Clinical trial NCT03500484
Conditions: Obesity, Childhood Neural Development
Sponsor: Yale University
Start date: 2018-06-06; Completion date: 2020-06-25
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To study the effects of liraglutide on neural responses to high fructose corn syrup (HFCS) in individuals with obesity.

Detailed description:
Adolescents are the highest consumers of sugar sweetened beverages (SSB) potentially because their developing brains are most susceptible to the rewarding neural effects of sugar consumption. Thus, we specifically target this population (adolescents) to understand neural mechanisms involved in excess sugar consumption which predisposes to the development of obesity, prediabetes, and type 2 diabetes.

Upon results entry, the data elements in protocol section of this record were updated to reflect the appropriate study phase and primary purpose that was inadvertently mischaracterized at the time of registration. One of the secondary outcomes was removed because it was a duplicate of the second primary outcome.

Arms: arm 1: Subjects will self-administer Liraglutide once daily for 12 weeks. arm 2: no intervention
Interventions: intervention 1: Liraglutide
Intervention descriptions: intervention 1: Liraglutide will be supplied in the following package sizes containing disposable, pre-filled, multidose pens. Each individual pen delivers doses of 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg or 3 mg (6 mg/mL, 3 mL). Liraglutide will be self-administered daily for 12 weeks under the following regimen: 0.6mg for 1 week, 1.2mg for 1 week, 1.8mg for 1 week, 2.4mg for 1 week, 3.0mg until week 12.

Protocol documents:
Prot_SAP_000.pdf: 
Title: Effect of liraglutide on neural responses to high fructose corn syrup in 
individuals with obesity. 
ClinicalTrials.gov ID: NCT03500484 
Last IRB Approval Date: 1/6/2021 
Protocol Version Date: 10/3/2020 
Document: Protocol and SAP 


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0
STUDY PROTOCOL
STUDY TITLE:  Effect of liraglutide on neural responses to high fructose corn syrup in
individuals with obesity.
ClinicalTrials.gov Identifier: NCT03500484
IND Number:  N/A
Investigational Product: Liraglutide
Yale Protocol Number: 2000022407
Version and Date: V15 October 3, 2020
Principal Investigator: 
Ania Jastreboff, MD, PhD
Yale University School of Medicine
333 Cedar Street, FMP-1
P.O. Box 208020
Yale University
Investigational Pharmacy Coordinator
Asaad Awan, PharmD
55 Park Street, LL – 15
New Haven, CT 06511
203-688-4872
Fax:  203-688-4890
asaad.awan@ynhh.org
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Table of Contents
STUDY SCHEMA .........................................................................................................................5
LIST OF ABBREVIATIONS........................................................................................................6
RATIONALE AND BACKGROUND..........................................................................................7
Rationale for Trial and Selected Patients......................................................................8
STATEMENT OF PURPOSE/OBJECTIVES ...........................................................................9
PHARMACEUTICAL AND THERAPEUTIC BACKGROUND..............................................9
Product Description & Rationale for Use.......................................................................9
Pharmacokinetics............................................................................................................10
Drug Interactions.............................................................................................................10
Drug Supply and Dose ...................................................................................................10
Storage and Stability and Handling Requirements....................................................11
Contraindications.............................................................................................................11
Warnings and Precautions.............................................................................................11
Adverse Reactions..........................................................................................................12
Ordering............................................................................................................................12
Accountability...................................................................................................................12
Destruction .......................................................................................................................12
STUDY PLAN AND PROCEDURES.......................................................................................13
Study Population .............................................................................................................13
Screening Procedures....................................................................................................13
Inclusion Criteria..............................................................................................................13
Exclusion Criteria ............................................................................................................13
Consent Process.............................................................................................................14
Study Entry/Registration ................................................................................................14
TREATMENT REGIMEN WITH LIRAGLUTIDE....................................................................15
Administration ..................................................................................................................15
Discontinuing Liraglutide................................................................................................15
Holding the Dose.............................................................................................................16
Restarting the Dose ........................................................................................................16
Safety Laboratory Procedures and Assessments......................................................16
Concomitant Medications...............................................................................................17
Diet and Other Considerations......................................................................................17
Duration of Therapy ........................................................................................................17
OTHER STUDY PROCEDURES .............................................................................................17
Oral Glucose Tolerance Test (OGTT) and Anthropometric Measures...................17
Continuous Glucose Monitor (CGM)............................................................................17
fMRI
18
Plasma Collection ...........................................................................................................20
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Sugar (HFCS) Drink........................................................................................................20
Eating Behavior Assessments ......................................................................................20
Heart Rate Monitoring: ...................................................................................................22
ASSESSING AND REPORTING ADVERSE EVENTS........................................................23
Definition...........................................................................................................................23
AE Expectedness............................................................................................................23
AE Attribution...................................................................................................................24
Procedure for Reporting Adverse Events....................................................................25
Minimizing Risks..............................................................................................................25
fMRI Data Collection and Processing..................................................................................26
ANALYSES AND STATISTICAL CONSIDERATIONS .......................................................26
DATA MANAGEMENT AND RECORD KEEPING...............................................................27
ADMINISTRATIVE AND REGULATORY...............................................................................28
Data safety and monitoring plan...................................................................................28
Project Team Meetings ..................................................................................................28
APPENDIX 1: TRIAL FLOW CHART......................................................................................29
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TRIAL SUMMARY
Abbreviated Title
Effect of liraglutide on neural responses to HFCS in
individuals with obesity
Trial Phase
2A
Indication
Healthy lean (n=15) and obese individuals (n=30)
Control
N/A
Product
Liraglutide
Number of Subjects
45
Estimated Enrollment 
Period
24 months
Aims
Aim 1 –  To investigate the effect of 12-16-week intervention with GLP-1 
analogue (liraglutide 3.0mg)  on eating behavior and food craving in 
individuals with obesity (age 15-39 yrs) who chronically consume SSBs (≥5 
SSBs/week).
Inclusion Criteria
1.
15-39 years old
2.
Lean (BMI 18.5-24.9 kg/m2) with normoglycemia with fasting 
plasma glucose (FPG) <100 mg/dL, 2-hour post oral glucose 
tolerance test (75gm glucose) glucose level <140 mg/dL and 
glycosylated hemoglobin (HbA1c) <5.7% or 
3.
Obese (BMI 30-45 kg/m2) with or without prediabetes (insulin 
resistance) but without diabetes <200 mg/dL,
4.
Ingest ≥5 sugar sweetened beverages per week,
5.
Weight stable for at least 6 months, 
6.
Able to provide written and verbal informed consent, 
7.
Able to read and write in English Able to read and write in English, 
Exclusion Criteria
1.
Current active participation in a weight loss program or weight 
loss of ≥10% of total body weight during the previous 6 months, 
2.
Prior bariatric surgery or current gastric balloon, 
3.
Following a vegetarian/vegan diet or dieting/restricting food due to 
significant food allergies, including but not limited to lactose 
intolerance and celiac disease, 
4.
Significant medical condition such as cardiac or pulmonary 
disease, coagulopathy, gastrointestinal disorder, known history of 
Type 1 or T2D, current psychiatric disorders (including suicidal 
ideation and depression), including eating disorders (DSM-IV 
criteria), neurological injury or illness
5.
Current use of weight-loss medications or supplements, 
psychiatric medications or anti-hyperglycemic medications (stable 
dose of metformin for > 6 months is acceptable),
6.
History of or family history of multiple endocrine neoplasia type 2 
(MEN-II) or medullary thyroid cancer, alcoholism, or previous 
history of pancreatitis, 
7.
Females who are pregnant or lactating, or who are unwilling to 
use proper contraception or remain abstinent,
Treatment Plan
Eligible obese subjects will self-administer Liraglutide once daily for 12-
16weeks. 
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STUDY SCHEMA
Screen patient for eligibility
Obtain consent
Obese 
TREATMENT: 
Administer Liraglutide 
Dose Titration for 30 days (included as part of 
12-16 week intervention)
12-16 weeks of Liraglutide with 
medication being shipped to the 
participant at monthly intervals 
12-16-week food snack task
Lean Controls
Baseline food snack task  
Baseline food snack task  
CGM Placement  
CGM Placement  
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LIST OF ABBREVIATIONS
AE – adverse event
FDA – Food and Drug Administration
fMRI – functional magnetic resonance imaging
HbA1c – hemoglobin A1c
HFCS – high fructose corn syrup
GLP-1 – Glucagon-like peptide 1 
PFC – pre frontal cortex
PI – principal investigator
RCT – randomized controlled trial
SAE – serious adverse event
SSB – Sugar sweetened beverage
T2D – Type 2 Diabetes
YCCI – Yale Center for Clinical Investigation
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RATIONALE AND BACKGROUND
Obesity and overweight has reached epidemic proportions in America with the current 
prevalence rate of 35% in adolescents1. This is particularly alarming since over 20% of obese 
adolescents develop prediabetes2 and the majority of obese adolescents will be obese in 
adulthood3 predisposing them to a myriad of diseases such as type 2 diabetes (T2D). In parallel 
with the obesity epidemic, added-sugar consumption has markedly increased in Western diets, 
and is postulated to be a contributor to this public health crisis4. Notably, adolescents are the 
highest consumers of added sugar, with ~20% of their caloric intake accounted for by sugar and 
nearly half of those calories from sugar-sweetened beverages (SSBs)5 which contain high 
fructose corn syrup (HFCS). Evidence indicates that increased consumption of sugars such as 
HFCS found in SSBs is associated with future weight gain6,7. Therefore, understanding the 
physiologic mechanisms modulating brain reward responses that may promote excess sugar 
consumption may provide insight into novel interventions to quell SSB ingestion, thus 
attenuating obesity in adolescents.
Indeed, excessive sugar intake is highly rewarding in the brain8. In recent studies, we have 
found that simple sugars such as glucose and fructose affect brain pathways implicated in 
regulation of appetite and reward. Specifically, glucose stimulates homeostatic (hypothalamic) 
brain regions and fructose stimulates hedonic (striatal) regions and both require activation of the 
prefrontal cortex (PFC), which exerts regulatory control over impulses, choices, and decision-
making, to regulate these brain regions to control food intake9. We previously reported that 
obese adolescents have decreased medial PFC (mPFC) control responses to consumption of 
glucose and fructose9, suggesting diminished capacity to down-regulate hedonic (striatal) and 
homeostatic (hypothalamic) brain responses that may affect eating behavior. Furthermore, we 
found hyperactivation of reward (striatal) responses to fructose ingestion in obese adolescents. 
Notably, these two highly rewarding simple sugars are rarely, if ever, consumed in isolation, but 
rather are ingested in combination forms such as HFCS10. Thus, the question arises: what 
interventions may attenuate excess sugar (SSB) consumption in obese adolescents by 
potentially decreasing the neural reward response to HFCS.
Increased ingestion of added sugars, such as HFCS in SSBs is associated with the obesity 
epidemic4, long- term weight gain6,7, T2D, and cardiovascular disease (CVD)22. Furthermore, 
ingestion of SSB’s may contribute to the development of T2D and CVD independent of 
obesity22. Notably, adolescents are the highest consumers of added-sugars5, thus studying this 
vulnerable population to elucidate novel therapeutic strategies to prevent the development of 
T2D is vital. It is striking that adolescents with obesity and prediabetes (insulin resistance) 
progress to develop T2D much more rapidly than adults with prediabetes, within 21 months vs. 
5 years, respectively21. Additionally, once adolescents develop obesity and T2D they often are 
not successful in maintaining glycemic control with lifestyle and metformin therapy or losing 
weight with lifestyle interventions, and subsequently their glycemic control deteriorates 
necessitating more aggressive pharmacological treatment such as insulin therapy23. It is clear 
that prevention of T2D in adolescents is imperative and interventions to mitigate SSB 
consumption, halt weight gain, and progression to T2D are critical. Yet, therapies to decrease 
added-sugar consumption, weight gain, and progression to T2D in adolescents are blatantly 
lacking. GLP-1 analogues improve glycemic control, contribute to weight loss, and may 
attenuate food preference for sweets15,16. Thus, it is important to elucidate how GLP-1 
analogues effect neural responses in reward-motivation pathways of the brain to affect food 
preference and contribute to weight loss in obese prediabetic adolescents. The expected 
results may significantly contribute to our understanding of neural mechanisms involved in 
GLP-1 analogue action to affect food preference and curb excess sugar intake in the setting of 
adolescent obesity and prediabetes and have important implications for clinical practice in the 
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care of obese prediabetic adolescents to prevent progression to T2D.
Rationale for Trial and Selected Patients
Adolescents are the highest consumers of SSB potentially because their developing brains are 
most susceptible to the rewarding neural effects of sugar consumption. The prefrontal cortex 
(PFC) (implicated in control of impulses, choices, and decision-making) is not fully developed 
in adolescents24, undergoing significant development into young adulthood25, and thus has not 
yet gained mature regulatory capacity over reward-motivation (striatal) and hunger-satiety 
(hypothalamic) brain regions, to control SSB intake and potentially mitigate excessive 
consumption in adolescents. Thus, we specifically target this vulnerable population 
(adolescents) to understand neural mechanisms involved in excess sugar consumption which 
predisposes to the development of obesity, prediabetes, and T2D.
As the original target study population is adolescents, we are now expanding the age group to 
include 15-17 year olds; we are basing this on several new studies which have been 
conducted recently and published, as well as the FDA approval of liraglutide for children age 
10-17 who have type 2 diabetes. As of June 2019, liraglutide is now FDA approved for 
treatment of type 2 diabetes in children 10 years and older68, 69. Liraglutide has been FDA 
approved for treatment of obesity in adults >18 years old since 2014, and was approved in 
December, 2020 for the treatment of obesity in adolescents aged 12-17 years;  additionally, 
several clinical trials have been conducted in children and adolescents (age 7-17 years old) 
with obesity alone without type 2 diabetes to assess safety, tolerability and dose. Liraglutide 
has been shown to have a similar safety, tolerability and pharmacokinetic profile in younger 
children (age 7-11 years) with obesity as in adults71. In a safety and tolerability trial, liraglutide 
was found to have a similar profile in terms of side effects and pharmacokinetics as in adults 
with obesity and adolescents with obesity (age 12-17 years) at the same dose used for weight 
management in adults70. Earlier in 2020, a clinical trial entitled “Effect of Liraglutide for Weight 
Management in Pubertal Adolescent Subjects With Obesity: 56-week Double-blind, 
Randomised, Parallel-group, Placebo-controlled, Multi-national Trial Followed by 26-week 
Period Off Study-drug” was completed, published, and liraglutide 3.0mg is now FDA-approved 
for treatment of adolescents (age 12-17 years old) with obesity, without diabetes72, 73. Given 
that liraglutide has been shown to have a similar safety profile in adolescents with obesity as 
adults with obesity, we believe it would be beneficial to lower the study’s age minimum to mid-
late adolescents (age 15-17) to better understand the neural mechanisms in adolescents with 
excess sugar consumption. Indeed, adolescents are the highest consumers of added sugar 
and sugar sweetened beverages and the polultation we are most interested in both for 
understanding underlying mechanisms which lead to or quell SSB consumption as well as 
treatment for this high risk population. 
The neural mechanisms involved in the reward response to “real-life” sugars, such as HFCS, 
may provide insight into novel interventions to quell SSB ingestion. Excessive sugar intake is 
highly rewarding in the brain8. Glucose stimulates homeostatic (hypothalamic) brain regions 
and fructose stimulates hedonic(striatal) regions and both require the prefrontal cortex (PFC) 
to regulate these brain region’s responses to control food intake9. In preliminary work, we 
found that obese adolescents have decreased medial PFC (mPFC) executive control response 
to ingestion of glucose and fructose9, suggesting diminished capacity to down-regulate 
hedonic (striatal) and homeostatic (hypothalamic) brain regions that may affect eating 
behavior. Furthermore, we found hyperactivation of reward (striatal) response to fructose 
ingestion in obese adolescents9. This is important because fructose in combination with 
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glucose makes up “real-life” sugar in forms such as HFCS found in SSBs10, but the impact of 
“real-life” sugar ingestion on neural responses in adolescents is not known. Thus, we chose to 
investigate brain response to ingestion of HFCS (60% fructose/40% glucose) as it is contained 
in the five most commonly consumed SSBs in the United States, including Pepsi, Coke, Dr. 
Pepper, Mountain Dew, and Sprite10.
Therapies to mitigate added-sugar consumption, weight gain, and progression to T2D in 
adolescents are blatantly lacking. GLP-1 analogues decreased food intake and potentially 
affect food preference away from sugar-containing food. We will elucidate neural mechanisms 
by which the GLP-1 analogue liraglutide tempers food intake and potentially alters food 
preference. Importantly, GLP-1 analogues may prove to be a novel intervention to curb excess 
sugar consumption by shifting preference away from beverages containing sugar and, thus, 
contribute to prevention of T2D.
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STATEMENT OF PURPOSE/OBJECTIVES
Aim 1 –  To investigate the effect of GLP-1 analogue (liraglutide 3.0mg) on eating behavior 
and food craving in individuals with obesity (age 15-39 yrs) who chronically consume SSBs 
(≥5 SSBs/week).
Exploratory Aim: To investigate the role of specific metabolic/hormonal responses (serum 
leptin, insulin, glucose, GLP-1, acyl-ghrelin) induced by food consumption, and in the setting 
of liraglutide treatment
PHARMACEUTICAL AND THERAPEUTIC BACKGROUND
Product Description & Rationale for Use
Liraglutide was approved for use in adults by the FDA in 2010 for T2D treatment and in 2014 for 
obesity treatment. It 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 with an initial body mass index (BMI) of 30 kg/m2 or greater (obese) or 27 
kg/m2 or greater (overweight) in the presence of at least one weight-related comorbid condition 
(e.g. hypertension, type 2 diabetes mellitus, or dyslipidemia).  Liraglutide, a GLP-1 analogue 
produced by Novo Nordisk used in the treatment of both obesity and T2D, contributes to weight 
loss11,13 and improves glycosylated hemoglobin levels11,12.
It is an intriguing therapeutic intervention to potentially affect food preference and decrease 
sugar consumption and attenuate weight gain. Liraglutide is an analogue of an incretin 
hormone, glucagon-like peptide-1 (GLP-1), which is secreted by L cells in of the small intestine 
in response to food ingestion17. GLP-1 dysregulation is noted in individuals with obesity and 
T2D with decreased GLP-1 levels post-parandially18. Of particular interest is how GLP-1 
analogues, such as liraglutide, decrease food intake, and alter food preference. 
Preclinical studies have demonstrated that liraglutide not only decreases food intake but also 
changes food preference14. Rats offered chow and candy, obtained 75% of their calories from 
candy and gained 15- 20% more weight that chow feed counterparts14; subsequently with 12-16 
weeks of liraglutide treatment the rats decreased their food intake and reversed food preference 
with an increase in chow intake and decrease in candy ingestion. In another study, rats treated 
with a GLP-1 analogue no longer preferred the environment which contained chocolate pellets 
in a conditioned place preference test16. Furthermore, in a mouse model, GLP-1 was released 
from taste-bud cells in response to sweet compounds37 and GLP-1 receptor knockout mice 
demonstrated decreased taste response to sweeteners38 and reduced behavioral response to 
sweet compounds (short-term lick test) compared to wild-type mice37. These studies suggest 
that GLP-1 is important in sweet taste sensitivity and that GLP-1 analogues may shift food 
preference away from sugar-containing foods. 
Pharmacokinetics
Absorption - Following subcutaneous administration, maximum concentrations of liraglutide are 
achieved at 11 hours post dosing. The average liraglutide steady state concentration (AUCτ/24) 
reached approximately 116 ng/mL in obese (BMI 30-45 kg/m2) subjects following administration 
of Saxenda®. Liraglutide exposure increased proportionally in the dose range of 0.6 mg to 3 mg. 
The intra-subject coefficient of variation for liraglutide AUC was 11% following single dose 
administration. Liraglutide exposures were considered similar among three subcutaneous 
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injection sites (upper arm, abdomen, and thigh). Absolute bioavailability of liraglutide following 
subcutaneous administration is approximately 55%. 
Distribution - The mean apparent volume of distribution after subcutaneous administration of 
liraglutide 3 mg is 20-25 L (for a person weighing approximately 100 kg). The mean volume of 
distribution after intravenous administration of liraglutide is 0.07 L/kg. Liraglutide is extensively 
bound to plasma protein (greater than 98%). 
Metabolism - During the initial 24 hours following administration of a single [3H]-liraglutide dose 
to healthy subjects, the major component in plasma was intact liraglutide. Liraglutide is endog-
enously metabolized in a similar manner to large proteins without a specific organ as a major 
route of elimination. 
Elimination - Following a [3H]-liraglutide dose, intact liraglutide was not detected in urine or 
feces. Only a minor part of the administered radioactivity was excreted as liraglutide-related 
metabolites in urine or feces (6% and 5%, respectively). The majority of urine and feces 
radioactivity was excreted during the first 6-8 days. The mean apparent clearance following 
subcutaneous administration of a single dose of liraglutide is approximately 0.9-1.4 L/h with an 
elimination half-life of approximately 13 hours, making liraglutide suitable for once daily 
administration.
Drug Interactions
Liraglutide has low potential for pharmacokinetic drug-drug interactions related to cytochrome 
P450 (CYP) and plasma protein binding.
Drug Supply and Dose
Liraglutide will be supplied in the following package sizes containing disposable, pre-filled, multi-
dose pens. Each individual pen delivers doses of 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg or 3 mg (6 
mg/mL, 3 mL). The study drug will be purchased from Novo Nordisk.
3 x Saxenda® pen NDC 0169-2800-13 
5 x Saxenda® pen NDC 0169-2800-15 
Each Saxenda® pen is for use by a single patient. A Saxenda® pen should never be shared 
between patients, even if the needle is changed.
To minimize side effects; liraglutide will be titrated over the first month: starting at a dose of 
0.6mg daily for 7 days, increasing to 1.2mg on day 8 for the next 7 days, increasing to 1.8mg on 
day 15 for the next 7 days, increasing to 2.4mg on day 22 for the next 7 days, and then 
increasing to 3.0mg on day 39 and continuing this dose for the remainder of the study (12-16 
weeks total). If a subject is not able to increase dose to 3.0mg, they will be maintained on the 
highest dose they are able to tolerate, at a minimum of 1.2mg. If a subject is not able to tolerate 
the medication at all or at a dose of at least 1.2mg, the medication will be discontinued and the 
subject will not continue in the study. 
Storage and Stability and Handling Requirements
Prior to first use, Saxenda® should be stored in a refrigerator between 36ºF to 46ºF (2ºC to 8ºC) 
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It should not be stored in the freezer or directly adjacent to the refrigerator cooling element. Do 
not freeze Saxenda® and do not use Saxenda® if it has been frozen. 
After initial use of the Saxenda® pen, the pen can be stored for 30 days 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). Keep 
the pen cap on when not in use. Saxenda® should be protected from excessive heat and 
sunlight. Always remove and safely discard the needle after each injection and store the 
Saxenda® pen without an injection needle attached. This will reduce the potential for
contamination, infection, and leakage while also ensuring dosing accuracy.
Contraindications
Personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia 
syndrome type 2, Hypersensitivity to liraglutide or any product components and Pregnancy.
Warnings and Precautions
Warnings and precautions include the following Thyroid C-cell Tumors, Acute Pancreatitis, 
Acute Gallbladder Disease, Serious Hypoglycemia, Heart Rate Increase, Renal Impairment, 
Hypersensitivity Reactions, and Suicidal Behavior and Ideation. 
Adverse Reactions
Most common adverse reactions, reported in greater than or equal to 5% are: nausea, 
hypoglycemia, diarrhea, constipation, vomiting, headache, decreased appetite, dyspepsia, 
fatigue, dizziness, abdominal pain, and increased lipase.  These will be reviewed with the 
participants.
Availability 
 
Liraglutide will be ordered directly from Novo Nordisk by the investigational pharmacy and 
shipped directly to the investigational pharmacy. 
Ordering
The study drug will be purchased from Novo Nordisk by the Investigational Pharmacy. 
Product will be shipped to the investigational pharmacy and over labeled as an IP.  The label 
will include address and telephone number, the protocol number, IP name, dosage form and 
strength (where applicable), amount of IP per container, lot number, expiration date (where 
applicable), medication identification/kit number, dosage instructions, storage conditions, and 
required caution statements and/or regulatory statements as applicable, as per local 
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regulations. Additional information may be included on the label as applicable per local 
regulations. 
Accountability
Only the pharmacist or designee will dispose study drug. A record of drug dispensed and 
administered to each patient must be maintained. The pharmacist will document the dose 
dispensed in the appropriate study records which will be reviewed during monitoring visits. In 
addition, the pharmacist needs to maintain an inventory log of all IP delivered, stored, dispensed 
and destroyed (including expiry date and batch number).
Destruction
The sponsor (or designee) will review with the investigator and relevant site personnel the 
procedures for documenting receipt of IP, as well as the procedures for counting, reconciling IP, 
and documenting this process. Used (and/or empty) syringes of enoxaparin will be destroyed 
locally. Unused syringes will be destroyed locally after sponsor’s approval for destruction. 
Documentation of all used and unused drug disposal must be maintained on site for review 
during monitoring visits.
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STUDY PLAN AND PROCEDURES
Study Population
We will enroll 45 adolescents/young adults age 15-39 who present at any of the Principal 
Investigator’s clinics where routine care is provided or may be recruited from the Yale New 
Haven Community via methods described below. 15 lean controls and 30 obese patients will be 
enrolled.  We will enroll controls (lean) subjects (lean adults and lean adolescents) who are at 
risk for developing obesity (i.e. individuals with a family history of obesity or metabolic disease).
Screening Procedures
Subjects will be identified and recruited from the local community via recruiting personnel in the 
Yale Center for Clinical Investigation (YCCI) and from the Yale Pediatric Obesity Clinic and the 
Yale Diabetes Center. We will utilize existing YCCI methods of recruitment including, fliers, web 
advertising, Yale research websites, and HelpUsDiscover. Potential participants will be initially 
screened for inclusion and exclusion criteria by phone by the research coordinator, and then, if 
initial study criteria are met, will be invited for an in-person visit at the Yale outpatient research 
unit (CSRU) or hospital research unit (HRU). Healthy lean and obese participants will be 
frequency matched on age, race/ethnicity and sex.
Inclusion Criteria
1.
15-39 years old
2.
Lean (BMI 18.5-24.9 kg/m2) with normoglycemia with fasting plasma glucose (FPG) 
<100 mg/dL, 2-hour post oral glucose tolerance test (75gm glucose) glucose level <140 
mg/dL and glycosylated hemoglobin (HbA1c) <5.7% or 
3.
Obese (BMI 30-45 kg/m2) with or without prediabetes (insulin resistance), which is 
defined as two of the following: 
a.
FPG <126 mg/dL
b.
2-hour post oral glucose tolerance test (75gm glucose)
c.
glucose level <200 mg/dL
d.
HbA1c <6.5% 
4.
Ingest >=5 sugar sweetened beverages per week
5.
Weight stable for at least 6 months 
6.
Able to read and write in English
7.
Able to provide written and verbal informed consent
Exclusion Criteria
1.
Current active participation in a weight loss program or weight loss of >=10% of total 
body weight during the previous 6 months
2.
Prior bariatric surgery or current gastric balloon 
3.
Following a vegetarian/vegan diet or dieting/restricting food due to significant food 
allergies, including but not limited to lactose intolerance and celiac disease 
4.
Significant medical condition such as cardiac or pulmonary disease, coagulopathy, 
gastrointestinal disorder, known history of Type 1 or Type 2 diabetes, current psychiatric 
disorders (including suicidal ideation and depression), current eating disorders (DSM-IV 
criteria), neurological injury or illness
5.
Current use of weight-loss medications or supplements, psychiatric medications or anti-
hyperglycemic medications (stable dose of metformin for > 6 months is acceptable)
6.
 History of or family history of multiple endocrine neoplasia type 2 (MEN-II) or medullary 
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APPROVED BY THE YALE UNIVERSITY IRB 1/6/2021
thyroid cancer, alcoholism, or previous history of pancreatitis
7.
Females who are pregnant or lactating, or who are unwilling to use proper contraception 
or remain abstinent,
Consent Process
Research staff and investigators permitted to consent patients will describe the trial in detail 
including the data collection requirements, risks, procedures, and alternative treatments. 
Patients will be made aware that they are under no obligation to a participate, that failure to 
participate will not adversely affect their care, and that they may withdraw consent at any time. 
Data will continue to be collected until the patient withdraws consent to use it. They will be given 
an opportunity to ask questions and have these answered to their satisfaction. The consent form 
will then be signed and dated by both the patient and the study personnel obtaining consent. If 
there are any questions regarding competence, the trial will not be offered to the patient. The 
consent process will be documented in the medical record.
Study Entry/Registration
Eligibility will be determined by the PI and/or research team using an eligibility checklist. Once a 
patient is confirmed eligible and consent is obtained the patient will be assigned a unique study 
ID. The study ID will be used when the patient is registered into OnCore, Yale’s Clinical Trials 
Management System and included on all related study documents. Subjects will be entered into 
OnCore by the study research team. 
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APPROVED BY THE YALE UNIVERSITY IRB 1/6/2021
TREATMENT REGIMEN WITH LIRAGLUTIDE 
To minimize side effects; liraglutide will be titrated over the first month: starting at a dose of 
0.6mg daily for 7 days, increasing to 1.2mg on day 8 for the next 7 days, increasing to 1.8mg on 
day 15 for the next 7 days, increasing to 2.4mg on day 22 for the next 7 days, and then 
increasing to 3.0mg on day 29 and continuing this dose for the remainder of the study (12-
16weeks total). This titration schedule (Table 1) will serve as a guide for study clinicians for 
liraglutide titration. Liraglutide will not be titrated up any faster than the above table outlines. If a 
participant experiences side effects (such as nausea and vomiting) the study drug will be titrated 
up more slowly by the study clinicians with close oversight, guidance, and approval from Dr. 
Jastreboff (the study PI). If a subject is not able to increase dose to 3.0mg (due to side effects 
such as nausea or vomiting), they will be maintained on the highest dose they are able to 
tolerate, at a minimum of 1.2mg. If the subject is not able to tolerate a dose of at least 1.2mg, 
the medication will be discontinued and the subject will not continue in the study. 
The participant will be provided with an information sheet detailing the study visits and the 
titration schedule (Appendix 3).
The study drug will be purchased from Novo Nordisk. 
Table 1: Dose Titration Over One Month
Drug
Day
Dose/
Potency
Dose 
Frequency
Route 
Treatment 
Period
Liraglutide
1-7
0.6mg 
1x daily
Subcutaneous
1 week
Liraglutide
8-14
1.2mg 
1x daily
Subcutaneous
1 week
Liraglutide
15-21
1.8mg
1x daily
Subcutaneous
1 week
Liraglutide
22-28
2.4mg
1x daily
Subcutaneous
1 week
Liraglutide
29-35
3.0mg
1x daily
Subcutaneous
Until 12 -
16 
week MRI
Administration
The medication is administered once daily subcutaneously via an injection pen. 
Each study participant will be taught how to administer the medication by the PI who will follow-
up with each subject at specified interval time points as outlined in Appendix 1 to ensure that 
participants are tolerating the liraglutide and adhering to taking the medication daily. The 
participant’s first administration will be observed to ensure that it is being doing properly. 
Discontinuing Liraglutide
If a subject is not able to tolerate the medication at all due to persistent vomiting or intolerable 
nausea, the medication will be discontinued and the subject will not continue in the study. If the 
subject’s mood changes while participating in the study, as assessed by PHQ-9, the PI will 
contact the subject and assess whether they need intervention and determine if they can 
continue in the study or if the drug should be discontinued. 
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Holding the Dose
Liraglutide will be stopped temporarily if ANY the following occur:
-
Persistent vomiting or nausea
-
Moderate-severe dehydration (as a result of nausea/vomiting)
-
Significant persistent abdominal pain 
-
Other side effects which the participant attributes to starting study drug
Restarting the Dose
-
If participant is amenable to trying the study drug again, the medication will be restarted 
within 4 days with phone call follow up to assess tolerability.  If participant is not able to 
tolerate the study drug on re-initiation then they will not continue in the study. If the 
participant does not want to participate in the study at any time point, they may withdraw 
from the study.
-
If the participant withdraws from the study at any point, they will be asked to complete 
the end of study questionnaires, dietary recalls and to return for a final weight, body 
composition measurement and end-of-study blood work. If the participants complete 
these visits, they will be compensated the same as if these vists had been completed at 
the end of the study. 
Safety Laboratory Procedures and Assessments
Participants’ screening/baseline laboratory assessment will include amylase/lipase, creatinine/ 
GFR, lipid profile, TSH, hemoglobin A1c, AST/ALT, calcitonin and hematocrit.  If participants’ 
screening laboratories are not within normal range, (they will be excluded from participation in 
the study.) they will be assessed by the study investigators and decision about participation in 
the study with be determined on an individual basis. For example, if the AST/ALT are greater 
than 3x the upper limit of normal the subject will not be included in the study.  
-
Participants’ screening visit will also include a questionnaire to assess suicidality and 
depression, using the Patient Health Questionnaire (PHQ-9) (Appendix 2). Because the 
co-occurrence of depression is higher in individuals with obesity, we anticipate that many 
of our subjects may have minimal to mild depression. Subjects will be excluded from 
participation in the study if the result of the screen is greater than or equal to 10 
(moderate to severe depression). They will also be referred to a psychologist if they 
score > 10. Any concern for suicide or self harm will be immediately addressed by 
implementing emergency petition (EP) procedures and/or calling 911. 
Obese participants being treated with Liraglutide will have weekly phone calls with the 
study physicians or nurse practitioner to monitor for any adverse effects. In addition, 
during the first week, the study physicians or nurse practitioner will follow-up with the 
participant with two additional phone calls to answer any questions he/she may have 
about medication administration as well as to discuss any potential side effects. 
Participants will be provided with contact information should they need to contact the 
study physicians or nurse practitioner at any time throughout the study. The participants 
will be asked to report any side effects or worsening of depression, suicidal thoughts or 
behavior, and/or any unusual changes in mood or behavior, to the study physicians or 
nurse practitioner right away.
Obese participants being treated with Liraglutide will have safety laboratory 
assessments performed at the following interval time points: week 0 (screening labs as 
above) and week 12-16 (end of study). These labs will include amylase, lipase, AST, 
APPROVED BY THE YALE UNIVERSITY IRB 1/6/2021


A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 1/ 6/ 2 0 2 1
A L T, c al cit o ni n  a n d a uri n e pr e g n a n c y t e st. D uri n g p h o n e s e s si o n s at w e e k s 4 a n d 8 t o 
m o nit or f or a n y a d v er s e e v e nt s, st u d y p er s o n n el will al s o a d mi ni st er t h e P H Q- 9 t o a g ai n 
a s s e s s s ui ci d alit y a n d a n y c h a n g e s i n m o o d. T h e P H Q- 9 will al s o b e a d mi ni st er e d at t h e 
at t h e s e c o n d f o o d s n a c k t a s k ( w e e k 1 2- 1 6, e n d of st u d y). Si n c e t h e q u e sti o n n air e r eli e s 
o n p ati e nt s elf-r e p ort, all r e s p o n s e s will b e v erifi e d b y t h e PI a n d t h e PI will c o nt a ct t h e 
s u bj e ct t o a s s e s s w h et h er t h e y n e e d i nt er v e nti o n a n d d et er mi n e if t h e y c a n c o nti n u e i n 
t h e st u d y or if t h e dr u g s h o ul d b e di s c o nti n u e d. If at a n y ti m e t h e s u bj e ct s c or e s > 1 0 o n 
t h e P H Q- 9, t h e y will b e r ef err e d t o a p s y c h ol o gi st, a n d a n y c o n c er n f or s ui ci d e or s elf 
h ar m will b e i m m e di at el y a d dr e s s e d b y i m pl e m e nti n g e m er g e n c y p etiti o n ( E P) 
pr o c e d ur e s a n d/ or c alli n g 9 1 1.
C o n c o mit a nt M e di c ati o n s
-  
Ot h er m e di c ati o n u s e will b e a s s e s s e d p er e x cl u si o n crit eri a.  If t h e p arti ci p a nt i s t o 
t a k e/ st art a n e w m e di c ati o n w hil e i n t h e st u d y t h e y will b e a s k e d t o i nf or m t h e st u d y PI 
i m m e di at el y t o a s s e s s c o n c o mit a nt m e di c ati o n u s e.
Di et a n d Ot h er  C o n si d er ati o n s
T h er e ar e  n o di et ar y or f o o d r e stri cti o n s 
D ur ati o n of  T h er a p y
F or O b e s e  p ati e nt s, Lir a gl uti d e will b e a d mi ni st er e d d ail y f or 1 2- 1 6 w e e k s. If a n y of t h e f oll o wi n g 
o c c ur, t h e m e di c ati o n will b e st o p p e d:
- 
P a n cr e atiti s ( s e v er e a b d o mi n al p ai n, i n cr e a s e d a m yl a s e/li p a s e)
- 
S e v er e d e h y dr ati o n
- 
T h e p arti ci p a nt c h o o s e s n ot t o c o nti n u e i n t h e st u d y
L e a n c o ntr ol s  will n ot b e gi v e n st u d y dr u g. 
O T H E R S T U D Y  P R O C E D U R E S
Or al Gl u c o s e  T ol er a n c e T e st ( O G T T) a n d A nt hr o p o m etri c M e a s ur e s
Aft er c o n s e nt  i s o bt ai n e d a n d at b a s eli n e pri or t o a n y st u d y pr o c e d ur e s, A nt hr o p o m etri c 
m e a s ur e s will b e t a k e n i n cl u di n g w ei g ht, p er c e nt f at m a s s, a n d t ot al f at m a s s ( m e a s ur e d wit h a 
T a nit a B o d y F at A n al y z er) a n d h ei g ht ( m e a s ur e d wit h a st a di o m et er). B MI will b e c al c ul at e d 
( w ei g ht [ k g] / h ei g ht [ m 2]). A uri n e pr e g n a n c y t e st will b e p erf or m e d o n f e m al e s. 
L e a n y o u n g  a d ult s will c o m pl et e 1 O G T T ( at b a s eli n e) a n d e a c h o b e s e y o u n g a d ult will 
c o m pl et e 2 O G T T s ( o n e at b a s eli n e a n d o n e at w e e k 1 0 of t h e i nt er v e nti o n wit h lir a gl uti d e).
S u bj e ct s will r e c ei v e  7 5 g gl u c o s e dri n k or all y ( Gl u c ol a). A n i ntr a v e n o u s (I V) c at h et er will b e 
pl a c e d a n d bl o o d s a m pl e s will b e t a k e n f or gl u c o s e a n d i n s uli n a s s a y s at ti m e p oi nt s - 2 0, 0, 1 0, 
2 0, 3 0, 4 5, 6 0, 7 5, 9 0, 1 0 5, 1 2 0 mi n ut e s. I n a d diti o n, f a sti n g a c yl- g hr eli n, l e pti n, H g b A 1 c, G L P- 1 
will b e dr a w n. W h ol e b o d y i n s uli n s e n siti vit y i n d e x ( W BI SI) will b e c al c ul at e d 
( W BI SI = 1 0, 0 0 0/[ ( F P G x f a sti n g pl a s m a i n s uli n) x ( m e a n O G T T gl u c o s e c o n c e ntr ati o n x m e a n 
O G T T i n s uli n c o n c e ntr ati o n)] 4 9 a s a m e a s ur e of i n s uli n r e si st a n c e. N o m or e t h a n 5 0 ml of bl o o d 
will b e dr a w n o n t h e O G T T d a y.
A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 1/ 6/ 2 0 2 1


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Continuous Glucose Monitor (CGM)
CGM enables measurement of glucose levels continuously throughout the day. To assess 
glucose variability, participants will be asked to use the CGM (FreeStyle Libre Pro) for up to 14 
days.  During their screening/baseline visit, a CGM sensor/transmitter will be placed on the 
participant’s upper arm and attached with an adhesive patch by a trained study staff member. 
The sensor includes a wire-like tip which will be under the participant’s skin in their fat tissue. 
The participants will be taught how to use the CGM. There are no restrictions on the participants 
while they wear the transmitter/sensor with regard to physical activity except for swimming. 
Participants will be blinded to the CGM monitor glucose levels as not to affect their activity or 
eating habits. The sensor will be removed by a trained study staff member by the end of day 14 
of wear. 
The CGM will be placed for a second time at the 8-week time interval during Liraglutide 
treatment and will be removed after 14 days of wear. Only obese participants will wear the CGM 
for a second time.
After the CGM is placed, participants will be provided with a BOOST® Original Nutritional Drink. 
They will be instructed to drink the BOOST on the follow day between 7:30 and 10:30am as a 
breakfast meal replacement (must drink on an empty stomach). 
fMRI
The original study included use of functional MRI to assess brain perfusion in the response to 
drinking HFCS in healthy lean and obese adolescent/young adult males and females. However, 
in light of the recent pandemic we would like to shift the focus of the study towards the 
evaluation of the effect of GLP-1 analogue on food craving and intake as well as glycemic 
variailbity and metabolic hormonal changes in response to food.
Plasma Collection
Prior to the food snack task, a nurse will insert one IV catheter to sample blood for metabolite 
and hormone analysis (heated hand). Baseline measurements of leptin/ghrelin, insulin, GLP-
1, cortisol and glucose will be collected. In addition, to assess how metabolic response to 
drinking HFCS relates to the neural responses observed, plasma samples will be obtained 
for leptin/ghrelin, insulin, GLP-1, glucose, and cortisol at specified interval time points. No 
more than 110mLs of blood will be drawn on each food snack task day.
Eating Behavior Assessments
To assess food preference and food intake before vs. after liraglutide intervention, eating 
behavior will be assessed in three ways;
Lab-based Food Brunch Task: At baseline and during the last week of treatment, each 
participant will undergo the food brunch task. Participants will be given the opportunity to eat 
ad libitum for 30 minutes with detailed measurement of food/drink consumed and video 
recording to assess eating topography. We will obtain signed permission prior to any video 
recording and the participant will know when they are being videotaped. The videotape 
recording will be used for research only. The recording will not be shown to the general public 
and will not be identified with the subject’s name, although their face may be included in the 
recording. Declining to be videotaped will not affect the participant’s study participation or 
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APPROVED BY THE YALE UNIVERSITY IRB 1/6/2021
treatment in any way.  
The food brunch task is adapted from Dr. Sinha on the basis of previous work on exposure to 
food cues and foods in the laboratory, which indicates that sufficient quantities, multiple food 
options and sufficient time available for eating are important variables modulating food intake. In 
the food brunch task, participants will be presented with a choice of the following foods, 
presented in 6 discrete bowls: skittles, M&Ms, chips, pretzels, cookies and popcorn. They will be 
offered the food and drinks and allowed to eat and drink as much as they like for 30 minutes. 
Video recordings will be assessed for frequency of times each bowl is touched/reached for, 
frequency of pick-ups and number of bites taken. The type and amount (weight and kilocalories) 
of food/drink consumed by each subject will be assessed before and after each session. All 
remaining items will be weighed by trained staff in the Yale Center for Clinical Investigation 
Metabolic Kitchen. 
The instructions will state: “There are different foods and drinks on the tray. We will leave these 
here for you and you can eat and drink as much or as little as you like during the next half hour”. 
We will draw labs at the following time intervals during the food brunch task: 0, 15 and 30 
minutes.
Participants will also be asked to complete the following questionnaires during each food snack 
test visit at 4 time points (baseline and then q 10 minute intervals): Hunger Scale, Anxiety Scale, 
DES-R and Food Craving Scale.
Real-life dietary intake: Participants will complete a detailed 1 week food record via a 
smartphone app, MetricWire. This will be administered during the 14 days that the participant is 
wearing the CGM. For obese participants, this will be completed a total of 2 times (obese 
participants wear the CGM 2 times). For lean participants, this will be completed once (lean 
participants wear the CGM once). During these time points, a 24-hour food recall, the National 
Cancer Institute’s (NCI) Automated Self-Administered 24-hour (ASA24®) dietary assessment 
tool, will also be administered and must be completed on 2 week days and 1 weekend day. 
Study personnel will call participants to complete the ASA24 over the phone.
Each participant will be taught how to accurately record their food and drink intake by the 
study registered dietician, doctors and/or nurse practitioner. 
Participants will also be asked to complete the following questionnaires at the screening visit to 
assess food cravings and consumption and eating behaviors: Yale Food Addiction Scale 
(YFAS), Food Craving Inventory (FCI) and Dutch Eating Behavior Questionnaire (DEBQ). For 
obese participants only, these questionnaires will be repeated at the second food snack task 
visit.
ASA24: The National Cancer Institute (NCI) created the Automated Self-
Administered 24-hour (ASA24®) dietary assessment tool, a web-based tool that 
enables multiple, automatically coded, self-administered 24-hour recalls. The ASA24 
system is freely available for use by researchers, clinicians, and teachers and can be 
used by researchers for epidemiologic, interventional, behavioral, or clinical 
research. Clinicians can utilize this system to collect 24-hour recalls or food records 
from patients and receive complete nutrient analysis of the foods and beverages 
consumed during the collection timeframe. Since ASA24 was released in 2009, 
greater than 3,900 studies have registered to use ASA24 and over 355,000 recall or 
record days were collected, as of December 2017. The ASA24 system consists of a 
Respondent Website used to collect dietary intake data and a Researcher Website 
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APPROVED BY THE YALE UNIVERSITY IRB 1/6/2021
used to manage study logistics and obtain nutrient and food group data files. 
Researchers do not provide the National Cancer Institute (NCI) or the ASA24 system 
with any identifying data for study Respondents. Rather, Researchers specify a user 
ID for each Respondent and download system-generated usernames and encrypted 
passwords that Respondents use to access the application. The ASA24 system also 
does not collect any identifying data directly from Respondents. However, IP address 
information is accessed for the purpose of routing information between the server 
and the Respondent's computer -- often the IP address is that of the user's Internet 
Service Provider (ISP). IP addresses are not stored or tracked by the ASA24 system. 
However, logs of connections are kept for audit trail purposes. This information is not 
mined in any way but would be available if there were a legal obligation to release it.
Other: Subjects unable to attend in person visits due to COVID-19 will be sent a weight 
measurement scale. 
ASSESSING AND REPORTING ADVERSE EVENTS
Definition
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in frequency 
and/or intensity) of a preexisting condition that is temporally associated with the use of 
enoxaparin is also an adverse event.
Adverse events may occur during the course of the use of the IP in clinical trials or within the 
follow-up period specified by the protocol, or prescribed in clinical practice, from overdose 
(whether accidental or intentional), from abuse and from withdrawal.
Serious adverse event. A serious adverse event is an AE occurring during any study phase 
(i.e., treatment, follow-up), that fulfills one or more of the following criteria:
1.
Results in death
2.
Is immediately life-threatening
3.
Requires in-patient hospitalization or prolongation of existing hospitalization
4.
Results in persistent or significant disability or incapacity
5.
Results in a congenital abnormality or birth defect
6.
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above
Each AE will be graded for severity per the NCI CTCAE version 4.0, and these criteria
must be used in grading the severity of AEs. The criteria can be found at:
http://ctep.cancer.gov/reporting/ctc.html
For those AEs, which are not listed as part of the NCI CTCAE version 4.0, the same grading 
system should be used, where: 

Mild corresponds to an event not resulting in disability or incapacity and which 
resolves without intervention 
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
Moderate corresponds to an event not resulting in disability or incapacity but which 
requires intervention 

Severe corresponds to an event resulting in temporary disability or incapacity and 
which requires intervention 

Life-threatening corresponds to an event in which the patient was at risk of death at 
the time of the event 

Fatal corresponds to an event that results in the death of the patient 
AE Expectedness
AEs can be ‘Unexpected’ or ‘Expected’. Expected AEs include Bleeding development of HIT, 
pain from subcutaneous administration of the drug, and anemia from blood draws.
Unexpected AEs are those AEs occurring in one or more patients participating in the research 
protocol, the nature, severity, or frequency of which is not consistent with either:

The known or foreseeable risk of AEs associated with the procedures involved in the 
research that are described in (a) the protocol-related document, such as the IRB-
approved research protocol, any applicable investigator brochure, and the current 
IRB-approved informed consent document, and other relevant sources of 
information, such as product labeling and package inserts; or

The expected natural progression of any underlying disease, disorder, or condition of 
the patient(s) experiencing the AE and the patient’s predisposing risk factor profile 
for the AE.
AE Attribution
The participating site investigator must attempt to determine if an AE is in some way related to 
the use of the study drug and define an attribution category. This relationship should be 
described as follows:

Definite – The AE is clearly related to the study treatment.
The event follows a reasonable temporal sequence from administration of the study 
drug, the event follows a known response pattern to the study drug and based on the 
known pharmacology of the study drug, the event is clearly related to the effect of the 
study drug. The AE improves upon discontinuation of the study drug and reappears 
upon repeat exposure.

Probable – The AE is likely related to the study treatment.
The event follows a reasonable temporal sequence from administration of the study 
drug, the event follows a known response pattern to the study drug AND the event 
cannot have been reasonably explained by an intercurrent medical condition OR the 
event cannot be the effect of a concomitant medication.

Possible – The AE may be related to the study treatment.
The event follows a reasonable temporal sequence from administration of the study 
drug and the event follows a known response pattern to the study drug BUT the 
event could have been produced by an intercurrent medical condition which, based 
on the pathophysiology of the condition, and the pharmacology of the study drug, 
would be unlikely related to the use of the study drug OR the event could be the 
effect of a concomitant medication.
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
Unlikely – The AE is doubtfully related to the study treatment.
AE does not have temporal relationship to intervention, could readily have been 
produced by the patient’s clinical state, could have been due to environmental or 
other interventions, does not follow known pattern of response to intervention, does 
not reappear or worsen with reintroduction of intervention

Unrelated – The AE is clearly NOT related to the study treatment.
The event is clearly due to causes distinct from the use of the study drug, such as a 
documented preexisting condition, the effect of a concomitant medication, or a new condition 
which, based on the pathophysiology of the condition, and the pharmacology of the study drug, 
would be unrelated to the use of the study. All SAEs will be reported to the project manager 
within 24 hours of the site becoming aware of the event.
Procedure for Reporting Adverse Events
All AEs will be recorded from the time the permission form is signed through the last dose of 
Liraglutide. AEs will be recorded on an Adverse Event log at and entered in OnCore within 72 
hours of the PI becoming aware of the event.
All AEs will be reported to regulatory authorities, IRB and investigators in accordance with all 
local applicable laws and regulations. 
All SAEs that are unexpected, which occur any time after the patient has consented up 
to the last dose of Liraglutide that are possibly, probably, or definitely related to the research 
notify the Yale Human Investigation Committee (within 5 days).
Minimizing Risks
Intravenous (IV) catheter insertion and blood drawing: The risks of bruising, clotting, and 
infection will be minimized by having venipuncture performed by trained and experienced 
personnel under sterile conditions. To avoid injury due to fainting, the IV will be inserted when the 
subjects are recumbent. The blood draws during the OGTT  will be obtained from the already 
inserted catheter to minimize discomfort. Subjects will be asked to not participate in other studies 
which involve blood draws for 8 weeks after study completion. Additionally, nursing staff have 
been trained to be conscious of minimizing blood loss by re-infusing saline discards. 
Oral Glucose Tolerance Test (OGTT): We use the Yale-New Haven Hospital (YNHH) 
standard of care guideline (blood sampling from a peripheral catheter) to re-infuse the blood 
saline discards. This method is used to prevent physiological anemia.  Any symptoms which 
may occur during the IV catheter placement or OGTT will be addressed appropriately and if 
further interventions are indicated the proper physician referrals will be made.
Continuous Glucose Monitor (CGM): The CGM poses no major risks to the subjects. 
Participants may feel a mild discomfort (pin prick sensation) during the sensor insertion. Some 
individuals may experience black and blueness of the skin at the insertion site of the CGM 
sensor, which resolves by itself in a few days. Redness and discomfort (inflammation) can occur 
at the sensor insertion site. Rarely sensors may fracture and a small piece may remain under 
the skin which will need to be removed by one of the study doctors. This may cause mild 
discomfort, bruising, or temporary bleeding. The CGM catheter will be placed under sterile 
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conditions by experienced study doctors or nurse practitioner. In case of signs of inflammation 
or bruise at the sensor insertion site, the sensor will need to be removed immediately and 
standard care should be applied. The participants will be given our contact information if they 
have any questions, concerns or problems.
Liraglutide (study drug): Screening labs will be done prior to the start of the study to ensure 
that participants renal and pancreatic (exocrine) function is within normal limits. Phone calls will 
be done to ensure study drug is being tolerated by participants (as shown in detail in Appendix 
1). Safety labs will be drawn at interval time points (weeks 4, 8 and 12-16) to ensure that renal, 
pancreatic, liver, and thyroid function remains within normal limits. In addition, a urine 
pregnancy test will be performed at these time points. The participant will be provided with a 
wallet card that includes the name of the drug and our contact information in the event that the 
participant receives outside care or experiences side effects and needs to contact us promptly 
(Appendix 4).
Confidentiality:  Study participation is voluntary and subjects are informed that they are free to 
drop out at any time without penalty. All data will be kept confidential except in cases of 
imminent danger to the participants.  Such limits to confidentiality will be clearly explained to 
participants verbally and in the written consent forms.  Confidentiality in regard to collected 
materials will be maintained via a numbered reference system maintained by the investigators.  
Subjects' names will appear only on a consent form and a "key" form kept by the Project Director in 
locked filing cabinets.  Only the PI, mentor, and main investigators will have access to any forms 
specifying both participant name and subject number.  All number coded subjective and biological 
data will be kept in locked offices with access only to investigators and research staff.  
Furthermore, good clinical and research practice procedures and HIPAA regulations will be 
followed.  No subjects are identified by name in any of the published literature and only by code in 
major data storage areas. The ASA24 have been designed to be compliant with HIPAA 
regulations. Both platforms encrypt data and do not collect any identifying data directly from 
participants.
ANALYSES AND STATISTICAL CONSIDERATIONS
Analysis of subjective ratings, plasma hormonal measures, Brunch Food Task, and diet 3-day 
food measures will be assessed using a mixed-model repeated measures analysis (PROC 
MIXED SAS V9.4, Cary, NC) to assess main effects and interactions for the fixed factors of 
obesity status (lean vs. obese) and time (before vs. after intervention), and subjects will be the 
random effect factor to accommodate correlation between repeated measures. Covariate 
adjustment will be included for age and sex. 
Using these random effects models applied to whole brain analysis for neural responses and 
mixed effects models for other analyses, the following specific hypotheses will be tested for 
each aim:
Sample size estimates are based on effect size determinations from our preliminary work and 
related previous research. Based on Jastreboff et al (2016)9 findings from lean (n=14) vs. 
obese (n=24) adolescents, we found an overall large effect sizes between d=0.65 and 0.56 
for the mPFC responses in the lean and obese adolescent groups, and d=0.68 and 0.53 for 
the striatal (caudate) response in the lean and obese adolescents as well as an effect size 
d=0.569 for lean vs. obese for the PFC connectivity with the striatum. The described fMRI 
liraglutide study by Farr et al.20 (n=18) found effect size placebo=0.53 and liraglutide=-0.47 for 
decreased activation in the parietal cortex. There are no specific studies examining the effect 
of liraglutide on CBF response to HFCS ingestion. Based on these earlier studies, we will 
include 45 subjects in our study; specifically, 15 healthy lean and 30 obese adolescents to 
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test the proposed hypotheses.
For the adolescents, the goal is to have pilot data inclusive of adolescents with the food snack 
task alone – to obtain funding inclusive of adolescent age and add to literature. The effects of 
the medication on eating behavior are fairly robust which is why I believe we were able to see 
differences in initial pilot data. The main goal is to investigate the impact on eating behavior 
(assessed in the food snack task) before and after the medication (so baseline vs. post 
intervention). The lean participants serve as “controls” in that after the medication, the 
individuals with obesity have eating behavior more similar to that observed in lean. We also 
do within subject comparison (obesity before medication vs. after) - that I the main question.  
DATA MANAGEMENT AND RECORD KEEPING
The principal investigator is required to prepare and maintain adequate and accurate case 
histories designed to record all observations and other data pertinent to the investigation on 
each individual treated in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must 
be explained. OnCore will be the designated electronic data capture tool. All data should be 
entered onto OnCore within 1 week of study entry.   
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ADMINISTRATIVE AND REGULATORY 
Data safety and monitoring plan
Authority for patient safety will reside exclusively with the Principal Investigator. She will ensure 
data quality and completeness. The PI has the authority to recommend that the study protocol 
be terminated, temporarily suspended, or amended. 
The data safety monitor for this study will be Jennifer Sherr, MD, PhD. Dr. Sherr is an Associate 
Professor in the department of Pediatrics (Pediatric Endocrinology) at Yale University School of 
Medicine. Dr. Sher is a licensed pediatric endocrinologist with over a decade of experience in 
conducting clinical trials in children and young adults with diabetes. Dr. Sherr is very familiar 
with the requirements for data safety monitoring. She also has several ongoing protocols with 
the Yale Human Investigation Committee (HIC). Dr. Sherr is not an investigator on the proposed 
study and would function as an independent monitor. Dr. Sherr will evaluate all Adverse and 
Serious Adverse Events and will assist the PI in preparing and sending the pertinent expedited 
reports to the appropriate persons as outlined above. She will monitor the study quarterly and 
review all adverse event sheets completed during that period. She will assist the PI in making 
critical decisions regarding subject’s continuation in the study for safety reasons. She will review 
the summary of all Adverse Events for this study, which will be reported annually to the Yale 
Human Investigation Committee (HIC) and the ADA.
Project Team Meetings
Scheduled meetings will be held weekly and will include the Principal investigators and research 
staff involved with the conduct of the protocol.
During these meetings, the investigators will discuss:
1.
Safety of protocol participants (adverse events and reporting)
2.
Validity and integrity of the data (data completeness on CRFs and complete source 
documentation)
3.
Enrollment rate relative to expectation of target accrual (eligible and ineligible 
participants)
4.
Retention of participants, adherence to the protocol and protocol violations
5.
Protocol amendments
CONFIDENTIALITY & SECURITY OF DATA
Data will be entered into OnCore. De-identified data will then be downloaded in Excel format for 
statistical analysis, which will be done on a HIPAA compatible, password protected encrypted 
laptop computer. All data entry will be performed by the study personnel. All source 
documentation will be retained at the research clinic in locked cabinets in locked offices. 
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APPENDIX 1: TRIAL FLOW CHART
Lean & Obese
Obese Only
Visit 1
CSRU
Visit 2
CSRU
Visit 3
CSRU
Visit 4
CSRU
Screen
Visit/CGM 
placement
Food Snack Task
Week 1
Weeks 2-3
Week 4
Weeks 5-7
Week 8
Weeks 9-11
Week 10: CGM 
placement
Week 12-16
Date
Compensation
$50
$50 
$50
$50 
+ $50 study 
completion 
bonus
Phone Call
2 calls
Side Effect 
Assessment
OGTT
Screen Labs
Labs
FCI & DEBQ
PHQ-9
CGM+BOOST, 
ASA 24 & App 
Food Record
Remove 14 
days later
Remove 
14 days 
later
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APPENDIX 2: PATIENT HEALTH QUESITONNAIRE (PHQ-9)
Over the last 2 weeks, how often have you been bothered by any of the following problems?
Not at 
all
Several 
days
More 
than 
half the 
days
Nearly 
every 
day
1. Little interest or pleasure in doing things
0
1
2
3
2. Feeling down, depressed, or hopeless
0
1
2
3
3. Trouble falling or staying asleep, or sleeping too 
much
0
1
2
3
4. Feeling tired or having little energy
0
1
2
3
5. Poor appetite or overeating
0
1
2
3
6. Feeling bad about yourself – or that you are a 
failure or have let yourself or your family down
0
1
2
3
7. Trouble concentrating on things, such as 
reading the newspaper or watching television
0
1
2
3
8. Moving or speaking so slowly that other people 
could have noticed. Or the opposite – being so 
fidgety or restless that you have been moving 
around a lot more than usual
0
1
2
3
9. Thoughts that you would be better off dead, or 
of hurting yourself
0
1
2
3
Total Score
Depression Severity
1-4
Minimal depression
5-9
Mild depression
10-14
Moderate depression
15-19
Moderately severe depression
20-27
Severe depression
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APPENDIX 3: PARTICIPANT INFORMATION SHEET
Participant Information
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APPENDIX 4: WALLET CARD
RESEARCH STUDY PARTICIPANT AT YALE
Participant name _____________________________________________
is participating in a study of Liraglutide.
Protocol #2000022407
Please call Dr. Jastreboff at (203) 737- 4777 
before taking any new medications. 
Also call in case of a serious medical problem 
or questions.
Thank you for your help.
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