Conditions: Obesity
Keywords: Weight Loss Bariatric Surgery
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 46
Healthy volunteers: yes

Brief summary:
Observational studies suggest that bariatric surgery is the most effective intervention for weight loss. Comparative effectiveness of Roux-en-Y Gastric Bypass (RYGB) and Sleeve Gastrectomy (SG) demonstrate that RYGB is significantly superior to SG in terms of weight loss and glycemic control. Both RYGB and SG increase GLP-1 concentrations which directly affect B-cell function. Data has shown that the postprandial rise in GLP-1 might affect feeding behavior after RYGB and to a lesser extent SG, where the increase in GLP-1 is less marked. In this study the investigators propose to randomize subjects undergoing SG to receive either placebo or Liraglutide, a GLP-1 receptor agonist, to compare weight loss and CV risk factors.

Detailed description:
A total of 75, non diabetic adults, scheduled for bariatric surgery at Mayo Clinic Rochester, will be enrolled. Of these, 25 will be scheduled for Roux-en-Y Gastric Bypass surgery (RYGB), while the remainder (50) will be scheduled for Sleeve Gastrectomy (SG). The study team will play no role in assignment of the surgical procedure. Following surgery, at month 3, subjects undergoing SG will be randomized to either Saxenda or placebo, subcutaneously once daily. Subjects randomized to Saxenda or placebo will take for the duration of the study (33 months). Follow up study visits for all subjects will be timed to coincide with the standard clinical follow up visits at months 3, 6, 9, 12, 18, 24, 30 and 36.

Arms:
arm 1: Subjects undergoing Sleeve Gastrectomy (SG) will be randomized 1:1 at the time of 3 month visit after bariatric surgery. arm 2: Subjects undergoing Sleeve Gastrectomy (SG) will be randomized 1:1 at the time of 3 month visit after bariatric surgery. arm 3: Twenty five subjects will be recruited from the Nutrition Clinic at Mayo Clinic Rochester prior to undergoing RYGB surgery.

Interventions: intervention 1: Saxenda intervention 2: Placebos intervention 3: RYGB
Intervention descriptions: intervention 1: Saxenda is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adult patients. Subjects will be recruited and screened prior to undergoing bariatric surgery. Subjects undergoing SG will be randomized 1:1 at month 3 post surgery to Saxenda, 0.6mg SQ daily, with weekly titration of 0.6mg until maintenance dose of 3mg/daily reached. Subjects will remain on study drug for duration of study (33 months). After undergoing surgery, study visits will be timed to coincide with the standard clinical follow-up visits at months 3, 6, 9, 12, 18, 24, 30 and 36. intervention 2: Subjects will be recruited and screened prior to undergoing bariatric surgery.Subjects undergoing SG will be randomized 1:1 at months 3 post surgery to Placebo, 0.6mg SQ daily, with weekly titration of 0.6mg until maintenance dose of 3mg/daily reached. Subjects will remain on study drug for duration of study (33 months). After undergoing surgery, study visits will be timed to coincide with the standard clinical follow-up visits at months 3, 6, 9, 12, 18, 24, 30 and 36. intervention 3: Subjects will be recruited and screened prior to undergoing bariatric surgery. After undergoing surgery, study visits will be timed to coincide with the standard clinical follow-up visits at months 3, 6, 9, 12, 18, 24, 30 and 36.

Protocol document:
Prot_SAP_001.pdf: 
 
 
Effect of GLP-1 receptor agonism on weight and 
caloric intake in subjects after sleeve 
gastrectomy 
 
NCT03115424 
 
May 2, 2023 


Version 0.09 May 2, 2023 
1
 
Effect of GLP-1 receptor agonism on weight and caloric 
intake in subjects after sleeve gastrectomy  
 
 
 
 
 
INVESTIGATOR-INITIATED STUDY PROPOSAL 
 
UNIVERSAL TRIAL NUMBER (UTN): U1111-1186-7919 
   
 
 
 
 
 
 
Endocrinology & Metabolism  
Mayo Clinic 
200 First ST SW, Rochester, MN55905 
 
 
Correspondence to:  
 
Adrian Vella MD 
Professor of Medicine 
Mayo Clinic, Rochester, MN 
, vella.adrian@mayo.edu 
 
 
 
 
 
 
 
 
 
 
 


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BACKGROUND AND SIGNIFICANCE: 
1) Obesity is a public health problem. In the United States the prevalence of obesity is 
rapidly increasing with 65% of adults and 17% of adolescents and children classified as 
being overweight or obese 1. This represents a doubling of obesity prevalence in adults, 
and a tripling in adolescents over the previous 25 years. Obesity is associated with 
multiple diseases, such as type 2 diabetes, non-alcoholic steatohepatitis and osteoarthritis, 
as well as being associated with increased frequency of risk factors for cardiovascular 
disease 2. Approximately 9% of national healthcare costs have been attributed to excess 
weight 3. The US Preventive Services Task Force has recommended that body mass index 
(BMI) is routinely assessed and weight management recommended for obese patients 4. 
Behavioral intervention with lifestyle and dietary modification usually achieves 
modest weight loss 4. While generally safe, most regain the weight lost within 5 years. 
Pharmacotherapy for obesity is considered for patients who have failed efforts at lifestyle 
modification and who have a BMI  30Kg/M2 or a BMI  27Kg/M2 in the presence of 
comorbidities such as diabetes 5. However, there have been significant concerns about the 
long-term safety of such medications and the currently available medications have 
relatively limited efficacy 6. Bariatric surgery is usually considered for patients who have 
a BMI  40Kg/M2 or a BMI  35Kg/M2 associated with comorbidities such as diabetes 5. 
Restrictive surgeries such as adjustable gastric banding (AGB) limit the capacitance of 
the stomach. Roux-en-Y gastric bypass (RYGB) is the most commonly performed bypass 
procedure and produces gastric restriction together with selective malabsorption. RYGB 
involves creation of a gastric pouch by separating the stomach across the fundus. 
Drainage of this 10-30ml pouch is achieved by a gastrojejunostomy. The distal end of the 
jejunum is then anastomosed ~ 150cm below the gastrojejunostomy effectively bypassing 
the distal stomach, duodenum and proximal jejunum. Duodenal switch (DS) is a variation 
of biliopancreatic diversion and involves a sleeve gastrectomy with division of the 
duodenum below the pylorus. The distal ileum is anastomosed to the short stump of the 
duodenum producing a ~ 100cm channel for nutrient absorption. The other end of the 
duodenum is closed and the remaining small bowel connected onto the enteral limb 75-
100cm from the ileocecal valve. (See 2 for illustrations & review).  
Observational studies suggest that bariatric surgery is the most effective 
intervention for weight loss producing an average weight loss of 30-35% that is 
maintained in ~ 60% of patients at 5 years 7. This has led to a dramatic increase in the 
number of procedures performed annually from 13,365 in 1998 to an estimated 102,794 
in 2003 8. A newer procedure, sleeve gastrectomy (SG) is a restrictive operation that has 
been performed much more frequently of late, comprising 34% of the ~ 110,000 bariatric 
surgeries performed in 2013. SG is projected to and may become the most frequent 
bariatric procedure in North America 9. SG may be cheaper than RYGB in terms of 
operative costs and because it is not a malabsorptive procedure, the costs of follow-up, 
and care of morbidities arising from micronutrient malabsorption, should be lower 10. 
Bariatric surgery effectively produces sustained weight loss in obesity and is widely 
performed in the United States 
 
2) Comparative effectiveness of RYGB and SG. It has been suggested that remission 
rate is associated with the length of bypass (~85% for standard RYGB, ~93% for long-
limb RYGB and ~98% with duodenal switch 11,12. Recent prospective, randomized 


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3
controlled trials have however reported lower remission rates for diabetes with RYGB 
although, it remains superior to medical therapy 13-15. Kashyap et al. has suggested that 
differences in fat loss and β-cell function between RYGB and SG occur  1 year after 
surgery 16. Of the 2 studies with 3 year follow-up, one in nondiabetic subjects 17 did not 
demonstrate clear differences in weight loss while in the other RYGB was significantly 
superior to SG in terms of weight and glycemic control 18. The obvious anatomic 
differences between the procedures result in differences in enteroendocrine secretion: 
postprandial GLP-1 concentrations are lower after SG compared to RYGB in the 
comparative studies undertaken in humans 16,19-22. On the other hand, a liquid meal, 
especially after gastric restriction, may not recreate conditions present after a solid meal 
23. Whether these differences can explain a divergence in metabolic outcomes remains 
unknown.  
 
3) GLP-1 and 
appetite. Both SG 
and RYGB 
increase GLP-1 
concentrations 
which directly 
affect β-cell 
function; 
however, this is of 
lesser magnitude 
in SG compared 
to RYGB 24,25. 
Our data shows 
that inhibition of 
endogenous GLP-
1 action increases 
free-choice caloric intake, providing a mechanism underlying differences between 
procedures. Neuronal GLP1R mediates the anorectic effects of GLP-126. Inhibition of 
GLP-1 action with Exendin-9,39 after RYGB (Fig. 1A) accelerates gastric emptying 25. 
This observation suggests that factors other than anatomy regulate the upper 
gastrointestinal response to food ingestion. The attraction of certain foods decreases after 
RYGB27 and appetite may be altered by enteroendocrine secretion28,29. A potential 
mechanism is via GLP-1 which alters gastrointestinal transit, gastric 
accommodation25,30,31 and has direct effects on hypothalamic nuclei outside of the blood-
brain barrier32. GLP-1 and GLP-1 receptor agonists decrease food intake and cause 
weight loss33,34. GLP-1 also modulates taste sensitivity in rodents35-38. The peripheral 
concentrations of GLP-1 observed in the early postprandial period in subjects post-
RYGB are similar to those observed after infusion at 1.5pmol/kg/min – an infusion rate 
that alters GI function39. More recently, activation of the GLP-1 receptor decreased food 
intake and food-related brain responses in patients with type 2 diabetes and in obese 
subjects as measured by functional Magnetic Resonance Imaging (MRI). These actions 
were blocked by Exendin-9,3940. It is therefore reasonable to consider that the 
postprandial rise in GLP-1 might affect feeding behavior after RYGB, and to a lesser 
extent SG, where the increase in GLP-1 is less marked 16,19-22.  
Figure 1: Gastric emptying (GE) at baseline and 4 wks after RYGB (A). 
After surgery subjects were studied with (Exendin-9,39) or without 
(Saline). GLP-1R blockade accelerated GE. In a separate experiment, 
240 minutes after a mixed meal, subjects ate from a free choice buffet. 
Calories consumed are recorded (B). GLP-1R blockade increased food 
consumption. 


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4
 
Given this background, the purpose of the present study is to address the following 
objective: - 
 
SPECIFIC OBJECTIVES: 
Determine the effects of liraglutide administration (3mg daily) on weight and 
cardiovascular risk factors in subjects who have undergone sleeve gastrectomy.  
 
RESEARCH DESIGN AND METHODS 
The study will only be initiated after it has completed review and approval by the Mayo 
Institutional Review Board (the IRB). Scientific review will initially be conducted by the 
Endocrine Research Unit and by the Clinical Research Trials Unit, prior to ethical 
approval by the IRB which will also approve all patient contact material, advertising and 
consent forms. The latter will be utilized to ensure informed, written consent is obtained 
at the time of screening where they will meet the principal investigator or a member of 
the team to ensure that participants meet entry criteria for the study, understand the risks 
of participation and the goals of the study.  
 
All Mayo IRB approved studies adhere to the Declaration of Helsinki and are conducted 
in accordance with ICH good clinical practice (GCP) guidelines. Dr. Vella in his role as 
sponsor-investigator will comply with all these guidelines as well as the other applicable 
regulatory and legal guidelines during study conduct and when obtaining and 
documenting informed consent. 
 
The nature of the information obtained for the purposes of the study will be explained in 
detail to each participant at the time of screening. Specifically, none of this information 
will become part of the medical record and cannot impact the availability and nature of 
care or access to healthcare. All information will be stored anonymously in the database 
and only the PI or one of his designates will have access to the data. 
 
Study Hypothesis: Agonism of the GLP-1 receptor by Liraglutide 3mg will increase 
weight loss and lower blood pressure and LDL-cholesterol compared to placebo after 
sleeve gastrectomy. 
 
1 Endpoint: Liraglutide administration (3mg daily) to participants after SG produces 
significantly greater weight loss from baseline compared to that observed 
in the group after sleeve gastrectomy who receive placebo. 
 
2 Endpoints:  
i. Liraglutide administration (3mg daily) to participants after SG produces will 
achieve weight loss that is inferior to that achieved by RYGB. 
ii. Greater numbers of participants after SG will have an LDL ≤ 100mg/dL and a 
systolic blood pressure ≤ 130mmHg results when receiving Liraglutide (3mg daily) 
compared to placebo. 
iii. Liraglutide administration (3mg daily) to participants after SG produces blood 
pressure and LDL-cholesterol lowering that is inferior to that achieved by RYGB. 


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We propose enrolling 60 non-diabetic adults scheduled for SG and 30 patients 
undergoing RYGB.  Patients scheduled for SG will be randomized to receive Liraglutide 
(3mg daily) in a double-blind, randomized, placebo-controlled fashion (randomized in a 
1:1 ratio). All participants will be followed longitudinally with serial measurement of 
outcome variables (weight, blood pressure, lipid profile, activity and satiety) over a three 
year period.  Our power calculations suggest that 25 patients per group will be sufficient 
to accomplish our goals even with a loss of 5 subjects per group to follow up. 
 
Bariatric 
Sx 
2008 
2009 
2010 
2011 
2012 
2013 
ND 
DM 
ND 
DM 
ND 
DM 
ND 
DM 
ND 
DM 
ND 
DM 
RYGB 
107 
46 
166 
70 
160 
63 
207 
83 
184 
64 
210 
59 
AGB 
9 
0 
27 
0 
10 
0 
34 
4 
8 
2 
3 
1 
SG 
0 
0 
25 
0 
32 
10 
62 
29 
78 
25 
102 
36 
Table 1: Total numbers of laparoscopic surgeries performed as 1st procedure at Mayo 
Clinic. AGB = Adjustable Gastric Banding; ND = Non-diabetic; DM = Diabetic 
patients. 
 
a) Subjects: A total of 75 patients will be recruited from the Nutrition Clinic at Mayo 
Clinic Rochester prior to undergoing bariatric surgery. Of these25 will be scheduled for 
RYGB while the remainder (50) are scheduled for SG. Healthy status will indicate that 
the participant has no known active systemic illnesses or active macrovascular disease. 
To be eligible subjects must be willing to participate in all the studies outlined. Baseline 
Visit: Subjects will provide written informed consent. To ensure they are healthy, 
subjects will undergo a history and physical examination including supine and standing 
blood pressure; blood collection for complete blood count, HbA1c, fasting lipid profile, 
electrolytes, hepatic panel and urine collection to exclude pregnancy in females of child 
bearing potential. Habitual activity levels41, and bowel symptoms 42 will be assessed. 
Patients will also complete 
Stunkard’s Eating Inventory43, 
The Weight Efficacy Life-
Style Questionnaire44 & Eating 
and Weight Patterns-Revised45 
will be used. Body 
Composition: % body fat will 
be measured using dual-energy 
X-ray absorptiometry (iDXA 
scanner; GE, Wauwatosa, WI). 
 
b) Inclusion Criteria:  
i. Participants will be eligible 
for bariatric surgery i.e., a 
BMI ≥ 35 kg/M2 in the presence of at least one weight-related comorbid condition 
including hypertension, obstructive sleep apnea or dyslipidemia. Alternatively, a BMI ≥ 
40 kg/M2 without comorbid conditions is deemed to confer eligibility for bariatric 
surgery at the Mayo Clinic. 
ii. Age will be between 20 and 65 years of age. 
 
Roux-en-Y Gastric Bypass
Sleeve Gastrectomy + Liraglutide (3mg)
Sleeve Gastrectomy + Placebo
Patients undergo 
bariatric surgery 
(assigned on 
clinical grounds)
3 months post-op
Figure 2: Study Design 


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6
iii. Subjects will have no active physical illness which will interfere with mobility or 
weight loss after bariatric surgery. 
iv. Prior to acceptance for surgery, patients seen in the bariatric clinic must undergo 
psychological assessment and complete a supervised comprehensive lifestyle program. 
Please refer to 46 for details. 
v. Female subjects (randomized to study drug) who are sexually active and able to become 
pregnant, must agree to use birth control methods for the duration of the study 
 
c) Exclusion Criteria: 
i. Prior use of glucose lowering medication in the 3 months prior to screening. 
ii. A fasting glucose ≥ 126mg/dl or an HbA1c ≥ 6.5% will be taken as evidence of type 2 
diabetes and therefore patients will be deemed ineligible for participation. 
iii. Prior abdominal surgery other than those that would not affect glucose metabolism, i.e., 
cholecystectomy, appendectomy, C-section or hysterectomy. 
iv. Pregnancy or active consideration of pregnancy during the period of study. Subjects 
will be discontinued if they become pregnant during the study. 
v. Hypersensitivity to liraglutide or any product components. 
vi. Personal or family history of medullary thyroid carcinoma or Multiple Endocrine 
Neoplasia type 2 in those who will undergo sleeve gastrectomy 
vii. Prior history of pancreatitis, cholelithiasis or cholecystitis. 
viii. Concurrent use of insulin or any other GLP-1 receptor agonist. 
ix. Active, severe psychiatric disease 
x. Pregnancy or breastfeeding  
 
d) Surgery: Subjects will then undergo the surgery to which they had been assigned on 
clinical grounds. At present there are no clear guidelines in this regard and a patient is 
assigned to a bariatric surgical procedure based mainly on clinical factors.  Clinical 
factors considered include the presence of specific obesity-related comorbid diseases and 
body mass index.  Also considered are the patient’s psychological complexity, social 
situation, and a patient’s particular preference. A prior history of severe gastro-
esophageal reflux is a relative contraindication to SG. Note that the study team will 
play no role in that decision other than to ensure that participants in either group 
are matched for age, sex and BMI. At Mayo Clinic, Rochester the standard protocol is 
to see patients back for care at 3, 6 and 12 months and then annually after bariatric 
surgery.  
e) Randomization: Subjects undergoing SG will be randomized (1:1) at the time of the 3 
month visit after bariatric surgery. A double-blind design will be utilized. Liraglutide will 
be started at 0.6 mg SUBQ daily for 1 week. Subsequently, Liraglutide will be increased 
by 0.6 mg SUBQ daily on a weekly basis till the maintenance dose of 3.0 mg/day is 
reached. The placebo dose will also be titrated in a similar fashion. The study medication 
will be dispensed by the research pharmacy which will handle randomization and ensure 
that blinding is maintained. SG subjects will return to the CRTU for dispensing of study 
drug at standard follow-up visits (months 6, 12, 24, 36) and also at months 18 and 30.   
Subjects undergoing RYGB will return to the CRTU at standard follow up visits, months 
3, 6, 12, 24, 36. Recruitment will continue till 50 subjects after SG are randomized and 25 
subjects after RYGB are enrolled.  


Version 0.09 May 2, 2023 
7
 
f) Study Visits: These will be timed to coincide with the standard follow-up visits at 3, 6, 
12, 24and 36 months after bariatric surgery.  In addition to a history and physical 
examination, blood will be collected for creatinine, fasting glucose, HbA1c, fasting lipid 
profile and hepatic panel, and urine collection to exclude pregnancy in females of child 
bearing potential.   Supine and standing blood pressure will also be measured as well as 
body composition using DXA (at months 12, 24 and 36). Habitual activity levels 41, 
bowel symptoms 42, Stunkard’s Eating Inventory 43, The Weight Efficacy Life-Style 
Questionnaire 44 & Eating and Weight Patterns-Revised 45  will be assessed. Collected 
data will include height, weight, blood pressure, pulse rate, medications used, and adverse 
events. During clinic visits, as per standard practice, subjects will meet with a dietitian 
and with a behavioral psychologist. Compliance will be assessed using an electronic 
record of food intake. The psychologist will use motivational enhancement and behavior 
change techniques to promote compliance with the dietary guidelines47. In addition, to 
ensure compliance with instructions to increase physical activity, which will be reiterated 
at each visit, we will gather information about daily step counts from step-counters or 
smartphones. 
 
g) Telephone follow up: The study coordinator will schedule monthly calls with each 
subject (or more frequently if necessary) to rapidly identify problems and help ensure 
compliance. 
 
h) Early Termination 
For any patient enrolled in the study, the study participation will be concluded after the 
last visit at month 36, or at early termination. Should any patients withdraw or be 
withdrawn from the study, all of the Early Termination assessments should be completed 
before early termination, if possible, including; blood collection for creatinine, fasting 
glucose, HbA1c, fasting lipid profile, hepatic panel, and urine collection to exclude 
pregnancy in females of childbearing potential.   Supine and standing blood pressure will 
also be measured as well as body composition using DXA. Habitual activity levels, 
bowel symptoms, Stunkard’s Eating Inventory, The Weight Efficacy Life-Style 
Questionnaire & Eating and Weight Patterns-Revised will be assessed. Collected data 
will include height, weight, blood pressure, pulse rate, medications used if applicable, 
and adverse events. 
 
i) Power Calculation: See detailed power calculations below. 
 
j) Adverse Event Monitoring: The most common adverse reactions associated with 
liraglutide use are nausea, dizziness, abdominal pain, increased lipase, hypoglycemia, 
diarrhea, constipation, vomiting, headache, decreased appetite and dyspepsia. Acute 
pancreatitis has been associated with liraglutide use. Relevant symptoms will be screened 
for at the time of routine follow-up as well as telephone follow-up.   
 
1) Interpretation: We will accept our primary hypothesis that administration of 3.0mg 
liraglutide to participants after SG increases weight loss compared to placebo if after 
unblinding, the liraglutide group has significantly greater weight-loss from baseline 


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8
compared to the SG + placebo group. Similarly, we will reject our 2 (i) hypothesis if the 
weight loss observed in participants who undergo SG and receive Liraglutide does not 
differ from that after RYGB. Such a conclusion would support a role of GLP-1 in the 
weight loss achieved (and maintained) after RYGB. The questionnaires collected over the 
duration of the study will be utilized to help generate hypotheses related to food intake as 
it is affected by liraglutide use after SG compared to placebo. As before, we will 
determine whether the addition of liraglutide to SG improves effects of SG on cholesterol 
and blood pressure 15. If this indeed the case, we will accept our 2 hypothesis (ii). If the 
high GLP-1 concentrations observed after RYGB modulate appetite and food intake as 
suggested by our preliminary data (Fig. 1), we would expect weight loss after RYGB to 
also lower cholesterol and blood pressure. We will reject our 2 (iii) hypothesis if the 
blood pressure and LDL-cholesterol lowering observed in participants who undergo SG 
and receive Liraglutide does not differ from that after RYGB. 
 
STATISTICAL CONSIDERATIONS: 
Using JMP® Pro 11.2.1 (SAS Institute) for the power calculation we established the 
following: - 
 
In a prior experiment15 we observed an overall [mean value ± (SD)] of % weight change 
after RYGB = -26.1 ± (8.7) at 1 year. Assuming similar variation, 25 subjects who 
complete the study in each group would provide approximately 80% power (at a 2-sided 
0.05 α level), to detect a  a 7.0% difference in weight change between SG + treatment vs. 
SG + placebo. An intention to treat analysis will be undertaken.  
 
In another, as yet unpublished experiment, 12 subjects studied before and 4 weeks after 
RYGB lost 11.0 ± 3.4 Kg within 4 weeks. Assuming similar variation, 25 subjects per 
group would provide approximately 80% power (at a 2-sided 0.05 α level), to detect a 
difference of a 2.7 Kg in weight between groups. 
 
Schauer et al.14 observed an overall [mean value ± (SD)] of weight change after RYGB = 
--29.4 ± (8.9) Kg. Assuming similar variation, 25 subjects per group would provide 
approximately 80% power (at a 2-sided 0.05 α level), to detect a 7.2kg between-group 
difference.  
 
In an experiment47 where subjects were fed a diet similar to that consumed after bariatric 
surgery, we observed a weight change after 12 weeks of -14.8 ± (4.2) Kg. Assuming 
similar variation, 25 subjects per group would provide approximately 80% power (at a 2-
sided 0.05 α level), to detect a 3.4kg between-group difference.  Using % weight change, 
we observed a % change of -14.0 ± (3.0), giving us power to detect a 2.5% difference. 
  
DATA HANDLING AND RECORD KEEPING: 
The key personnel identified in this grant application have completed the required 
education on the protection of human research participants. The institution has 
established a formal program entitled the Mayo Investigator Training Program or MITP. 


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The MITP is a web based educational course designed to provide all personnel involved 
in human subject research with training about human subject protection. All Mayo 
personnel engaged in human subject research are required to complete the course. As 
detailed in the consent form, the expected risks include: 
 
Blood sampling. Blood samples are collected by venipuncture for this study. Bruising 
can occur with venipuncture, as can fainting, etc. Risk Monitoring / Risk Reduction: 
The samples are collected using aseptic technique in designated venipuncture areas of the 
Clinic where facilities are available should untoward reactions (fainting, etc.) occur. 
Given the aseptic nature of the sample collection and the small risk of bruising, the 
monitoring plan is focused on advising volunteers to call the investigators should they 
have unusual pain or discomfort from the venipuncture site.  
 
Radiation. Subjects will be exposed to radiation in this study. Lean body mass, percent 
body fat and visceral adiposity will be measured at the time of screening using DEXA 
(dual energy x-ray absorptiometry). Risk Monitoring / Risk Reduction: In all instances, 
the amount of radiation that a volunteer will receive will be well below levels that result 
in significant risk of harmful effects.  Proposed radiation exposure will be reviewed by 
the Mayo Clinic Radiation Safety Board prior to initiation of any study. Women who 
could become pregnant will be required to have a negative pregnancy test prior to 
participation in each study utilizing radioactive tracers. The Mayo CRTU body 
composition core has a QDR4500 with fan scan technology which allows body 
composition to be performed in only a few minutes.   
 
Confidentiality: All studies expose participants to the psychosocial risks arising from 
any breach in confidentiality. The risks include anxiety, confusion, and damage to family 
relationships or a compromised ability to obtain insurance or employment. These risks 
may not be confined to the individual but may extend to other family members. Risk 
Monitoring/Risk Reduction: The nature of the information obtained will be explained in 
detail to each participant – specifically none of this information will become part of the 
medical record and cannot impact the availability and nature of care or access to 
healthcare. All information will be stored anonymously in the database and only the PI or 
one of his designates will have access to the data.  
 
Adequacy of Protection against Risk 
Informed written consent. All protocols and all techniques to be used will be approved 
by the Mayo Clinic Institutional Review Board prior to initiation of any studies.  
Informed written consent will be obtained from subjects after the nature and possible 
consequences of the study have been explained. Eligibility will only be ascertained after 
informed, written consent has been obtained. 
Confidentiality. Confidentiality of all medical records is strictly maintained by 
established procedures. The original study data are kept in the study facility and are 
entered into a computer under the direction of a biostatistician.  Physical records are 
stored under lock and electronic records through security passwords.  The PI will review 
all data.  Physicians carry pagers. Volunteers have access to the Mayo Clinic paging 
operator 24 hr/day. Violations of confidentially will be immediately reported to the IRB 


Version 0.09 May 2, 2023 
10
and Data Monitoring Board. Study records will not identify subjects by name, rather 
using a numeric code. 
 
ETHICS: 
The risks to the subjects are small being primarily those of blood withdrawal and 
exposure to radiation. An understanding of the mechanisms by which bariatric surgery 
causes weight loss and the role of the GLP-1 receptor could potentially benefit all 
patients with obesity. In our opinion, the proposed protocols will provide sufficient new 
information on the effect of sleeve gastrectomy and Liraglutide (3mg) on weight that the 
potential benefit to be derived from the studies outweighs the minimal risks inherent in 
the execution of the studies. The investigative team will comply with the Declaration of 
Helsinki and ICH-GCP. Importance of the knowledge to be gained. The incidence and 
prevalence of obesity continues to increase. Understanding how sleeve gastrectomy and 
GLP-1 receptor agonists interact to affect weight maintenance will help in the 
development of new therapies to prevent and treat obesity. 
 
STUDY SCHEDULE: 
Please see study design. 
 
STUDY DRUGS AND MATERIALS: 
Packaging and Labelling of Study Medication(s), Storage and Drug Accountability 
of Study Medication(s), Randomization and Blinding 
Liraglutide 6 mg/ml, 3 mL prefilled pen-injector, solution for s.c. injection and Placebo, 3 
mL prefilled pen-injector, solution for s.c. injection will be handled by the research 
pharmacy which will dispense medication as per our prior practice. Medication will be 
stored in a refrigerator between 36ºF to 46ºF (2ºC to 8ºC). It will be protected from light 
and will not be frozen. During use, after dispensing to study subjects it will be used 
within 30 days and stored at controlled room temperature (59°F to 86°F; 15°C to 30°C) 
or in a refrigerator (36°F to 46°F; 2°C to 8°C). It will be protected from light and will not 
be frozen during this period. 
 
ADVERSE EVENTS: 
Definitions 
 
Adverse Event (AE): 
An AE is any undesirable medical event occurring to a subject in a clinical trial, whether 
or not related to the trial product(s). This includes events reported from the first trial 
related activity after the subject has signed the informed consent and until post treatment 
follow-up period as defined in the protocol. The following should not be recorded as AEs, 
if recorded as medical history/concomitant illness on the CRF at screening: 
• Pre-planned procedure, unless the condition for which the procedure was planned has    
worsened from the first trial related activity after the subject has signed the informed 
consent 


Version 0.09 May 2, 2023 
11
• Pre-existing conditions found as a result of screening procedures 
 
Clinical Laboratory Adverse Event: 
A clinical laboratory AE is any clinical laboratory abnormality regarded as clinically 
significant i.e., an abnormality that suggests a disease and/or organ toxicity and is of a 
severity, which requires active management, (i.e., change of dose, discontinuation of trial 
product, more frequent follow-up or diagnostic investigation). 
 
Serious Adverse Event (SAE): 
A serious AE is an experience that at any dose results in any of the following: 
• Death 
• A life-threatening* experience 
• In-patient hospitalisation or prolongation of existing hospitalization 
• A persistent or significant disability/incapacity 
• A congenital anomaly/birth defect 
• Important medical events that may not result in death, be life-threatening*, or require 
  hospitalization may be considered an SAE when, based upon appropriate medical 
judgement, they may jeopardise the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
• Suspicion of transmission of infectious agents  
*The term life-threatening in the definition of SAE refers to an event in which the subject was at risk of 
death at the time of the event. It does not refer to an event which hypothetically might have caused death if 
it was more severe. 
 
Serious Adverse Drug Reaction (SADR):  
An adverse drug reaction (ADR) is an adverse event (AE) for which a causal relationship 
to the trial product is at least possible i.e., causal relationship is conceivable and cannot 
be dismissed. Serious adverse reaction (SAR): Adverse event which fulfils both the 
criteria for a Serious Adverse Event and the criteria for an Adverse Reaction. 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR):  
An SAE which is unexpected and regarded as possibly or probably related to the 
trial/study product by the investigator.  
 
Non-Serious Adverse Event: 
A non-serious AE is any AE which does not fulfil the definition of an SAE. 
 
Severity Assessment Definitions: 
• Mild: Transient symptoms, no interference with the subject’s daily activities 
• Moderate: Marked symptoms, moderate interference with the subject’s daily activities 
• Severe: Considerable interference with the subject’s daily activities, unacceptable 
 
Relationship to study medication Assessment Definitions: 
• Probable: Good reasons and sufficient documentation to assume a causal relationship 
• Possible: A causal relationship is conceivable and cannot be dismissed 
• Unlikely: The event is most likely related to an etiology other than the trial product 
 


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Outcome Categories and Definitions: 
• Recovered: Fully recovered or by medical or surgical treatment the condition has 
returned to the level observed at the first trial related activity after the subject signed the 
informed consent 
• Recovering: The condition is improving and the subject is expected to recover from the 
event. This term should only be used when the subject has completed the trial 
• Recovered with sequelae: As a result of the AE, the subject suffered persistent and     
significant disability/incapacity (e.g., became blind, deaf, paralysed). Any AE 
recovered with sequelae should be rated as an SAE 
• Not recovered 
• Fatal 
• Unknown 
 
All adverse events will be reported to the Mayo Clinic IRB and the Safety Monitoring 
Panel.  
1. The Serious Adverse Events/Deviations Subcommittee of the Mayo Institutional 
Review Board meets at intervals of not less than every 2 weeks, except as otherwise 
determined by the Chair of the IRB. 
2. The Subcommittee is comprised of two members, one member required from each of 
the following groups: 
 
 
Group 1: Chair of the IRB or one of the Co-Vice Chairs 
 
 
Group 2: Secretary of the IRB or Assistant Secretary of the IRB    
4. The PI will report serious adverse events to the chair of the IRB using the Serious 
Adverse Event Reporting Form.  If the investigator receives a report or other 
materials (i.e., Medwatch form) from an external source regarding the event(s), a 
copy of these supporting documents will be attached to the Serious Adverse Event 
Reporting (SAE) form.  The PI will sign each Serious Adverse Event form.  A copy 
of the current consent form will be submitted with the actual risk highlighted in the 
current consent form.  Or, if the PI recommends any changes to the consent form 
document, a printed and electronic version of the revised consent form will be 
attached. 
5. The IRB office will review the incoming reports and triage according to the nature of 
the event: 
• Reports of serious adverse events that result in taking immediate action will 
be given first priority.   
• Reports of serious adverse events for which the PI recommends changes to the 
consent form document will be given 2nd priority.  
• All other reports will then be prioritized. 
6. The Subcommittee will review the reports in the order specified by the triage above.  
The members will review the SAE form and supporting materials.  If additional 
information is necessary, the Subcommittee will contact the PI (or study coordinator 
if the PI is unavailable) by conference call.  After review of the information, the 
Subcommittee will make an initial determination of the seriousness of the event and 
determine what actions, if any, will be required. 
7. FDA regulations do not require non-serious adverse events (those that do not fall into 
the categories outlined in step 3 above) to be reported to the IRB.  If non-serious 


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13
adverse events are reported to the IRB, these reports will be signed by a member of 
the Subcommittee and returned to the investigator.  The IRB will not retain a copy of 
these materials in the IRB office or files. 
8. For serious adverse events that the Subcommittee determines to be unrelated to the 
study drug/device/intervention, the original report and supporting materials will be 
kept in the IRB file.  The Subcommittee will review such reports, and if the 
Subcommittee agrees with the determination that the event was unrelated to study 
drug/device/intervention, then a copy of the report will be returned to the PI.  The 
IRB office will retain a list of the studies for which unrelated serious adverse events 
are reported.  Serious but unrelated adverse event reports will not be included in the 
minutes of the meeting. 
9. For all serious adverse event reports that are determined by the Subcommittee to be 
definitely, probably, or possibly related to the study drug/device/intervention, or if it 
is unknown what the relationship is at the present time, the Subcommittee will review 
the reports and related materials and include them in the minutes of the meeting.  The 
Subcommittee meeting minutes will be referred to the Full Board for final action.  For 
these adverse events which are unexpected and require a change in the consent form, 
the Chair or a Vice-Chair will be the primary reviewer upon referral to the Full 
Board. 
10. The convened IRB shall take whatever action(s) it deems appropriate.  These actions 
may include but are not limited to: 
• modification of the protocol, 
• modification of the consent form document, 
• modification to the timetable for continuing review requirements,  
• suspension of new enrollment into the study, 
• suspension of the study, or 
• termination of the study.  
Any studies that are suspended or terminated will be promptly reported to the sponsor 
that has provided funding for the study and/or to the FDA if the study involves an 
IND or an IDE. 
11. All other events not requiring suspension or termination shall be reported to the FDA 
through the normal reporting channel (notification from the investigator to the 
sponsor to the FDA). 
12. The minutes generated by the Subcommittee are approved by the convened IRB.   
The convened IRB will generate a subsequent minute excerpt only if additional action 
is taken (i.e., approval of revised consent form, revisions to the protocol, etc.). 
 
Follow-up of Adverse Events 
We will provide adequate medical care to the study subject for any study-related adverse 
events, including clinically significant laboratory values related to the study regardless of 
their insurance status. All adverse events classified as serious or severe or 
possibly/probably related to the trial product will be followed until the subject has 
recovered and all queries have been resolved.  
 
Pregnancy 


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Study subjects will be instructed to notify the sponsor-investigator immediately if they 
become pregnant. We will report to Novo Nordisk any pregnancy occurring during the 
trial period. Further participation in the study will be discontinued but telephone follow-
up will continue to monitor the pregnancy and its outcome. The investigator will report to 
Novo Nordisk information about the pregnancy, pregnancy outcome, and health of the 
newborn infant(s), as well as AEs in connection with the pregnancy, and AEs in the 
foetus and newborn infant. Pregnancy complications will be recorded as adverse event(s). 
If the infant has a congenital anomaly/birth defect this will be reported as a serious 
adverse event. 
 
Dr. Vella will be responsible for reporting of all adverse events including serious adverse 
events (SAE), suspected unexpected serious adverse reactions (SUSARs), serious adverse 
drug reactions (SADRs) to the competent authority and IRB based upon federal 
regulations and local IRB policies.  
 
Dr. Vella will report to Novo Nordisk all SAEs, SUSARs, and SADRs at the same time 
such events are reported to regulatory authorities or within 15 days from the PI becoming 
aware of such adverse events, whichever comes first. 
 
State that the sponsor-investigator will collect the following information at minimum for 
each of these events: 
1. Study name 
2. Patient identification (e.g., initials, sex, age) 
3. Event (preferably a diagnosis) 
4. Drug (e.g., Norditropin Simplex®) 
5. Reporter identification (e.g., Name, or initials) 
Also 6) Causality, and 7) Outcome might be reported, but this is not mandatory. 
 
Collection, Recording and Reporting of Adverse Events 
All events meeting the definition of an adverse event must be collected and reported from 
the first trial related activity after the subject has signed the informed consent and until 
the end of the posttreatment follow-up period as stated in the protocol.  
 
LIABILITY AND SUBJECT INSURANCE: 
During and following a subject’s participation in trial, Mayo Clinic will provide adequate 
medical care to the study subject for any study-related adverse events, including 
clinically significant laboratory values related to the study. This medical care for study 
subjects will be provided regardless of their insurance status. 
 
Dr. Vella will be responsible for the conduct of the study and Mayo Clinic agrees to 
defend, indemnify, and hold harmless Novo Nordisk, any of its parent companies, 
affiliates, or subsidiaries, and their respective officers, directors, employees, agents, 
representatives, distributors, salespersons, customers, licensees, and end-users from and 
against any claim, suit, demand, loss, damage, expense or liability imposed by any third 
party arising from or related to: (a) any breach of sponsor-investigator's obligations or 


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15
representations; or (b) sponsor-investigator’s negligent or grossly negligent use or willful 
misuse of the study drug, the results, or services derived therefrom.  This indemnification 
shall not apply in the event and to the extent that a court of competent jurisdiction or a 
duly appointed arbiter determines that such losses or liability arose as a result of Novo 
Nordisk’s gross negligence, intentional misconduct, or material breach of its 
responsibilities.  
 
PREMATURE TERMINATION OF STUDY: 
We do not anticipate circumstances that would lead to premature termination of the study. 
However, adverse events which are unexpected and require a change in the consent form, 
will be reported to the IRB. The convened IRB shall take whatever action(s) it deems 
appropriate.  These actions may include but are not limited to: 
• modification of the protocol, 
• modification of the consent form document, 
• modification to the timetable for continuing review requirements,  
• suspension of new enrollment into the study, 
• suspension of the study, or 
• termination of the study.  
Any studies that are suspended or terminated will be promptly reported to the sponsor.  
 
PUBLICATION PLAN: 
We plan to submit relevant data in abstract form to either the Endocrine Society or 
Obesity Society annual meeting. Subsequently, we intend to publish results in a journal 
such as Diabetes, Journal of Clinical Endocrinology & Metabolism or Obesity. The study 
will be registered with clinicaltrials.gov.  
 


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