The Effect of Glucagon Like Peptide-1 (GLP-1) on Glycaemic Profile and Eating Behaviour Following Gastrectomy
Phase: NA
Conditions: Gastric Cancer, Dumping Syndrome
Sponsor: Cambridge University Hospitals NHS Foundation Trust

 
1 
 
FULL/LONG TITLE OF THE STUDY 
The effect of glucagon like peptide-1 (GLP-1) on glycaemic profile and 
eating behaviour following gastrectomy 
 
 
 
 
 
 
 
 
SHORT STUDY TITLE / ACRONYM 
Gastrectomy, eating behaviour and GLP-1 
 
 
 
 
 
 
This protocol has regard for the HRA guidance and order of content; OR 
 
 
 

 
Gastrectomy, eating behaviour and GLP-1 
 
   
 
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RESEARCH REFERENCE NUMBERS 
IRAS: 218762 
CUH R&D: A094265 
 
PROTOCOL VERSION NUMBER AND DATE 
Protocol v1.1 24th  November 2016 
 
OTHER RESEARCH REFERENCE NUMBERS  
University of Cambridge Insurance Ref: 609/M/C/1763 
 
CO-SPONSORS  
Cambridge University Hospitals NHS Foundation Trust 
University of Cambridge 

 
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FULL/LONG TITLE OF THE STUDY 
The effect of glucagon like peptide-1 (GLP-1) on glycaemic profile and eating behaviour following 
gastrectomy 
 
SHORT STUDY TITLE / ACRONYM 
Gastrectomy, eating behaviour and GLP-1 
 
PROTOCOL VERSION NUMBER AND DATE 
V1.1 24/11/2016 
 
 

 
Gastrectomy, eating behaviour and GLP-1 
 
   
 
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RESEARCH REFERENCE NUMBERS 
 
IRAS Number: 
218762 
SPONSORS Number: 
A094265 
 
Clinicaltrials.gov 
NCT02971631 
 
 

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

 
Gastrectomy, eating behaviour and GLP-1 
 
   
 
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KEY STUDY CONTACTS 
Chief Investigator 
Mr Geoffrey Roberts 
Metabolic Research Laboratories and MRC Metabolic Diseases 
Unit 
University of Cambridge 
WT-MRC Institute of Metabolic Science (Level 4) 
Addenbrooke's Site (B289), Cambridge, CB2 0QQ, UK 
Gpr25@cam.ac.uk 
Tel: 07740 782742; 01223 767176 
Study Co-ordinator 
Geoffrey Roberts, details as above 
Sponsor 
Cambridge University Hospitals NHS Foundation Trust and 
University of Cambridge 
Stephen Kelleher 
R&D Manager 
Cambridge University Hospitals 
1 Hills Road 
Cambridge 
CB2 0QQ 
Tel: 01223 217418 
Fax: 01223 34849 
Email: r&denquiries@addenbrookes.nhs.uk 
Funder(s) 
Wellcome Trust 
Cambridge Biomedical Research Centre Seed Fund 
Key Protocol Contributors 
Professor Fiona Gribble 
Dr Frank Reimann 
Mr Richard Hardwick 
Professor Rebecca Fitzgerald 
Professor Paul Fletcher 
Dr Hisham Ziauddeen 
 
 

 
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STUDY SUMMARY 
 
Study Title 
The effect of glucagon like peptide-1 (GLP-1) on glycaemic 
profile and eating behaviour following gastrectomy 
Internal ref. no. (or short title) 
Gastrectomy, eating behaviour and GLP-1 (GaS) 
Study Design 
Double blind, randomised, crossover physiological study. 
Study Participants 
16 patients who have undergone total gastrectomy 
Planned Size of Sample (if applicable) 16 
Follow up duration (if applicable) 
3 study visits (one screening, two intervention) 
Planned Study Period 
2 years 
Research Question/Aim(s) 
 
To investigate the role of GLP-1, an incretin gut hormone, on 
the altered eating behaviour and glucose homeostasis 
experience following gastrectomy. 
 
 
 
 
 

 
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FUNDING AND SUPPORT IN KIND 
FUNDER(S) 
(Names and contact details of ALL organisations 
providing funding and/or support in kind for this 
study) 
FINANCIAL AND NON FINANCIAL SUPPORT 
GIVEN 
Wellcome Trust 
Part of the joint investigator award of 
Professor Gribble and Dr Reimann 
Wellcome 
Trust 
/ 
NIHR 
Addenbrooke’s 
Clinical Research Centre 
All participant facing work will be carried out 
in the core funded ACRC, and so benefit from 
the core grants awarded to this facility within 
Cambridge University Hospitals from the 
Wellcome Trust / NIHR 
 
 
 
 

 
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ROLE OF STUDY SPONSOR AND FUNDER 
The University of Cambridge and Cambridge University Hospitals NHS Foundation Trust are co-
sponsors of this study. The sponsors provide oversight of study design and implementation, as well as 
providing the facilities required for the study and access to the necessary patient populations. The 
sponsors have no control over the final decisions regarding data analysis or interpretation, or publication 
of the research findings. 
This study is funded through a Wellcome Trust joint investigator award held by Professor Gribble and 
Dr Reimann, for the study of the enteroendocrine system in health and disease. The funding bodies 
have no influence over data interpretation or dissemination of results. 
 
 
 
 

 
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ROLES AND RESPONSIBILITIES OF STUDY MANAGEMENT COMMITEES/GROUPS & 
INDIVIDUALS 
This study has been designed by the CI with substantial contributions from a steering group made up of 
the named co-investigators. Oversight of the study, data analysis and publication will be the 
responsibility of the CI supported by this group. 
 
 
 
 

 
Gastrectomy, eating behaviour and GLP-1 
 
   
 
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Protocol contributors 
The protocol was written by the CI, with the assistance of the named co-investigators. 
It has been reviewed and approved by the sponsors prior to submission to the REC to ensure it meets 
local guidelines and regulations. 
The sponsors and funders have no input to data analysis, interpretation, dissemination of results or 
manuscript writing. 
We have engaged an interested local patient and his family to ensure this study is designed and 
performed in a fashion that is acceptable to our target population. They have reviewed our protocols 
and assisted with the final version. 
 
KEY WORDS: 
 
Gastrectomy 
GLP-1 
Eating behaviour 
Hypoglycaemia 
 

 
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LIST of CONTENTS 
GENERAL INFORMATION 
Page No. 
TITLE PAGE  
1 
RESEARCH REFERENCE NUMBERS 
 
2 
SIGNATURE PAGE 
5 
KEY STUDY CONTACTS 
 
6 
STUDY SUMMARY 
7 
FUNDING 
 
8 
ROLE OF SPONSOR AND FUNDER 
9 
ROLES & RESPONSIBILITIES OF STUDY STEERING GROUPS AND INDIVIDUALS   
10 
LIST of CONTENTS  
12 
STUDY FLOW CHART 
 
13 
SECTION  
1. BACKGROUND 
 
14 
2. RATIONALE 
 
15 
3. THEORETICAL FRAMEWORK 
15 
4. RESEARCH QUESTION/AIM(S)  
15 
5. STUDY DESIGN/METHODS 
16 
6. STUDY SETTING 
19 
7. SAMPLE AND RECRUITMENT 
19 
8. ETHICAL AND REGULATORY COMPLIANCE 
20 
9. DISSEMINATION  POLICY 
23 
10. REFERENCES 
24 
11. APPENDICIES 
26 
 
 
 

 
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STUDY FLOW CHART 
 
 

 
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STUDY PROTOCOL 
The effect of glucagon like peptide-1 (GLP-1) on glycaemic profile and eating behaviour following 
gastrectomy. 
1 
BACKGROUND 
It is well established that surgery on the upper gastrointestinal tract profoundly alters appetite, weight 
and glucose homeostasis. This is harnessed in the treatment of obesity and type two diabetes1 but 
can have significant deleterious effects in the lean population undergoing surgery for cancer2. At 
present, there is no adequate understanding of the pathophysiological basis of these changes, 
although it is suspected that gut hormones, bile acids and neuro-cognitive factors may play a role3,4. 
Approximately 2500 gastric and oesophageal resections are carried out annually in the UK for cancer, 
with a 50% five year survival rate. Long-term quality of life after gastrectomy is known to be poor, with 
a high prevalence of “dumping syndrome”, a poorly understood constellation of symptoms2. There is 
no effective treatment, or indeed understanding of the underlying cause, of these symptoms. This is a 
significant unmet need in the field of cancer survivorship. 
The role of the (Glucagon-like-peptide-1) GLP-1 – insulin axis in the resolution of obesity and diabetes 
after bariatric surgery has been studied by several groups, and is suspected to play a role in the 
severe hypoglycaemias seen by some patients5. No one to date has assessed the role of GLP-1, a gut 
derived hormone responsible for potentiating the insulin response and suppressing appetite, in the 
symptoms seen after gastrectomy for cancer. A pilot study run by our group has demonstrated 
significantly elevated levels of GLP-1 and insulin, and altered appetite and satiety responses, in a 
cohort of five post-gastrectomy patients. The exact physiological effect of the GLP-1 elevation is 
however less clear, and temporary blockade of the GLP-1 axis will allow us to define the physiological 
changes resulting from GLP-1 secretion versus other altered physiological pathways in this group. 
This study is a double-blind, crossover physiological study of the effects of excess GLP-1 secretion on 
glycaemic profile and cognitive eating behaviour factors in the post-gastrectomy population. 
Participants will attend for two study visits, on one occasion receiving an infusion of Exendin 9-39, a 
peptide antagonist of GLP-1 action, and on the other a placebo infusion. They will undergo a glucose 
tolerance test including serial blood tests and measures of hunger and satiety, and then have an ad 
libitum meal, with measurement of amount and speed of eating, as well as simple cognitive tasks to 
assess food / reward behaviour. These tasks include food-related attentional bias using a dot-probe 
task6 and food-motivation behaviour using a validated grip-strength measurement task7. 
Exendin 9-39 is a peptide that has been used by several groups in the USA and Europe to investigate 
the effects of GLP-1 on physiological and cognitive factors, with no published serious adverse events. 
It has not previously been used in the gastrectomy population, but has been used in healthy 
volunteers and patients who have undergone bariatric surgery. It has an extremely short half-life and 
the effects cease within several minutes of cessation of the infusion. It is not at present a licensed 
medication, and is available for use as an investigative compound, manufactured to GMP standard by 
Bachem AG. Based on a review of the literature, and advice from a group at Stanford University who 
have used Exendin 9-39 infusions in the post-bariatric surgery population, the infusion will be 
commenced with a bolus of 7500pmol/kg and run at a rate of 500pmol/kg/minute. 
The assessment of food and reward behaviour, and glucose homeostasis, requires controlling for 
confounding factors. These include diabetes and depression and will be assessed prior to study 
participation. 

 
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2 
RATIONALE  
At present, there is no physiological understanding of the altered glucose homeostasis and eating 
behaviour seen in patients after gastrectomy. There is a growing population of patients surviving long-
term after surgery for gastric cancer, including some in their teens and twenties who have undergone 
prophylactic surgery for high risk genetic mutations. Our group works with the researchers leading the 
Familial Gastric Cancer Study, who provide clinical care, and research, for the familial gastric cancer 
population in the UK. This group has identified, through patient seminars, the need for further research 
into the long-term consequences of gastrectomy as a key priority. 
This study aims to assess the role of one specific hormone, GLP-1, which is known from our pilot data 
to be excessively secreted in response to food in this population. Ultimately, a better understanding of 
this pathway may lead to novel investigative and treatment paradigms, for a condition presently 
lacking either. 
3 
THEORETICAL FRAMEWORK 
We hypothesize that blockade of the GLP-1 axis using Exendin 9-39 in the post-gastrectomy 
population will: 
1. Ameliorate the excessive post-prandial insulin response seen in this patient group, as 
evidenced during a 50g oral glucose tolerance test by: 
a. Increased nadir blood glucose 
b. Reduced total insulin secretion 
2. Ameliorate the increased satiety signalling and consequent effects on food intake, hunger and 
satiety, and food motivation during and after an ad libitum meal, as evidenced by: 
a. Increased eating rate and food intake during ad libitum meal 
b. Increased hunger and decreased satiety ratings during and immediately after the ad 
libitum meal 
c. Increased attention to and motivation for food both prior to and after the ad libitum meal 
4 
RESEARCH QUESTION/AIM(S) 
4.1 
Objectives 
 
1. To identify the role of the excessive GLP-1 secretion experienced by post-gastrectomy patients 
in the physiological and behavioural symptoms seen after gastrectomy: 
a. Post-prandial hypoglycaemia 
b. Altered hunger / satiety scores 
c. Altered food attention bias and reward behaviour 
d. Altered food motivation and intake at ad libitum meal 
4.2 
Outcome 
The key outcome of this study is the understanding of the physiological effects of excessive GLP-1 
secretion seen in the gastrectomy population. To this end, Exendin 9-39, which is an antagonist of 
GLP-1 activity, will be used to block GLP-1 activity. This is a physiological study of the actions of GLP-
1, not an investigation of the effects of Exendin 9-39. 
 

 
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5 
STUDY DESIGN and METHODS of DATA COLLECTION AND DATA ANALYIS 
Each participant will attend for three visits – a screening visit and two study visits (matched visits, one 
with placebo infusion and one with Exendin 9-39 infusion). 
Screening visit 
The purpose of this visit is to ensure there are no comorbidities which may be exacerbated by, or 
confound, the study protocol. The participant will have the study explained to them, be asked to 
consent to participation and then be asked a full medical and surgical history, and receive blood and 
cognitive screening tests as detailed: 
 
Blood tests – Full blood count, thyroid function, renal function, HbA1c (diabetes screen). 
Validated questionnaire tools – Three factor eating questionnaire, Barratt’s impulsivity scale, 
PHQ9 and GAD7 for anxiety and depression, Dumping severity score 
Demographic measures – Age, past medical history, details of gastrectomy and other 
associated treatments (chemotherapy or radiotherapy), current medications, family history, 
height, weight, waist / hip circumference. 
Symptomatic measures – free discussion of participant reported post-gastrectomy 
consequences, changes in eating behaviour and food preference and behavioural adaptations. 
Study visit 
Participants will be admitted to the Clinical Research Facility at Addenbrooke’s Hospital the night prior 
to each study visit, to allow for provision of a standard meal and commencement of the study soon 
after waking the following morning. Participants will receive an infusion of either placebo (1% human 
albumin in sterile water) or Exendin 9-39 (dissolved in 1% human albumin in sterile water), with an 
initial bolus of 7500pmol/kg and at a rate of 500pmol/kg/minute. Participants and investigators will be 
blinded to the infusion contents, with the infusion schedule randomised by sealed envelopes prepared 
in advance. We will use a balanced randomisation protocol, with half of participants undergoing 
placebo at their first visit. Visit schedule and interventions are as the table below, with discharge at 
approximately 1700, after the post-infusion meal. Participants will be provided with a symptom diary 
during and for twenty four hours after the visit to monitor for any adverse events. 
All female participants of child-bearing age are to receive a urinary pregnancy test on each infusion 
visit. 
Key study measures are: 
1. Continuous glucose monitor – a Dexcom G4 continuous subcutaneous glucose monitor will be 
used to measure interstitial glucose levels at 5 minute intervals. This is a key outcome 
measure, as well as a safety measure to monitor for hypoglycaemia during the OGTT. The 
device is CE marked for the monitoring of glucose profile and in widespread use. 
2. Blood tests – blood will be collected and centrifuged, and plasma assayed for hormonal 
mediators of glucose homeostasis (including insulin, glucagon and GLP-1). Maximum volume 
of blood collected across 3 visits will be 250ml. 
3. Simple reaction time task – a straightforward measure of reaction time wherein a participant 
clicks a key in response to a stimulus on a computer screen, will act as a control / baseline 
measure to identify between and intra-participant variability in response times that may 
influence other cognitive tasks. 

 
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4. Visual analogue scales – participants will be asked to mark how hungry, sated or nauseous 
they feel on a 10cm visual analogue scale. 
5. Sigstad score – a validated measure of post-gastrectomy symptoms, to be completed on a tick 
box sheet during the OGTT. 
6. Attention bias task – participants will be asked to fixate on a central mark on a computer 
screen, and will then be shown two images conflicting as to their depiction of food (i.e. food vs 
not food, or high energy vs low energy food), under one of which appears a dot. The speed 
with which they indicate the side of the dot, with regard for the associated image, identifies 
their degree of food attention bias. 
7. Food motivation task – a validated measure of food motivation, using grip strength as a 
measure of degree of work the participant will undertake to receive particular food related 
rewards and stimuli. 
8. Eating rate / food intake – a universal eating monitor (a set of hidden scales placed beneath a 
meal) will examine rate and amount of consumption of a standard ad libitum meal. 
9. Liking ratings – visual analogue scales of how much the participant likes the meal. 
All questionnaires and tasks are validated. 
Data will be collected in paper format, stored in a locked cabinet in a secure area of Addenbrooke’s 
Hospital, and transcribed in anonymous fashion to a database on a secure University of Cambridge 
server. Data storage and analysis will be carried out using Microsoft Excel and R. 
Exendin 9-39 will be sourced from Bachem AG, who produce GMP grade Exendin 9-39 with 
appropriate supporting documentation and guarantees. It will be stored as per supplier guidance in the 
Addenbrooke’s pharmacy, or another appropriate secure storage area, and made up to a standard 
dilution in 1% human albumin in 0.9% sterile saline. Randomisation will be administered by means of 
sealed envelopes, with each visit provided with either an infusion of Exendin 9-39, or placebo (1% 
human albumin in 0.9% sterile saline). Both infusions will be at a rate determined by the weight of the 
participant and stock concentration of Exendin 9-39, and provide a 7500pmol/kg (25.27µg/kg) bolus of 
Exendin 9-39 followed by a 500pmol/kg/minute (1.685µg/kg/minute) infusion. Infusions will be 
administered through an appropriately maintained clinical infusion pump on the CRF. 
 
 

 
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Approximate time 
Task 
Test 
Infusion 
0800 
Insert continuous glucose 
monitor and venous cannula 
 
 
0820 
Fasting bloods and cognitive 
measures 
Blood sample, simple reaction 
time task, visual analogue 
scales (VAS) for hunger, 
satiety, nausea, Sigstad 
 
0840 
Start infusion 
 
 
0900 
Fasting / blockaded measures 
Blood sample, simple reaction 
time task, attention bias, food 
motivation, VAS, Sigstad 
0910 
50g oral glucose drink (OGTT) 
 
0925 
OGTT measures 
Blood sample, VAS, Sigstad, 
attention bias 
0940 
OGTT measures 
Blood sample, VAS, Sigstad, 
food motivation 
0955 
OGTT measures 
Blood sample, VAS, Sigstad, 
simple reaction time task 
1010 
OGTT measures 
Blood sample, VAS, Sigstad 
1025 
OGTT measures 
Blood sample, VAS, Sigstad, 
(SRTT if hypoglycaemic) 
1040 
OGTT measures 
Blood sample, VAS, Sigstad 
1045 
Post-OGTT cognitive tasks 
Attention bias, food 
motivation, simple reaction 
time task 
1115 
Bloods then ad libitum meal, 
VAS at 5 minute intervals, liking 
ratings twice (5 minutes into 
meal, and at completion of 
meal) 
Blood sample, universal 
eating monitor, VAS, liking 
ratings 
1200 OR 10 
minutes after 
completion of meal 
Post meal bloods and cognitive 
tasks, then stop infusion 
(approx. 1230) 
Attention bias, food 
motivation, bloods 
1230 until next 
meal (appr 1700) 
Hunger / satiety scores every 30 
minutes, meal then discharge 
VAS 
 
Study visit timeline 
 
 

 
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6 
STUDY SETTING 
The study will be performed in the Wellcome Trust-NIHR Clinical Research Facility at Addenbrooke’s 
Hospital. The staff and infrastructure of the CRF bring considerable expertise and experience in 
research involving metabolic factors and infusion of blinded agents. Each study visit will be supported 
by at least a dedicated nurse and doctor for the duration of the visit. 
7 
SAMPLE AND RECRUITMENT 
7.1  
Eligibility Criteria 
7.1.1 Inclusion criteria  
Participants must be: 
 
At least 3 months post completion of treatment for gastric cancer, or prophylactic gastrectomy 
 
Aged at least 18 years 
 
Able to tolerate an oral glucose tolerance test 
 
Able to understand and retain all information regarding the study and give informed consent. 
 
Willing to receive an infusion of human albumin solution 
7.1.2 Exclusion criteria  
Participants must not: 
 
Have a diagnosis of diabetes 
 
Have a history of untreated anaemia in the last 3 months 
 
Be aged under 18 years 
 
Have active gastric cancer 
 
Be pregnant or attempting to conceive 
7.2  
Sampling 
 
7.2.1  Size of sample 
Up to sixteen participants will be recruited for this study, each to complete one screening and two 
randomised study visits (placebo and Exendin 9-39). Previous data shows a between visit correlation of 
glucose measurement of 0.52, with standard deviation of 0.5. Salehi et al demonstrated mean nadir blood 
glucose of 3.9mmol/L (standard deviation 0.6) with GLP-1 blockade and 2.6mmol/L (0.6) with placebo in 
post-bariatric surgery patients5. Based on this data, we have conservatively estimated an effect size of 
0.5 (based on mean change in nadir glucose of 0.5mmol/L. To detect this change with 90% power at a 
5% significance level requires a sample size of 13. The recruitment of sixteen participants will allow for 
drop outs, and for the possibility that more data will be required to reach significance in the previously 
unstudied (in this group) outcomes of food motivation and reward behaviour. 
7.2.2  Sampling technique 
Participants will be sampled from all patients under follow up after total gastrectomy by the Cambridge 
Oesophago-gastric centre at Addenbrooke’s Hospital, or known to the service through the Familial 
Gastric Cancer Study (provided they have indicated an interest in being contacted regarding future 
research). We will select participants with suspected or proven post-prandial hypoglycaemia based on 
oral glucose tolerance tests performed as part of clinical care or other research projects administered 
by our study team. 

 
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7.3 
 Recruitment 
Participants will be identified as having post-prandial hypoglycaemia (based either on symptoms or a 
previous glucose tolerance test) and initially approached by clinicians or clinical researchers involved 
in their care. If they are interested in receiving further information regarding the study, they will be 
contacted by a member of the study team. They will be provided with written information on the study, 
and if they wish to proceed, be invited to attend the CRF for a screening visit, at which time they will 
be formally consented by a member of the study team. 
Participants will be paid an honorarium of £30 for each infusion visit (in line with current practice in our 
unit), and be fully reimbursed for travel costs. 
7.3.1 Sample identification 
Participants will be identified as meeting the inclusion / exclusion criteria by a clinician involved in their 
care, if necessary in discussion with the CI, who is a member of the clinical team of the Cambridge 
Oesophago-Gastric centre. 
7.2.2 Consent 
Participants will be asked to give written consent using a standard consent form at the time of the 
screening visit. They will be provided with written literature regarding the study prior to this occasion, 
and will have adequate time to ask questions, and withdraw consent should they wish. Only 
participants able to give fully informed consent will be recruited to this study, with capacity assessed 
by a clinically trained member of the study team. 
 
8 
ETHICAL AND REGULATORY CONSIDERATIONS 
8.1 
Assessment and management of risk 
This is a physiological study, using a well described test (oral glucose tolerance test) with a blinded 
infusion of a peptide or placebo. 
Oral glucose tolerance testing (OGTT) in this group has been carried out by our and several other 
groups. There is a risk of hypoglycaemia developing during the test period, for which the participant 
will be closely monitored using a continuous subcutaneous glucose monitor. A robust protocol is in 
place for the management of hypoglycaemia during an OGTT in this population, including the 
administration of intravenous glucose, or glucagon, should this be necessary (in our experience, this 
has never occurred). Other risks of the study visit and OGTT include pain and bruising at the 
cannulation site. 
Exendin 9-39 has been used by multiple groups in Europe and the USA, with published results from 
259 infusions in 240 participants4,8-22. No serious adverse events have been ascribed to the use of 
Exendin 9-39, which is unsurprising given it is a highly selective blocker of the GLP-1 receptor with a 
very short half-life. It is however possible that the participant may manifest an allergic reaction to the 
peptide, or to the human albumin in which it is dissolved. To facilitate early diagnosis and appropriate 
treatment should this occur, all participants will be closely monitored by dedicated nurse and doctor 
during the infusion. The study will take place on a clinical research ward within Addenbrooke’s 
Hospital, with full resuscitation equipment and access to the hospital’s emergency medical team 
should it be necessary. The CRF has experience in running phase 1 clinical trials, including first in 
human studies, which carry a greater burden of risk than this proposed study. 

 
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All adverse events (AEs) will be recorded as per the table and figure below. During study visits, 
participants will be questioned regarding adverse symptoms, and asked to keep a symptom diary for 
24 hours post visit to ensure all AEs are recognised. All non-serious AEs will be documented and 
submitted in the annual safety report. 
All SAEs will be reported to the sponsor within 5 working days of the investigative team being made 
aware of the event. SAEs will also be included in the annual safety report. The participants will have 
24 hour contact details for the investigators in case a suspected SAE occurs following the study visit. 
In the event of a potential SAE occurring, the investigators will arrange for the participant to be 
reviewed promptly. Depending upon the severity of the event, the participant will be reviewed in the 
Wellcome Trust Clinical Research Facility (WTCRF) or will be advised to go straight to A&E (for 
example, if anaphylaxis is suspected). 
 
Expected 
events 
All events 
recorded? 
All events reported? 
Timescale for reporting 
Non-serious 
Adverse 
Event 
(AE)  
Documented 
in protocol 
Yes 
Reported in annual study 
report only. 
Annually 
in 
study 
report.  
Serious Adverse 
Event (SAE) 
Documented 
in protocol 
Yes 
Reported 
to 
sponsor 
within 5 working days. 
Reported in annual study 
report. 
Reported to sponsor 
within 5 working days. 
 
 
 

 
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8.2  
Research Ethics Committee (REC) review & reports 
 
Before the start of the study, approval will be sought from a REC and the HRA for the study 
protocol, informed consent forms and other relevant documents.  
 
Substantial amendments that require review by REC will not be implemented until the REC 
and HRA grant a favourable opinion for the study and full R&D approval is in place 
 
All correspondence with the REC and HRA will be retained. 
 
It is the Chief Investigator’s responsibility to produce the annual reports as required. 
 
The Chief Investigator will notify the REC and HRA of the end of the study. 
 
An annual progress report (APR) will be submitted to the REC and HRA within 30 days of 
the anniversary date on which the favourable opinion was given, and annually until the study 
is declared ended. 
 
If the study is ended prematurely, the Chief Investigator will notify the REC and HRA, 
including the reasons for the premature termination. 
 
Within one year after the end of the study, the Chief Investigator will submit a final report 
with the results, including any publications/abstracts, to the REC and HRA. 
8.3  
Peer review 
Peer review has been sought from two researchers independent to the research team. 
8.4  
Patient & Public Involvement 
A patient representative has advised on the design of this study, including acceptability of the study 
protocol. The concept of this study was raised at a patient and family event for the Familial Gastric 
Cancer population, with positive feedback on the concept of studying the causes of post-operative 
symptoms. The research findings will be disseminated to the interested patient groups through the bi-
annual Familial Gastric Cancer workshop, and directly to any participant interested in the results. 
8.5 
Regulatory Compliance  
 
Before any site can enrol patients into the study, the Chief Investigator/Principal Investigator 
or designee will apply for NHS permission from the site management organisation, HEI or 
NHS Research & Development (R&D).  
 
For any amendment that will potentially affect a site’s NHS permission, the Chief 
Investigator/ Principal Investigator or designee will confirm with that site’s R&D department 
that NHS permission is ongoing 
 
The MHRA has reviewed this protocol and confirmed it does not require a clinical trial 
authorisation 
 
This study will be registered with clinicaltrials.gov for the purposes of public reporting of a 
study involving human participants. 
8.6  
Protocol compliance  
Protocol compliance will be monitored by the CI, with any accidental deviations being immediately 
reported to CI and sponsor. Frequent deviations will be investigated by the research team and 

 
Gastrectomy, eating behaviour and GLP-1 
 
   
 
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sponsor, and if necessary the study paused for review, notification of the REC and HRA and 
amendments. 
8.7 
Data protection and patient confidentiality  
The data custodian is the CI. The study and all investigators will comply with the Data Protection Act 
1998 with regards to the collection, storage, processing and disclosure of personal information and will 
uphold the Act’s core principles. Data will be managed to a written policy, with participant identifiable 
information stored in paper format in a locked cabinet in a secure area within Addenbrooke’s Hospital. 
All electronic records will be anonymised and held on secure servers within the University of 
Cambridge, with the key held by the CI and access only granted to key clinical members of the 
research team. Identifiable data will be held for up to 20 years following the completion of the study 
(MRC guidance), with fully anonymised results uploaded to the University of Cambridge Data 
Repository for at least 20 years, in line with current open access requirements. 
8.8 
Indemnity 
1. What arrangements will be made for insurance and/or indemnity to meet the potential legal liability 
of the sponsor(s) for harm to participants arising from the management of the research? 
 
As the co-sponsor is Cambridge University Hospitals NHS Foundation Trust, indemnity 
will be provided through NHS indemnity schemes 
2. What arrangements will be made for insurance and/ or indemnity to meet the potential legal liability 
of the sponsor(s) or employer(s) for harm to participants arising from the design of the research? 
 
As the research has been designed by a substantive employee of the University of 
Cambridge, insurance will be sought through the University insurance policy (Ref: 
609/M/C/1763). 
3. What arrangements will be made for insurance and/ or indemnity to meet the potential legal liability 
of investigators/collaborators arising from harm to participants in the conduct of the research? Note 
that if the study involves sites that are not covered by the NHS indemnity scheme (e.g. GP surgeries 
in primary care) these investigators/collaborators will need to ensure that their activity on the study 
is covered under their own professional indemnity. 
 
As the research is with NHS patients on a NHS site, indemnity will be provided by NHS 
schemes. 
No arrangements have been made for payment of compensation in the event of harm to the participants 
where no legal liability arises. 
 
8.9 
Amendments  
Application for any future amendments will be made by the study team in line with study requirements and 
developments in the scientific background to the study. Amendments to the protocol will be written by the 
CI or a delegated study team member in discussion with the sponsor’s R&D department. The decision 
about whether an amendment constitutes a substantial amendment will be made by the study team and 

 
Gastrectomy, eating behaviour and GLP-1 
 
   
 
24 
 
sponsor’s R&D department. Amendments will be submitted to the REC and HRA through the IRAS system 
with all necessary amended versions of the protocol or paperwork. 
All versions of study paperwork will be stored on secure University of Cambridge servers, with an 
amendment record stored in the appendix of the active protocol version. 
8.10 
Access to the final study dataset 
The final dataset will be available to the study team, which is based entirely on one site. Specific consent 
will be sought from participants for persistent anonymous storage and analysis of study data and 
publication of the basic data with associated metadata through an open access information repository. 
 
9 
DISSEMINATION POLICY 
9.1  
Dissemination policy 
The data will be owned by the Gribble / Reimann group within the Institute of Metabolic Science, University 
of Cambridge. On completion of the study, the final results will be tabulated, presented to the REC and 
HRA as a final report, presented to scientific meetings and submitted for peer-reviewed publication. There 
are no time limits on publication of this work. 
The work is being undertaken within a research group supported by the MRC, Wellcome Trust and NIHR 
BRC, who will be acknowledged in publications accordingly. Equally, some aspects of the research will be 
undertaken through hub facilities (e.g. the NIHR BRC Phenotyping hub), which will be acknowledged for 
their role as per local guidelines. 
Participants will be able to request their individual results, which will be provided once analysis and quality 
assurance have been performed. This will be provided with a detailed explanation of the findings and the 
opportunity to answer questions. 
The full study outcome will also be made available to participants on request, following completion of the 
study. 
The anonymised dataset, metadata and any code for analysing the results will be published with open 
access on a data repository (e.g. the University of Cambridge Data Repository). This will be done on 
completion of the study and after publication of the research findings. 
9.2  
Authorship eligibility guidelines and any intended use of professional writers 
Authorship of the final report and generated peer reviewed papers will follow ICMJE criteria, to include 
researchers making a substantial contribution to study design, data collection or analysis, or writing or 
editorial oversight. 
 
 

 
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10 
REFERENCES 
1. 
Pournaras DJ, le Roux CW. Type 2 diabetes: multimodal treatment of a complex disease. The 
Lancet. 2015;386(9997):936-937. 
2. 
Mine S, Sano T, Tsutsumi K, et al. Large-scale investigation into dumping syndrome after 
gastrectomy for gastric cancer. J Am Coll Surg. 2010;211(5):628-636. 
3. 
Jorgensen NB, Dirksen C, Bojsen-Moller KN, et al. Improvements in glucose metabolism early 
after gastric bypass surgery are not explained by increases in total bile acids and fibroblast 
growth factor 19 concentrations. J Clin Endocrinol Metab. 2015;100(3):E396-406. 
4. 
Jorgensen NB, Dirksen C, Bojsen-Moller KN, et al. Exaggerated glucagon-like peptide 1 
response is important for improved beta-cell function and glucose tolerance after Roux-en-Y 
gastric bypass in patients with type 2 diabetes. Diabetes. 2013;62(9):3044-3052. 
5. 
Salehi M, Gastaldelli A, D'Alessio DA. Blockade of Glucagon-like Peptide 1 Receptor Corrects 
Post-prandial Hypoglycemia After Gastric Bypass. Gastroenterology. 2014;146(3):669-680 
e662. 
6. 
Seage CH, Lee M. Do disinhibited eaters pay increased attention to food cues? Appetite. 
2016;108:151-155. 
7. 
Ziauddeen H, Subramaniam N, Cambridge VC, Medic N, Farooqi IS, Fletcher PC. Studying 
food reward and motivation in humans. J Vis Exp. 2014(85). 
8. 
Svane MS, Bojsen-Moller KN, Nielsen S, et al. Effects of endogenous GLP-1 and GIP on 
glucose tolerance after Roux-en-Y gastric bypass surgery. Am J Physiol Endocrinol Metab. 
2016;310(7):E505-514. 
9. 
Richard JE, Anderberg RH, Göteson A, Gribble FM, Reimann F, Skibicka KP. Activation of the 
GLP-1 receptors in the nucleus of the solitary tract reduces food reward behavior and targets 
the mesolimbic system. PLoS One. 2015;10(3):e0119034. 
10. 
ten Kulve JS, Veltman DJ, van Bloemendaal L, et al. Endogenous GLP-1 mediates 
postprandial reductions in activation in central reward and satiety areas in patients with type 2 
diabetes. Diabetologia. 2015;58(12):2688-2698. 
11. 
Vetter ML, Wadden TA, Teff KL, et al. GLP-1 plays a limited role in improved glycemia shortly 
after Roux-en-Y gastric bypass: a comparison with intensive lifestyle modification. Diabetes. 
2015;64(2):434-446. 
12. 
Melhorn SJ, Tyagi V, Smeraglio A, Roth CL, Schur EA. Initial evidence that GLP-1 receptor 
blockade fails to suppress postprandial satiety or promote food intake in humans. Appetite. 
2014;82:85-90. 
13. 
Richard JE, Farkas I, Anesten F, et al. GLP-1 receptor stimulation of the lateral parabrachial 
nucleus reduces food intake: neuroanatomical, electrophysiological, and behavioral evidence. 
Endocrinology. 2014;155(11):4356-4367. 
14. 
Shah M, Law JH, Micheletto F, et al. Contribution of endogenous glucagon-like peptide 1 to 
glucose metabolism after Roux-en-Y gastric bypass. Diabetes. 2014;63(2):483-493. 
15. 
Steinert RE, Schirra J, Meyer-Gerspach AC, et al. Effect of glucagon-like peptide-1 receptor 
antagonism on appetite and food intake in healthy men. Am J Clin Nutr. 2014;100(2):514-523. 
16. 
van Bloemendaal L, RG IJ, Ten Kulve JS, et al. GLP-1 receptor activation modulates appetite- 
and reward-related brain areas in humans. Diabetes. 2014;63(12):4186-4196. 
17. 
Jimenez A, Casamitjana R, Viaplana-Masclans J, Lacy A, Vidal J. GLP-1 action and glucose 
tolerance in subjects with remission of type 2 diabetes after gastric bypass surgery. Diabetes 
Care. 2013;36(7):2062-2069. 
18. 
Woerle HJ, Carneiro L, Derani A, Goke B, Schirra J. The role of endogenous incretin secretion 
as amplifier of glucose-stimulated insulin secretion in healthy subjects and patients with type 2 
diabetes. Diabetes. 2012;61(9):2349-2358. 

 
Gastrectomy, eating behaviour and GLP-1 
 
   
 
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19. 
Witte AB, Gryback P, Jacobsson H, et al. Involvement of endogenous glucagon-like peptide-1 
in regulation of gastric motility and pancreatic endocrine secretion. Scand J Gastroenterol. 
2011;46(4):428-435. 
20. 
Salehi M, Aulinger B, Prigeon RL, D'Alessio DA. Effect of endogenous GLP-1 on insulin 
secretion in type 2 diabetes. Diabetes. 2010;59(6):1330-1337. 
21. 
Salehi M, Vahl TP, D'Alessio DA. Regulation of islet hormone release and gastric emptying by 
endogenous glucagon-like peptide 1 after glucose ingestion. J Clin Endocrinol Metab. 
2008;93(12):4909-4916. 
22. 
Schirra J, Nicolaus M, Roggel R, et al. Endogenous glucagon-like peptide 1 controls endocrine 
pancreatic secretion and antro-pyloro-duodenal motility in humans. Gut. 2006;55(2):243-251. 
 
 

 
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11.  
APPENDICIES 
 
11.1 
Appendix 1- Required documentation  
Protocol v1 22/11/2016 
GaS PIS v2 17/11/2016 
GaS Consent form v2 17/11/2016 
CVs – CI and academic supervisor 
GaS GP letter v1 03/11/2016 
GaS hunger / satiety / nausea v1 07/11/2016 
GaS likings ratings v1 07/11/2016 
GaS Sigstad score v1 07/11/2016 
GaS participant invitation letter v1 11/11/2016 
GaS PHQ9 v1 11/11/2016 
GaS GAD7 v1 11/11/2016 
GaS DSS v1 11/11/2016 
GaS TFEQ v1 11/11/2016 
GaS study card v1 17/11/2016 
GaS symptom diary v1 20/11/2016 
 
13.2 
Appendix 2 – Amendment History 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
 
 
 
 
 
 
List details of all protocol amendments here whenever a new version of the protocol is produced. 
Protocol amendments must be submitted to the Sponsor for approval prior to submission to the REC 
committee.