetes) will be explored.   
 
 
 

 
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6. 
Statistical analyses 
 
6.1 
Analyses of quantitative data 
 
The analyses will be based on intention to treat and will include all randomised patients.  
Analyses will be adjusted for design factors included in the cohort minimisation.  The 
proportion of patients with at least 50% excess weight loss at three years will be compared 
using logistic regression.  HRQOL scores (and other continuous outcomes measured at 
multiple time points) will be compared using a mixed regression model with baseline and 
post-surgery measures modelled jointly.  Changes in treatment effect with time will be 
assessed by adding a treatment by time interaction to the model and comparing models 
using a likelihood ratio test. Time to event outcomes will be compared using survival 
methods for interval censored data. Model fit will be assessed and alternative models and/or 
transformations (e.g. to induce normality) will be explored where appropriate. Frequencies of 
adverse events will be described. Treatment differences will be reported with 95% 
confidence intervals (CIs). A detailed analysis plan will be prepared during the feasibility 
phase 1. Interim analyses will be decided in discussion with the Data Monitoring and Safety 
Committee (DMSC).  There is no intention to compare any outcomes between groups after 
phase 1; the only analyses will be descriptive statistics to summarise recruitment to decide 
whether the trial satisfies the progression criteria.  
 
We will monitor the trial to ensure that each surgeon does approximately equal numbers of 
operations of each type. In this situation, in contrast to expertise-based randomisation where 
each surgeon only performs one type of operation (and hence forms a cluster), clustering by 
surgeon is less relevant to the sample size and is usually ignored (on the basis that 
intraclass correlation is negligible, personal communication Prof D Altman).  However, we 
will take the data structure into account, i.e. nesting of patients by surgeon and centre, in the 
primary analyses. 
 
6.2 
Analyses of qualitative data 
 
In-depth interviews and recruitment appointments will be audio-recorded.  Interviews will be 
fully transcribed, and the data will be analysed using the methods of constant comparison to 
elicit themes that will be written up into descriptive accounts that will be shared with the 
study team [48].  In the recruitment study, the aspects of most interest will be issues of 
equipoise among surgeons/recruiters, and the acceptability of the procedures and the 
information provided to patients.  The data from recruitment appointments will be 
documented through summaries of the content, with thematic analyses of areas of the 
appointments where information is articulated by recruiters and interpreted by patients.  This 
will be supplemented by targeted conversation analysis focussing on areas of appointments 
where communication appears problematic [48].  Data will be transcribed as required, and 
then incorporated into training programmes and materials or used in individual confidential 
feedback for recruiters. In-depth interviews with a sample of trial participants in each arm will 
focus on experiences of management following surgery and outcome, and will be analysed 
thematically.    
 
For the process evaluation interview, audio and observational data will initially be coded 
separately, resulting in two separate coding frames. Relevant themes will then be 
considered together, with the interview data being used to confirm, challenge, or clarify the 
observation findings. The intention is to take an inductive approach to the data analysis, 
enabling theories to be derived from the data. Additionally, negative cases will actively be 
sought; patients, surgeons or other team members with contrasting views or attitudes, as 
this will help gain deeper understanding of the data. 
 

 
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It will be possible to synchronise video and observation recordings using the Observer XT 
10.5 software, as well as audio recordings, as all equipment can be activated 
simultaneously. 
 
6.3 
Subgroup analyses 
 
Two subgroup analyses are planned; outcomes will be described for patients i) with and 
without diabetes mellitus at baseline and ii) with a BMI < 40 and with a BMI ≥ 40 at baseline.  
Differences in treatment effect between the two subgroups will be tested by including 
interaction terms to the analysis model. These are secondary analyses as the study is not 
powered to detect subgroup differences. 
 
6.4 
Frequency of analyses 
 
The primary analysis will take place when follow-up is complete for all recruited participants.  
No formal interim analysis is planned.  Safety data will be reported to the DMSC at a 
frequency agreed with DMSC members, together with any additional analyses the committee 
request. 
 
6.5 
“Metabolomics sub-study” 
 
The Brainshake and Metabolon platforms will generate data on >200 and >800 metabolites 
respectively and therefore analytical approaches designed to reduce data dimensionality.. In 
the first instance, analysis of principal components describing the main variance in metabolic 
profile will be used to allow for the detailed description of the on and off-target biological 
events associated with bariatric surgery (both generally and specific to surgery type). In 
addition to this and explicitly concerning the impact of BMI change, there will be a 
comparison of metabolic profile before and one year post-surgery accounting for surgery 
type and pertinent co-variables. 
 
 

 
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7. 
Trial management 
 
The trial will be managed by the Clinical Trials and Evaluation Unit (CTEU Bristol) of the 
Bristol Heart Institute.  The CTEU Bristol is an UK Clinical Research Collaboration registered 
Clinical Trials Unit.  The CTEU Bristol will prepare all the trial documentation and data 
collection forms, specify the randomisation scheme, develop and maintain the study 
database, check data quality as the trial progresses, monitor recruitment and carry out trial 
analyses in collaboration with the clinical investigators.  
 
7.1 
Day-to-day management 
 
The trial will be managed by a TMG, which will meet face to face or by teleconference 
monthly during the feasibility phase 1 and bi-monthly thereafter. The TMG will be chaired by 
the Chief Investigator and will include all members of the named research team (see Chief 
Investigators & Research Team Contact Details above).   
 
A research nurse/coordinator in each centre will be responsible for identifying potential trial 
participants, seeking informed participant consent, randomising participants, liaising with the 
theatre planning manager, collecting trial data and ensuring the trial protocol is adhered to.  
 
7.2 
Monitoring of sites  
 
7.2.1 Initiation visit 
 
Before the study commences training session(s) will be organised by CTEU Bristol. These 
sessions will ensure that personnel involved fully understand the protocol, CRFs and the 
practical procedures for the study. 
 
7.2.2 Site monitoring 
 
The trial coordinating centre (CTEU) will carry out regular monitoring and audit of 
compliance of centres with GCP and data collection procedures described in section 5 
above. 
 
7.3 
Trial Steering Committee and Data Monitoring and Safety Committee 
 
The TSC is made up of representatives of By-Band-Sleeve TMG and independent members. 
The HTA will appoint members of this committee and the DMSC.  
 
 
 
 

 
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8. 
Safety reporting 
 
Serious and other adverse events will be recorded and reported in accordance with the 
International Conference for Harmonisation of Good Clinical Practice (ICH GCP) guidelines 
and the Sponsor’s Research Related Adverse Event Reporting Policy (see Figure 2). 
 
In this population all three interventions are low risk but some SAEs will be ‘expected’. These 
will be reported to the CTEU and data on these adverse events collected during the trial will 
be reported regularly by the CTEU to the trial DMSC for review and to the Sponsor and the 
UK Research Ethics Committee (REC) when required.  
 
 
Figure 2  
Serious adverse event reporting flow chart  
 
 
 
 
8.1 
Expected adverse events 
 
The following adverse events are ‘expected’ in the period from surgery to discharge from 
hospital after the operation: 
 
Peri-operative events  
Cardiovascular including, 
• 
Acute myocardial infarction 
• 
Dysrrythmia 
• 
Cardiac arrest 
 
Bleeding requiring blood transfusion 
Bleeding requiring acute endoscopy +/- possible injection for bleeding 
Bleeding not requiring intervention 
 
Serious adverse event/reaction identified 
Is this event/reaction expected (i.e. listed in protocol)? 
Yes 
No 
Report to sponsor 
Causally related to the 
study intervention? 
Yes 
No 
Resulted in death? 
Report event to 
the DMSC as 
required 
Yes 
No 
Report to sponsor 
Report event to the 
DMSC as required 
Report event to the 
REC and DMSC 
immediately 
(maximum 15 days) 

 
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Iatrogenic injury to any organ requiring intervention, including  
• 
Spleen 
• 
Liver 
• 
Bowel 
• 
Major blood vessels in abdomen 
 
Anaphylaxis to anaesthetic agent or drug given during surgery or during recovery prior to 
discharge 
 
Post-operative events 
Pulmonary complications, including: 
• 
Intubation and ventilation for any reason 
• 
Initiation of mask continuous positive airway pressure ventilation after weaning from 
ventilation 
• 
Pneumonia 
 
Thromboembolic complications, including: 
• 
Deep vein thrombosis 
• 
Pulmonary embolus 
 
Renal complications, including: 
• 
Urinary tract infection  
• 
Acute renal failure 
• 
New haemofiltration/dialysis 
• 
Urinary retention  
 
Infective complications, including: 
• 
Wound infection/breakdown  
• 
Gastric band or port site infection  
• 
Urinary tract infection 
 
GI complications, including: 
• 
Oesophagitis 
• 
Leak from gastric staple line at angle of his, or elsewhere 
• 
Leak from gastro-jejunal anastomosis  
• 
Leak from jejuno-jejunal anastomosis 
• 
Upper GI bleed 
• 
Stomach ulcer 
• 
Small bowel obstruction  
• 
Acute gastric dilatation 
• 
Fistula 
• 
Port site hernia 
• 
Internal hernia 
• 
Gastric stricture  
• 
Infective intra-abdominal collection  
 
Neurological complications 
• 
Permanent stroke 
• 
Transient ischaemic attack (TIA) 
 
Bleeding requiring reoperation or blood transfusion 
Bleeding requiring acute endoscopy +/- possible injection for bleeding 
 
Band complications, including, 

 
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• 
Band slippage – proximal or distal  
• 
Flipped port 
• 
Gastric band infection 
• 
Port site infection 
• 
Leakage from tubing 
• 
Leakage – damage to port or tubing  
 
Re-operation for any reason, including, 
• 
Band repositioning 
• 
Removal of band for any reason, including intolerance 
• 
Removal of port (under general anaesthetic) 
• 
Re-siting of port (general anaesthetic) 
• 
Small bowel obstruction or perforation 
• 
Division of adhesions 
• 
Closure of internal hernia defects 
• 
Diagnostic laparoscopy alone 
• 
Placement of feeding jejunostomy 
• 
Placement of T-tube into gastric staple line  
 
Re-interventions for any reason, including, 
• 
Upper GI endoscopy 
• 
Endoscopic clipping 
• 
Upper GI dilation 
• 
Radiological drain placement 
• 
Radiological stent placement for leak from gastric staple line  
• 
Enteral feeding 
• 
Total parenteral nutrition (TPN) feeding 
• 
Placement of chest drain  
• 
Removal of port (under local anaesthetic)  
• 
Re-siting of port (under local anaesthetic) 
 
Investigations for any reason, including,  
• 
Chest X-ray 
• 
Abdominal X-ray 
• 
Barium swallow 
• 
CT scan 
 
Other complications 
• 
Rhabdomyolysis 
• 
Fluid/electrolyte problems 
• 
Acute cholecystitis/biliary colic 
• 
Cholangitis/common bile duct stones 
• 
Other abscess/infection/fever 
• 
Unplanned admission to ITU/HDU 
• 
Hypoglycaemia  
• 
Hyperglycaemia 
• 
Iron deficiency/anaemia  
 
Death in hospital  
 
The following adverse events are ‘expected’ after discharge from hospital: 
 
Infective complications, including: 
• 
Wound infection/breakdown  

 
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• 
Gastric band or port site infection 
 
GI complications, including: 
• 
Oesophagitis  
• 
Leak from gastric staple line at angle of his, or elsewhere 
• 
Leak from gastro-jejunal anastomosis  
• 
Leak from jejuno-jejunal anastomosis 
• 
Upper GI bleed 
• 
Stomach ulcer 
• 
Acute gastric dilatation 
• 
Gastric stricture 
• 
Fistula 
• 
Port site hernia 
• 
Internal hernia 
• 
Infective intra-abdominal collection 
 
Thromboembolic complications, including: 
• 
Deep vein thrombosis 
• 
Pulmonary embolus 
 
Neurological complications 
• 
Permanent stroke 
• 
Transient ischaemic attack (TIA) 
 
Re-operation for any reason, including, 
• 
Repositioning of the band 
• 
Removal of band for any reason including band intolerance 
• 
Removal of port (under general anaesthetic) 
• 
Re-siting port under general anaesthetic) 
• 
Division of adhesions 
• 
Small bowel resection 
• 
Closure of internal hernia defects 
• 
Diagnostic laparoscopy alone 
• 
Laparoscopic drain placement 
• 
Placement of feeding jejunostomy  
• 
Placement of T-tube into gastric  staple line 
• 
Placement of chest drain  
• 
Joint replacement or repair (e.g. knee replacement) 
• 
Cosmetic surgery (e.g. removal of excess skin) 
 
Re-intervention for any reason, including,  
• 
Upper GI endoscopy 
• 
Endoscopic clipping 
• 
Upper GI dilatation 
• 
Enteral feeding 
• 
TPN feeding 
• 
Radiological drain placement 
• 
Removal of port (under local anaesthetic) 
• 
Re-siting of port (under local anaesthetic)  
 
Investigations for any reason, including,  
• 
Chest X-ray 
• 
Abdominal X-ray 
• 
Barium swallow 

 
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• 
CT scan 
 
Other complications 
• 
Fluid/electrolyte problems 
• 
Acute cholecystitis/biliary colic 
• 
Cholangitis/common bile duct stones 
• 
Iron deficiency/anaemia  
 
8.2 
Period for recording serious adverse events 
 
Data on adverse events will be collected from consent for participation for the duration of the 
participant’s 3 year follow-up period.   
 
 
 
 

 
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9. 
Ethical considerations 
 
9.1 
Review by an NHS Research Ethics Committee  
 
Ethics review of the protocol for the trial and other trial related essential documents (e.g. PIL 
and consent forms) will be carried out by a UK Research Ethics Committee (REC). Any 
amendments to these documents, after a favourable opinion from the REC has been given, 
will be submitted to the REC for approval prior to implementation. 
 
9.2 
Risks and anticipated benefits for trial participants and society 
 
All participants will undergo one of the three standard operations currently carried out for 
severe and complex obesity in the NHS. They may expect to experience the weight loss 
benefits of surgery and experience the side effects of each procedure.  
 
9.3 
Information to potential trial participants of possible benefits and known risks 
 
The risks and benefits of the three treatment options will be fully explained. In particular, the 
uncertain medium to long-term results after the three procedures will be communicated.  
 
9.4 
Obtaining informed consent from participants 
 
All participants will be required to give written informed consent.  This process, including the 
information about the trial given to patients in advance of recruitment, is described above in 
section 5.11.   The research nurse/trial coordinator/PI/clinical research fellow will be 
responsible for the consent process, which will be described in detail in the Trial Manual. 
 
 
 
 

 
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10. 
Research governance 
 
This study will be conducted in accordance with: 
• 
The Medicine for Human Use (Clinical Trial) Regulations 2004 
• 
International Conference for Harmonisation of Good Clinical Practice (ICH GCP) 
guidelines 
• 
Research Governance Framework for Health and Social Care 
 
10.1 
Sponsor approval 
 
Any amendments to the trial documents will be approved by the sponsor prior to submission 
to the REC. 
 
10.2 
NHS approval 
 
Any amendments to the trial documents approved by the REC will be submitted to the Trust 
R & D departments for information and approval.  
 
10.3 
Investigators' responsibilities 
 
Investigators will be required to ensure that local research approvals have been obtained 
and that any contractual agreements required have been signed off by all parties before 
recruiting any participant.  Investigators will be required to ensure compliance to the protocol 
and study manual and with completion of the CRFs.  Investigators will be required to allow 
access to study documentation or source data on request for monitoring visits and audits 
performed by the Sponsor or CTEU Bristol or any regulatory authorities. 
 
Investigators will be required to read, acknowledge and inform their trial team of any 
amendments to the trial documents approved by the REC that they receive and ensure that 
the changes are complied with. 
 
10.4 
Monitoring by sponsor 
 
The study will be monitored and audited in accordance with the Sponsor’s policy, which is 
consistent with the Research Governance Framework.  All study related documents will be 
made available on request for monitoring and audit by the sponsor and the relevant REC. 
 
10.5 
Indemnity 
 
This study is sponsored by the University of Bristol.  
 
10.6 
Clinical Trial Authorisation 
 
 Band, Bypass and Sleeve are not classed as investigational medicinal products and 
therefore a Clinical Trial Authorisation from the MHRA is not required. 
 
 
 
 

 
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11. 
Data protection and participant confidentiality 
 
11.1 
Data protection 
 
Data will be collected and retained in accordance with the UK Data Protection Act 1998. 
 
11.2 
Data handling, storage and sharing 
 
11.2.1 Data handling 
 
Data will also be entered into a purpose-designed SQL server database.  Information 
capable of identifying individuals and the nature of treatment received will be held in the 
database with passwords restricted to By-Band-Sleeve study staff.  Information capable of 
identifying participants will not be removed from the CTEU or clinical centres or made 
available in any form to those outside the study.   
 
Access to the database will be via a secure password-protected web-interface (NHS clinical 
portal). Study data transferred electronically between the University of Bristol and the NHS 
will only be transferred via a secure NHSnet network in an encrypted form.  
 
Data will be entered promptly and data validation and cleaning will be carried out throughout 
the trial. Standard operating procedures (SOPs) for database use, data validation and data 
cleaning will be available and regularly maintained.   
 
11.2.2 Data storage 
 
All study documentation will be retained in a secure location during the conduct of the study 
and for 10 years after the end of the study, when all patient identifiable paper records will be 
destroyed by confidential means. Prior to destruction, paper records will be scanned and 
stored on the University server with limited password controlled access.  Where trial related 
information is documented in the medical records, these records will be identified by a label 
bearing the name and duration of the trial in accordance to policy of the sponsor. In 
compliance with the MRC Policy on Data Preservation, relevant ‘meta’-data about the trial 
and the full dataset, but without any participant identifiers other than the unique participant 
identifier, will be held indefinitely (University server).  A secure electronic ‘key’ with a unique 
participant identifier, and key personal identifiers (.e.g. name, date of birth and NHS number) 
will also be held indefinitely, but in a separate file and in a physically different location (NHS 
hospital server). These will be retained because of the potential for the raw data to be used 
subsequently for secondary research. 
 
11.2.3 Data sharing 
 
Data will not be made available for sharing until after publication of the main results of the 
study.  Thereafter, anonymised individual patient data will be made available for secondary 
research, conditional on assurance from the secondary researcher that the proposed use of 
the data is compliant with the MRC Policy on Data Preservation and Sharing regarding 
scientific quality, ethical requirements and value for money.  A minimum requirement with 
respect to scientific quality will be a publicly available pre-specified protocol describing the 
purpose, methods and analysis of the secondary research, e.g. a protocol for a Cochrane 
systematic review.  The second file containing patient identifiers would be made available for 
record linkage or a similar purpose, subject to confirmation that the secondary research 
protocol has been approved by a UK REC or other similar, approved ethics review body. 
 
 

 
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12. 
Dissemination of findings  
 
The findings will be disseminated by usual academic channels, i.e. presentation at 
international meetings, as well as by peer-reviewed publications and through patient 
organisations and newsletters to patients, where available. A full report for the HTA will be 
written after each phase of the trial. 
 
 
13. 
References 
 
1. 
Centre NI. Health survey for England 2006 Latest Trends. 2006. 
2. 
WHO. Obesity and Overweight (WHO Fact Sheet No. 311). 2006. 
3. 
O'Brien PE, Dixon JB, Brown W, Schachter LM, Chapman L, Burn AJ, et al. The 
laparoscopic adjustable gastric band (Lap-Band): a prospective study of medium-term 
effects on weight, health and quality of life. Obesity surgery. 2002;12(5):652-60. Epub 
2002/11/27. 
4. 
Clegg AJ, Colquitt J, Sidhu MK, Royle P, Loveman E, Walker A. The clinical 
effectiveness and cost-effectiveness of surgery for people with morbid obesity: a systematic 
review and economic evaluation. Health technology assessment. 2002;6(12):1-153. Epub 
2002/08/28. 
5. 
Law C, Power C, Graham H, Merrick D. Obesity and health inequalities. Obes Rev. 
2007;8 Suppl 1:19-22. Epub 2007/02/24. 
6. 
Allender S, Rayner M. The burden of overweight and obesity-related ill health in the 
UK. Obes Rev. 2007;8(5):467-73. Epub 2007/08/25. 
7. 
Puhl RM, Moss-Racusin CA, Schwartz MB, Brownell KD. Weight stigmatization and 
bias reduction: perspectives of overweight and obese adults. Health Educ Res. 
2008;23(2):347-58. Epub 2007/09/22. 
8. 
Throsby K. "How could you let yourself get like that?" Stories of the origins of obesity 
in accounts of weight loss surgery. Soc Sci Med. 2007;65(8):1561-71. Epub 2007/07/27. 
9. 
Picot J, Jones J, Colquitt JL, Gospodarevskaya E, Loveman E, Baxter L, et al. The 
clinical effectiveness and cost-effectiveness of bariatric (weight loss) surgery for obesity: a 
systematic review and economic evaluation. Health technology assessment. 2009;13(41):1-
190, 215-357, iii-iv. Epub 2009/09/04. 
10. 
NICE. Obesity: the prevention, identification, assessment and management of 
overweight and obesity in adults and children. London2006; Available from: 
http://www.nice.org.uk/nicemedia/live/11000/30365/30365.pdf. 
11. 
Birkmeyer NJ, Dimick JB, Share D, Hawasli A, English WJ, Genaw J, et al. Hospital 
complication rates with bariatric surgery in Michigan. JAMA. 2010;304(4):435-42. Epub 
2010/07/29. 
12. 
Ltd. DCS. National Bariatric Surgery Registry. 2nd Report. Dendrite Clinical Systems 
Ltd.; 2014; Available from: http://demo.e-
dendrite.com/csp/bariatric/FrontPages/nbsrfront.csp. 
13. 
Strong S, Higgs S, Streets C, Titcomb D, Barham P, Blazeby J, et al. Aorto-conduit 
fistula developing four years after esophagectomy. J Surg Case Rep. 2012;2012(2):8. 
14. 
Buchwald H, Estok R, Fahrbach K, Banel D, Sledge I. Trends in mortality in bariatric 
surgery: a systematic review and meta-analysis. Surgery. 2007;142(4):621-32; discussion 
32-5. Epub 2007/10/24. 
15. 
O'Brien PE, McPhail T, Chaston TB, Dixon JB. Systematic review of medium-term 
weight loss after bariatric operations. Obesity surgery. 2006;16(8):1032-40. Epub 
2006/08/12. 
16. 
Flum DR, Belle SH, King WC, Wahed AS, Berk P, Chapman W, et al. Perioperative 
safety in the longitudinal assessment of bariatric surgery. N Engl J Med. 2009;361(5):445-
54. Epub 2009/07/31. 

 
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17. 
Tice JA, Karliner L, Walsh J, Petersen AJ, Feldman MD. Gastric banding or bypass? 
A systematic review comparing the two most popular bariatric procedures. Am J Med. 
2008;121(10):885-93. Epub 2008/10/01. 
18. 
O'Brien P. Is weight loss more successful after gastric bypass than gastric banding 
for obese patients? Nat Clin Pract Gastroenterol Hepatol. 2009;6(3):136-7. Epub 
2009/02/11. 
19. 
Parikh MS, Fielding GA, Ren CJ. U.S. experience with 749 laparoscopic adjustable 
gastric bands: intermediate outcomes. Surg Endosc. 2005;19(12):1631-5. Epub 2005/10/20. 
20. 
Caiazzo R, Arnalsteen L, Pigeyre M, Dezfoulian G, Verkindt H, Kirkby-Bott J, et al. 
Long-term metabolic outcome and quality of life after laparoscopic adjustable gastric 
banding in obese patients with type 2 diabetes mellitus or impaired fasting glucose. Br J 
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Angrisani L, Lorenzo M, Borrelli V. Laparoscopic adjustable gastric banding versus 
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Demerdash HM, Sharara G, Katri K. Differential effects of gastric bypass and 
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Sach TH, Barton GR, Doherty M, Muir KR, Jenkinson C, Avery AJ. The relationship 
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Morris C, O'Grada C, Ryan M, Roche HM, Gibney MJ, Gibney ER, et al. The 
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14. 
Amendments to protocol 
 
Amendment 
number 
(i.e. REC 
and/or 
MHRA 
amendment 
number) 
Previous 
version 
Previous 
date 
New 
version 
New 
date 
Brief summary 
of change 
Date of 
ethical 
approval 
(or NA if 
non-
substantial) 
1 
1 
31 
August 
2011 
2 
6 August 
2012 
Removed hiatus 
hernia >5cm 
from exclusion 
criteria 
Clarified when 
baseline weight 
will be 
measured 
Changed post-
discharge 
follow-up from 6 
weeks to 4 
weeks 
Added  
• 
maximum 
weight recorded 
in medical 
records 
• 
Epworth 
sleepiness scale 
and HADS 
questionnaire 
• 
assessment 
at 3 months for 
both groups 
• 
participant 
contact by email 
or SMS and the 
option to 
complete 
questionnaires 
on-line 
• 
timing of 
expected events 
added 
• 
qualitative 
research – 
process 
evaluation and 
development of 
surgical manual  
• 
qualitative 
research – non-
participant 
8 October 
2012 

 
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Amendment 
number 
(i.e. REC 
and/or 
MHRA 
amendment 
number) 
Previous 
version 
Previous 
date 
New 
version 
New 
date 
Brief summary 
of change 
Date of 
ethical 
approval 
(or NA if 
non-
substantial) 
observation of 
consultations  
Updated 
expected 
adverse events 
to and 
distinguished 
between events 
expected before 
and after 
discharge 
following surgery 
3 
2 
6 August 
2012 
4  
(version 3 
submitted 
but not 
approved) 
3 March 
2014 
Biliary and 
gastric limbs 
changed from 
100cm and 
200cm to 75cm 
and 150cm 
respectively 
Clarified when 
randomisation 
takes place and 
when baseline 
weight will be 
measured  
Revised follow-
up schedule so 
that with the 
exception of the 
4 week post-
surgery follow-
up all follow-up 
is timed to be 
post 
randomisation 
Removed  
• 
discontinuatio
n of CPAP as a 
criterion for 
resolution of 
sleep apnoea 
• 
follow-up at 3 
months  
Added  
• 
not suitable 
for bypass for 
medical reasons 
25 March 
2014 

 
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Amendment 
number 
(i.e. REC 
and/or 
MHRA 
amendment 
number) 
Previous 
version 
Previous 
date 
New 
version 
New 
date 
Brief summary 
of change 
Date of 
ethical 
approval 
(or NA if 
non-
substantial) 
to the exclusion 
criteria 
• 
sleep study at 
3 years for 
participants with 
sleep apnoea at 
recruitment  
• 
patient 
reported 
outcomes, 
consensus 
meeting and 
Delphi survey of 
patients for core 
outcome set 
• 
EQ-5D-5L 
questionnaire 2 
weeks before 
surgery 
4 
4 
3 March 
2014 
5 
8 August 
2014 
Addition of EQ-
5D-5L at 
recruitment for 
patients 
agreeing to 
follow-up at 3 
years but not 
randomisation 
2 October 
2014 
5 
5 
8 August 
2014 
7 
(version 6 
submitted 
but not 
approved) 
6 May 
2015 
Adaptation of 
protocol to 
include a third 
group, Sleeve 
Updated  
• background 
literature 
•  eligibility 
criteria to reflect 
updated NICE 
guidance 
• expected 
recruitment 
figures 
Reinstated 
hiatus hernia 
>5cm as an 
exclusion criteria 
Clarified 
mandatory and 
8 May  
2015 

 
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Amendment 
number 
(i.e. REC 
and/or 
MHRA 
amendment 
number) 
Previous 
version 
Previous 
date 
New 
version 
New 
date 
Brief summary 
of change 
Date of 
ethical 
approval 
(or NA if 
non-
substantial) 
optional 
components of 
surgery and 
concomitant 
interventions.   
Removed 
National 
Bariatric Surgery 
Registry from 
data collection 
table  
Removed 
minimisation by 
surgeon as in 
many centres a 
pooled operating 
list is used 
Period of data 
storage changed 
to 10 years 
6 
7 
06 May 
2015 
8 
29 May 
2015 
Removal of 
“surgeon 
unwilling” as an 
exclusion 
criteria.  Addition 
of exclusion 
criteria reflecting 
main reasons 
why surgeons 
are unwilling to 
randomise. 
Clarification of 
trial 
interventions. 
Paragraph 
explaining the 
transfer of 
samples from 
sites to 
University of 
Bristol added. 
Section on 
expected 
adverse revised 
following review 
by study team. 
29 June 
2015 

 
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Amendment 
number 
(i.e. REC 
and/or 
MHRA 
amendment 
number) 
Previous 
version 
Previous 
date 
New 
version 
New 
date 
Brief summary 
of change 
Date of 
ethical 
approval 
(or NA if 
non-
substantial) 
7 
8 
29 May 
2015 
9 
02  Nov  
2015 
Changes in the 
section 
describing 
surgical 
interventions. 
Added two 
expected 
adverse events 
after discharge 
from hospital: 
joint 
replacement 
or repair, and 
cosmetic 
surgery. 
2nd 
December 
2015 
8 
9 
02 Nov 
2015 
10 
22 April 
2016 
The frequency 
and duration of 
follow up 
clarified to make 
it explicit that 
randomised 
patients will be 
followed up for 
weight and QoL 
to 8 years. 
Removal of 
statement that 
staff measuring 
outcomes at 3 
years will be 
blinded to the 
treatment 
allocation, as 
this is not 
feasible.  
14th June 
2016 
9 
10 
22 April 
2016 
11 
20 May 
2017 
Addition of 
“metabolomics 
sub-study“ 
Clarified data 
collection 
beyond 36 
months. 
Clarified data 
collection for 
non-randomised 
participants 
21 July 
2017 

 
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Amendment 
number 
(i.e. REC 
and/or 
MHRA 
amendment 
number) 
Previous 
version 
Previous 
date 
New 
version 
New 
date 
Brief summary 
of change 
Date of 
ethical 
approval 
(or NA if 
non-
substantial) 
(Table 4 has 
been added). 
Corrected 
recruitment 
targets in Table 
5. 
10 
11 
20 May 
2017 
12 
09 April  
2018 
Revised timing 
of the start of 
the sub-study to 
after completion 
of recruitment to 
the trial (or 
earlier if TMG 
agree).  
Removed 
recruitment to 
the non-
randomised 
cohort. 
Updated Table 
4. 
Closure of 
iatrogenic 
mesenteric 
defects has 
been made 
mandatory for 
Bypass surgery. 
North Bristol 
Trust added as 
a new recruiting 
site in Table 5. 
Added 
participant 
payment for 
completion and 
return of 
questionnaires 
23 April 
2018 
12 
12 
09 April 
2018 
13 
28 Sept 
2018 
Section 5.15 
now states that 
participants will 
receive a £10 
voucher when 
they complete 
their 
questionnaires 
at the12 months 
15 
November 
2018 
 
 
 
 
 
 

 
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Amendment 
number 
(i.e. REC 
and/or 
MHRA 
amendment 
number) 
Previous 
version 
Previous 
date 
New 
version 
New 
date 
Brief summary 
of change 
Date of 
ethical 
approval 
(or NA if 
non-
substantial) 
and 36 months 
follow up 
appointments. 
 
 
13 
13 
28 Sept 
2018 
14 
8 July 
2020 
In section 5.13 
we have added 
the option for 
follow-up visits 
to take place at 
the participant’s 
home as an 
alternative to a 
hospital visit. 
In section 6.3 
we have added 
a second sub 
group analysis 
to include 
diabetes status 
and BMI  
 
29 July 
2020