Clinical trial NCT04883346
Conditions: Obesity Status Post Sleeve Gastrectomy
Keywords: Children glucagon-like peptide Weight Loss pharmacotherapy for obesity Bariatric Surgery
Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Start date: 2021-06-21; Completion date: 2024-04-30
Enrollment: 34 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

Metabolic Bariatric Surgery, including a surgery called vertical sleeve gastrectomy, is the most effective weight loss treatment for severe obesity. However, many adolescents who have this surgery still have obesity 1 year later or regain weight. Researchers want to see if a drug can help.

Objective:

To learn if liraglutide can help adolescents who still have obesity 1 year or more after vertical sleeve gastrectomy lose additional weight.

Eligibility:

Healthy adolescents ages 12-20.99 years who are 1-10 years post vertical sleeve gastrectomy and have a BMI of 30 kg/m2 or \>=95th percentile for age and sex.

Design:

Participants will be screened with:

Medical history

Physical exam

Questionnaires about their mood and feelings about their weight

Blood and urine tests

Nutrition counseling. They will keep a diet log.

A test where they view and respond to pictures of food

Wrist accelerometer set-up. They will wear an accelerometer (a device like a watch) on their wrist for 14 days. It will measure their physical activity.

Some screening tests will be repeated during the study.

Participants will have an oral glucose tolerance test. They will ingest a sweet liquid. Blood samples will be taken.

Participants will take liraglutide daily for 16 weeks. They will learn how to inject it under their skin.

Participants will have a body scan to measure muscle and fat.

Participants will be invited to eat as much as they want at a buffet meal at NIH. How much food they eat will be calculated. They will assess their appetite and mood before and after the meal.

Participation will last for 7 months. Participants will have up to 7 study visits....

Detailed description:
Study Description:

This trial is an open-label Phase II non-randomized pilot study conducted at the NIH Clinical Center to investigate the efficacy of daily subcutaneous injection of liraglutide, a glucagon-like peptide-1 (GLP1) analogue to promote reduction of body mass index (BMI) in adolescents who continue to have obesity (BMI (Bullet)30 or BMI \>=95th percentile for age and sex) 1 year or more after vertical sleeve gastrectomy (SG). We hypothesize that administration of liraglutide will be associated with reduction in BMI in such adolescents.

Objectives:

Primary objective: To determine the effect size for the change in BMI of liraglutide 3.0 mg daily subcutaneously at 16 weeks in adolescents who have obesity after SG, in order to use the observed changes to determine the sample size of a subsequent randomized, controlled investigation.

Hypothesis:

The Primary Endpoint is estimation of required sample size for a later randomized controlled trial through calculation of effect size for change in body mass index (BMI) from baseline to 16 weeks of liraglutide. The hypothesis is: The data will be sufficient to calculate the effect size for change in BMI from baseline to 16 weeks for a 2-group experiment (placebo versus liraglutide).

Secondary objectives:

To study the effects of 16 weeks of liraglutide 3.0 mg subcutaneously on change in mean BMI and fat mass in adolescents who underwent vertical sleeve gastrectomy (SG) \>=1y prior to study initiation but still have obesity or have a recrudescence of obesity despite surgery. To compare the effects of liraglutide on BMI and fat mass in enrolled participants who had a poor initial response to SG (\<20% BMI reduction at BMI nadir) vs. those with a typical post-SG weight loss (\>=20% BMI reduction at BMI nadir).

Additional Objectives:

To examine the effects of daily subcutaneous liraglutide in enrolled participants on changes in body composition, metabolic syndrome markers, energy intake, glucose tolerance, gastrointestinal (GI)

hormone concentrations, appetite, free living physical activity, mood, suicidality, weight related quality of life, self-perception of body image, and secretome.

Endpoints:

Primary Endpoint: Estimation of required sample size for a later RCT through calculation of effect size for change in body mass index (BMI) from baseline to 16 weeks of liraglutide.

Key Secondary Endpoints:

Changes in BMI and fat mass after 16 weeks of liraglutide Comparison of changes in BMI and fat mass after 16 weeks of liraglutide in participants who had a poor initial response to SG (\<20% BMI reduction at BMI nadir) vs. those with a typical post-S weight loss (\>=20% BMI reduction at BMI nadir) Tolerability and safety of liraglutide 3.0 mg.

Additional (exploratory) Endpoints: Change from baseline to 16 weeks of liraglutide in:

1. Proportion reducing BMI by at least 5% and 10%
2. BMI standard deviation score for age and sex (BMIz)
3. Body weight
4. Percentage total body fat mass by DXA
5. Appetite score using visual analog scale (VAS)
6. Attention bias to highly palatable images
7. Energy intake at buffet meal
8. Free living physical activity by accelerometry
9. Metabolic syndrome markers (waist circumference, systolic and diastolic blood pressure, lipids, fasting plasma glucose level)
10. Fasting plasma insulin and HOMA-IR index
11. 2-hour oral glucose tolerance test (OGTT) insulin and glucose measurements
12. Hemoglobin A1C
13. Plasma GI hormones (GLP-1 and PYY) during OGTT
14. Weight related quality of life (QoL) score
15. Beck Depression Inventory total score
16. Body-Esteem Scale Score for Adolescents and Adults
17. Columbia Suicide Severity Rating Scale
18. Secretome analysis
19. Stool microbiome analysis

Arms: arm 1: Treated with Liraglutide
Interventions: intervention 1: Liraglutide
Intervention descriptions: intervention 1: Liraglutide by subcutaneous injection administered daily. Dose will be initiated at 0.6mg per day and increased to a maximum of 3.0 mg per day as tolerated.

Protocol documents:
Prot_SAP_000.pdf: 
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Abbreviated Title: Liraglutide in Teens Post-SG
Version Date: 1/30/23
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Abbreviated Title: Liraglutide in Teens Post-SG
NIH IRB #: iRIS assigned number. 000241
Sponsor: NICHD - IND Exemption PIND 154663
Version Date: 1/30/23
Title: Phase II Trial of Liraglutide (Saxenda(R), Novo Nordisk) in Adolescents with Obesity 
After Sleeve Gastrectomy: A Pilot Open-Label Study
Principal Investigator: Jack A. Yanovski, MD, PhD
Lead Associate Investigator:  Anna Zenno, MD
NIH Principal Investigator:
Jack A. Yanovski, MD, PhD
SGO/DEMGEO/DIR, NICHD
10 Center Dr, Building 10, Rm 1-3330, MSC 1103
Bethesda, MD 20892-1103
Phone: 301-496-0858
Fax:  301-480-4271
E-mail: jy15i@nih.gov
Investigational Agents (if applicable):
Drug Name:
Saxenda
IND Number:
Exempt - PIND 154663
Sponsor:
NICHD
Manufacturer:
Novo Nordisk A/S
This project is a multi-institutional protocol with NIH and Children’s National Hospital (CNH).   
The NIH IC is the Coordinating Center and Sponsor. John Perreault in the OCD will be the 
Clinical Safety Officer for this trial. 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................2
STATEMENT OF COMPLIANCE ................................................................................................6
1
PROTOCOL SUMMARY.......................................................................................................7
1.1
Synopsis ............................................................................................................................7
1.2
Schema............................................................................................................................10
1.3
Schedule of Activities (SOA) .........................................................................................11
2
INTRODUCTION .................................................................................................................14
2.1
Study Rationale...............................................................................................................14
2.2
Background .....................................................................................................................16
2.3
Risk/Benefit Assessment.................................................................................................18
2.3.1
Known Potential Risks ............................................................................................18
2.3.2
Known Potential Benefits........................................................................................21
2.3.3
Assessment of Potential Risks and Benefits............................................................21
3
OBJECTIVES AND ENDPOINTS.......................................................................................22
4
STUDY DESIGN ..................................................................................................................24
4.1
Overall Design ................................................................................................................24
4.2
Scientific Rationale for Study Design.............................................................................25
4.3
Justification for Dose ......................................................................................................25
5
STUDY POPULATION........................................................................................................25
5.1
Inclusion Criteria.............................................................................................................26
5.2
Exclusion Criteria ...........................................................................................................26
5.3
Inclusion of Vulnerable Participants...............................................................................27
5.3.1
Participation of NIH Staff or family members of study team members..................27
5.4
Inclusion of Pregnant Women, fetuses or neonates ........................................................27
5.5
Lifestyle Considerations .................................................................................................27
5.6
Screen Failures................................................................................................................27
5.7
Strategies for Recruitment and Retention .......................................................................27
5.7.1
Costs ........................................................................................................................28
5.7.2
Compensation ..........................................................................................................28
6
STUDY INTERVENTION ...................................................................................................29
6.1
Study Interventions(s) Administration............................................................................29


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6.1.1
Study Intervention Description................................................................................29
6.1.2
Dosing and Administration......................................................................................30
6.2
Preparation/Handling/Storage/Accountability................................................................33
6.2.1
Acquisition and Accountability ...............................................................................33
6.2.2
Formulation, Appearance, Packaging, and Labeling...............................................33
6.2.3
Product Storage and Stability ..................................................................................33
6.2.4
Preparation...............................................................................................................33
6.3
Measures to Minimize Bias: Randomization and Blinding ............................................33
6.4
Study Intervention Compliance ......................................................................................33
6.5
Concomitant Therapy......................................................................................................33
7
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .....................................................................................34
7.1
Discontinuation of Study Intervention............................................................................34
7.2
Participant Discontinuation/Withdrawal from the Study................................................35
7.3
Lost to Follow-up............................................................................................................35
8
STUDY ASSESSMENTS AND PROCEDURES.................................................................36
8.1
Screening Procedures......................................................................................................36
8.1.1
Screening activities performed prior to obtaining informed consent ......................36
8.1.2
Screening activities performed after a consent for screening has been signed........37
8.2
Efficacy Assessments......................................................................................................38
8.2.1
Clinical Evaluations.................................................................................................38
8.2.2
Biospecimen Evaluations.........................................................................................41
8.2.3
Correlative Studies for Research/Pharmacokinetic Studies ....................................42
8.2.4
Samples for Genetic/Genomic Analysis..................................................................42
8.3
Safety and Other Assessments ........................................................................................42
8.4
Adverse Events and Serious Adverse Events .................................................................44
8.4.1
Definition of Adverse Event....................................................................................44
8.4.2
Definition of Serious Adverse Events (SAE) ..........................................................44
8.4.3
Classification of an Adverse Event..........................................................................45
8.4.4
Time Period and Frequency for Event Assessment and Follow-Up........................47
8.4.5
Adverse Event Reporting.........................................................................................47
8.4.6
Serious Adverse Event Reporting............................................................................47


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8.4.7
Events of Special Interest ........................................................................................48
8.4.8
Reporting of Pregnancy ...........................................................................................48
8.5
Unanticipated Problems ..................................................................................................49
8.5.1
Definition of Unanticipated Problems (UP) ............................................................49
8.5.2
Unanticipated Problem Reporting ...........................................................................49
8.5.3
NIH Intramural IRB Reporting of IND Safety Reports...........................................49
9
STATISTICAL CONSIDERATIONS ..................................................................................49
9.1
Statistical Hypothesis......................................................................................................49
9.2
Sample Size Determination.............................................................................................50
9.3
Populations for Analyses ................................................................................................51
9.3.1
Evaluable for toxicity ..............................................................................................51
9.3.2
Evaluable for objective response.............................................................................51
9.3.3
Evaluable Non-Target Disease Response................................................................51
9.4
Statistical Analyses .........................................................................................................51
9.4.1
General Approach....................................................................................................51
9.4.2
Analysis of the Primary Endpoint............................................................................52
9.4.3
Analysis of the Secondary Endpoint(s) ...................................................................53
9.4.4
Safety Analyses .......................................................................................................54
9.4.5
Baseline Descriptive Statistics.................................................................................54
9.4.6
Planned Interim Analyses........................................................................................54
9.4.7
Sub-Group Analyses................................................................................................54
9.4.8
Tabulation of individual Participant Data................................................................54
9.4.9
Exploratory Analyses...............................................................................................55
10
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................55
10.1
Informed Consent Process ..............................................................................................55
10.1.1
Consent/Assent Procedures and Documentation.....................................................55
10.1.2
Consent for minors when they reach the age of majority........................................57
10.1.3
Considerations for Consent of NIH staff, or family members of study team 
members.................................................................................................................................58
10.1.4
Consent of Subjects who are, or become, decisionally impaired ............................58
10.2
Study Discontinuation and Closure.................................................................................58
10.3
Confidentiality and Privacy ............................................................................................58


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10.4
Future use of Stored Specimens and Data ......................................................................59
10.5
Safety Oversight..............................................................................................................60
10.6
Clinical Monitoring.........................................................................................................61
10.7
Quality Assurance and Quality Control..........................................................................61
10.8
Data Handling and Record Keeping ...............................................................................62
10.8.1
Data Collection and Management Responsibilities.................................................62
10.8.2
Study Records Retention .........................................................................................62
10.9
Protocol Deviations and Non-Compliance .....................................................................62
10.9.1
NIH Definition of Protocol Deviation .....................................................................63
10.10 Publication and Data Sharing Policy ..............................................................................63
10.10.1 Human Data Sharing Plan .......................................................................................63
10.10.2 Genomic Data Sharing Plan.....................................................................................64
10.11 Collaborative Agreements...............................................................................................64
10.11.1 Agreement Type ......................................................................................................64
10.12 Conflict of Interest Policy...............................................................................................64
11
ABBREVIATIONS ...............................................................................................................64
12
REFERENCES ......................................................................................................................66


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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.


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PROTOCOL SUMMARY
1.1
SYNOPSIS
Title:
Phase II Trial of Liraglutide (Saxenda, Novo Nordisk) in 
Adolescents with Obesity After Sleeve Gastrectomy: A Pilot Open-
Label Study
Study Description:
This trial is an open-label Phase II non-randomized pilot study 
conducted at the NIH Clinical Center to investigate the efficacy of 
daily subcutaneous injection of liraglutide, a glucagon-like peptide-1 
(GLP1) analogue to promote reduction of body mass index (BMI) in 
adolescents who continue to have obesity (BMI ≥30 or BMI ≥95th 
percentile for age and sex) 1 year or more after vertical sleeve 
gastrectomy (SG).  We hypothesize that administration of liraglutide 
will be associated with reduction in BMI in such adolescents. 
Objectives:
Primary objective:  To determine the effect size for the change in 
BMI of liraglutide 3.0 mg daily subcutaneously at 16 weeks in 
adolescents who have obesity after SG, in order to use the observed 
changes to determine the sample size of a subsequent randomized, 
controlled investigation. 
Hypothesis: The Primary Endpoint is estimation of required sample 
size for a later randomized controlled trial through calculation of 
effect size for change in body mass index (BMI) from baseline to 16 
weeks of liraglutide. The hypothesis is: The data will be sufficient to 
calculate the effect size for change in BMI from baseline to 16 weeks 
for a 2-group experiment (placebo versus liraglutide).
Secondary objectives: 
To study the effects of 16 weeks of liraglutide 3.0 mg subcutaneously 
on change in mean BMI and fat mass in adolescents who underwent 
vertical sleeve gastrectomy (SG) ≥1y prior to study initiation but still 
have obesity or have a recrudescence of obesity despite surgery.
To compare the effects of liraglutide on BMI and fat mass in enrolled 
participants who had a poor initial response to SG (<20% BMI 
reduction at BMI nadir) vs. those with a typical post-SG weight loss 
(≥20% BMI reduction at BMI nadir).
Additional Objectives:
To examine the effects of daily subcutaneous liraglutide in enrolled 
participants on changes in body composition, metabolic syndrome 
markers, energy intake, glucose tolerance, gastrointestinal (GI) 
hormone concentrations, appetite, free living physical activity, mood, 


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suicidality, weight related quality of life, self-perception of body 
image, and secretome. 
Endpoints:
Primary Endpoint: Estimation of required sample size for a later 
RCT through calculation of effect size for change in body mass index 
(BMI) from baseline to 16 weeks of liraglutide.  
Key Secondary Endpoints: 
Changes in BMI and fat mass after 16 weeks of liraglutide
Comparison of changes in BMI and fat mass after 16 weeks of 
liraglutide in participants who had a poor initial response to SG 
(<20% BMI reduction at BMI nadir) vs. those with a typical post-SG 
weight loss (≥20% BMI reduction at BMI nadir)
Tolerability and safety of liraglutide 3.0 mg.
Additional (exploratory) Endpoints: Change from baseline to 16 
weeks of liraglutide in:
1. Proportion reducing BMI by at least 5% and 10%
2. BMI standard deviation score for age and sex (BMIz)
3. Body weight
4. Percentage total body fat mass by DXA
5. Appetite score using visual analog scale (VAS)
6. Attention bias to highly palatable images
7. Energy intake at buffet meal
8. Free living physical activity by accelerometry 
9. Metabolic syndrome markers (waist circumference, systolic 
and diastolic blood pressure, lipids, fasting plasma glucose 
level)
10. Fasting plasma insulin and HOMA-IR index
11. 2-hour oral glucose tolerance test (OGTT) insulin and glucose 
measurements
12. Hemoglobin A1C 
13. Plasma GI hormones (GLP-1 and PYY) during OGTT
14. Weight related quality of life (QoL) score
15. Beck Depression Inventory total score
16. Body-Esteem Scale Score for Adolescents and Adults 
17. Columbia Suicide Severity Rating Scale
18. Secretome analysis
19. Stool microbiome analysis
Study Population:
Up to a total of 50 male and female adolescents age <21 years old 
from Washington D.C., Maryland, and Virginia who underwent SG 
at least 1 year prior to enrollment and have BMI ≥30 kg or ≥95th 


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percentile for age and sex in order to enroll at least 40 who are 
eligible and agree to take liraglutide for 16 weeks.
Phase:
Phase II
Description of 
Sites/Facilities 
Enrolling 
Participants:
We will primarily recruit participants who previously underwent SG 
from Children’s National Hospital (CNH), in Washington, DC, a 
high-volume pediatric bariatric surgery center in our area. 
Participants will be assessed at the NIH Clinical Center for all study 
visits. Eligible participants may also be interviewed by telephone.
Description of Study 
Intervention:
Eligible patients will be treated with daily subcutaneous liraglutide 
(starting at 0.6 mg daily with weekly dose escalations up to 3.0 mg 
per day or max tolerated dose) for up to 16 weeks. 
Study Duration:
36 months
Participant 
Duration:
7 months (28 weeks)
(16 weeks on Study Drug and 12 weeks off Study Drug)


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1.2
SCHEMA
Flow diagram of open label trial 
Prior to 
Enrollment
Screening 
Visit
Visit 1
0 weeks
Weekly Phone Calls
Weeks 1, 2, and 3
Visit 2
4 weeks
Visit 3
8 weeks
Visit 4
12 weeks
Visit 5
16 weeks
Visit 6
28 weeks
Screen potential participants by inclusion and exclusion criteria over phone; obtain history, 
documentation of surgery date and procedure, schedule for Screening Visit. 
Obtain informed consent/assent. Perform pregnancy test in females.  Perform history and 
physical, and baseline assessments.  If eligible, set up accelerometer.  Refer to Section 1.3, 
Schedule of Activities
Complete eligibility checklist when all results available
Return Accelerometer. Initiate study intervention: liraglutide, with dose escalation. 
Refer to Section 1.3, Schedule of Activities
Follow-up assessment of safety and study intervention dose check
Refer to Section 1.3, Schedule of Activities
Follow-up assessment of safety and study intervention dose check
Refer to Section 1.3, Schedule of Activities
Follow-up assessment of safety and study intervention dose check.  Set up accelerometer
Refer to Section 1.3, Schedule of Activities
 
Follow-up assessment of safety and study intervention dose check.  Measure primary 
outcome and secondary outcomes.  Discontinue liraglutide
Refer to Section 1.3, Schedule of Activities
Final Assessment of BMI off medication 
Refer to Section 1.3


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1.3
SCHEDULE OF ACTIVITIES (SOA)
Procedures
Phone Screen - ≤4 
wks before baseline
Screening Visit
Study Visit 1
Day 0
Study Visit 2
Day 28 +/- 10 days
Study Visit 3
Day 56+/-10 days
Study Visit 4         
Day 84 +/- 10 days
Study Visit 5
Day 112 +/-10 days 
Final Study Visit 6
Day 196+/- 10 days
Informed consent
X
Demographics
X
X
Medical history
X
X
Nutrition Counselling1
X
X
X
X
X
X
  
Injection Teaching
X
Administer study intervention2
    X-----------------------------------X
Concomitant medication review
X
  X------------------------------------------X
Physical exam (including height and weight)3
X
X
X
X
X
X
X
Waist circumference4
X
X
X
Vital signs5
X
X
X
X
X
X
X
Pregnancy test 6
X
X
X
X
X
X
Screening labs (CBC, A1C, acute care panel, 
hepatic panel, mineral panel, ESR, CRP, 25-
OH vitamin D, PT, PTT, urinalysis)
X
Adverse event review and evaluation
   X--------------------------------------------X
DXA
X
X
Metabolic syndrome markers7
 
X
X
2-hour Oral glucose tolerance test (OGTT)
X
X
Blood draw (Hb A1C, Plasma GI hormones: 
GLP-1,  PYY, research samples to be saved)
X
X
Stool sample collection (optional)
X
X
Energy intake at buffet meal
X
X
Appetite score pre and post meal using 
visual analog scale (VAS)
X
X
Attention bias to palatable images study 
X
X
Free living physical activity by 
accelerometry set -up
X
X
Weight related quality of life (QoL) score
X
X
Beck Depression Inventory
X
X
Columbia Suicide Severity Rating Scale
X
X
Body-Esteem Scale
X
X
Blood Sample for Secretome Analysis
X
X


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1. Participants will meet with Nutrition Staff from the NIH Clinical Center to review 
instructions on keeping a log of their dietary intake at the Screening Visit, to review 
the intake log at Study Visits 1 and 5, and to receive standard obesity lifestyle 
management advice at Study Visits 1, 2, 3, 4, and 5.
2. First dose of liraglutide administered at the end of the visit after injection teaching.
3. Interim medical history for changes in health and limited symptom-directed physical 
examination, including injection sites at visits 2 through 5.
4. Waist circumference measured by Clinical Center Nutrition Staff.
5. Systolic and diastolic blood pressure measured after 5 minutes of rest.
6. Serum or urine pregnancy test (only for women of childbearing potential).
7. Fasting total, HDL- and LDL-cholesterol, triglycerides, fasting plasma glucose 
concentration
Summary Description:
Prior to Enrollment: The protocol will be explained to the participant and their parent (if the 
subject is <18 years of age).  Research team will preliminarily determine participant’s eligibility 
by inclusion and exclusion criteria over the phone.  
Screening Visit:  We will obtain informed assent and consent from the participant and their 
parent/guardian before initiating any research procedures.  Each participant will undergo a 
history and physical examination (measuring weight, height, and blood pressure), and have 
screening labs drawn, and testing on attention bias to highly palatable images.  Female 
participants will undergo a pregnancy test. Each participant will also answer a series of 
questionnaires, meet with Nutrition Staff from the NIH Clinical Center to review instructions on 
keeping a log of their dietary intake, and undergo set-up of a wrist accelerometer to measure free 
living physical activity.  They will also receive material to collect stool at home if they choose to 
turn in stool samples at Visit 1.   
Visit 1: 
Each participant will undergo a brief history and directed physical examination at the NIH 
Clinical Center. Female participants will undergo a pregnancy test. They will then have fasting 
blood work followed by oral glucose tolerance testing (OGTT), DXA scan, appetite testing, and 
energy intake measurement at a lunch buffet meal at the NIH Clinical Center. Each participant 
will have the option to turn in stool samples collected at home or during their clinic visit.  They 
will meet with Nutrition Staff to review their food log, receive standardized education on a 
healthy diet and physical activity, and measure their waist circumference. The wrist 
accelerometer will be returned. The participants will receive teaching on administration of 
subcutaneous study medication and receive their first dose at the end of Visit 1.
Phone Calls 1-3: Each participant will receive three weekly phone calls between Visit 1 and Visit 
2 to discuss side effects and dose titration of study drug.  
Complete Case Report Forms (CRFs)
X
X
X
X
X
X
X


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Visits 2-4: Each participant will undergo a brief history and directed physical examination to 
include injection site examination at monthly visits.  Weight, height, and blood pressure will be 
measured at each visit.   All participants will be assessed for adverse effects of study drug.   
Female participants will undergo a repeat pregnancy test at every visit.  All participants will meet 
with Nutrition Staff to receive standardized education on a healthy diet.  Used 1-month supply of 
liraglutide pens will be returned to research team and new 1-month supply of liraglutide will be 
provided to participant.  At visit 4, a wrist accelerometer to measure free living physical activity 
will be placed and testing on attention bias to highly palatable images will be conducted. They 
will also receive material to collect stool at home if they choose to turn in stool samples at Visit 
5.   
Visit 5 (at ~16 weeks):  Each participant will undergo a history and physical examination and 
female participants will undergo a pregnancy test. All participants will then undergo fasting 
blood work followed by 2-hour oral glucose tolerance testing, questionnaires, testing on appetite, 
DXA scan, and energy intake measurement at a buffet meal at the NIH Clinical Center. They 
will meet with Nutrition Staff to review their 1-week food log and receive standardized 
education on a healthy diet and physical activity. Each participant will have the option to turn in 
stool samples collected at home or during their clinic visit.   Used 1-month supply of liraglutide 
pens will be returned to research team.  Liraglutide be will discontinued at this visit.  The wrist 
accelerometer will be returned.
Visit 6 (off medication, at ~28 weeks):  Each participant will undergo and history and physical 
examination.  Weight, height, and waist circumference will be measured.  


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 INTRODUCTION
1.4
STUDY RATIONALE
Obesity is a global epidemic that is associated with multiple co-morbidities and disability 
in both children [1] and adults.  In the United States, in 2015-2016 [2], 20.6% of children and 
adolescents age 12-19 years had obesity (defined as BMI≥95th percentile for age and sex for the 
Centers for Disease Control standards [3]) and 7.7% had severe obesity (BMI ≥120% of the 95th 
percentile) [2].  Obesity-related diseases previously rare in adolescents [4-6] including type 2 
diabetes [7-10], are increasingly diagnosed, with those having rapid early weight gain most at 
risk [11, 12].  The appearance of obesity-associated conditions in childhood leads to an earlier 
onset of related medical complications [13-15]; severe obesity also increases risk from COVID-
19 infection [16-19].  Some [20-22] though not all [23-25] studies suggest pediatric obesity has a 
unique impact on later health, even independent of adult weight; Regardless, there is unanimity 
that adolescent obesity is a strong risk factor for persistence into adulthood and medical 
complications.  Without effective strategies to treat adolescent obesity, millions of adolescents 
will enter adulthood with the physical and psychological consequences of excess adiposity.  
Adolescent obesity also has the potential to reverse the improvements in life-expectancy that 
occurred during the 20th century in the U.S [26, 27] and to cause more functional disability in 
those who survive to old age [28].
Initial management of obesity involves making lifestyle modifications to increase 
physical activity and adopt a healthy and well-balanced diet.  However, most adolescents achieve 
only mild to moderate weight loss with reduction of BMI by -1 to -2 kg/m2 and have difficulty 
implementing and sustaining their lifestyle changes [29].  Adolescents who continue to have 
severe obesity or have obesity with complications such as sleep apnea or diabetes despite 
lifestyle modification are sometimes prescribed pharmacologic agents, but options are limited; 
Orlistat, a lipase inhibitor is FDA approved for children ≥12 years, and phentermine, a 
norepinephrine reuptake inhibitor for short-term use (12 weeks) is FDA approved for adolescents 
>16 years [30, 31].  Both have modest efficacy with approximately 3% mean BMI reduction [30, 
31].  Liraglutide, a glucagon-like peptide 1 (GLP1) agonist is the latest medication to be 
approved for chronic weight management in children 12 years and older with BMI ≥30 kg/m2.  A 
double-blind, placebo-controlled phase 3 study showed that after 56 weeks, patients treated with 
liraglutide achieved a statistically significant reduction in BMI SDS of -0.23 compared with no 
reduction in the placebo group (estimated treatment difference: -0.22; 95% CI, -0.37, -0.08; P 
=.0022) [32].
Other agents have also been used off-label in some pediatric patients with variable results 
and unknown long-term outcomes.  Consequently, an increasing number of patients with 
moderate to severe obesity and its comorbidities who fail to lose weight despite lifestyle and 
pharmacologic intervention are undergoing metabolic and bariatric surgery (MBS), which is 
currently considered the most effective treatment of severe obesity and its associated 
comorbidities, and is recommended by both the American Society for Metabolic and Bariatric 
Surgery (ASMBS) and the American Academy of Pediatrics (AAP) [33, 34].   
The two most common surgical approaches used in children and adolescents with obesity 
are sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB).  In 2015, 66.6% of cases 
were SG and 28.5% were RYGB among adolescents age 18-21 years who underwent MBS in the 


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United States[35].  SG involves removal of 80-90% of the greater curvature of the stomach and 
achieves weight loss by restricting food intake whereas RYGB entails creating a small gastric 
pouch from the upper stomach that is connected directly to the middle portion of the small 
intestine (jejunum), bypassing the rest of the stomach and the upper portion of the duodenum. 
RYGB induces both restriction and changes in absorption.  Both SG and RYGB have also been 
proposed to alter the metabolic/humoral milieu to reduce drive to eat [36].  
Weight loss occurs rapidly following RYGB and SG and generally reaches a peak by 12 
months postoperatively.  The Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) 
study, the largest prospective multi-center observational study to date in pediatrics with 242 
adolescents (≤ 19 years of age, mean BMI of 53) showed that among 67 patients who had SG, 
BMI decreased from 50 kg/m2 at baseline to 37 kg/m2 (26% reduction) and among 161 patients 
who had RYGB, BMI decreased from 54 kg/m2 at baseline to 39 kg/m2 (28% reduction) three 
years post-operatively [37].  Thus, although most patients experienced significant weight loss 
with a 26 to 28% reduction in BMI following MBS, 75% still met criteria for obesity (BMI>30 
kg/m2; Figure 1).  Furthermore, many patients experienced weight regain after reaching their 
weight nadir at approximately 1 year [37-41] that places them at continued risk for the metabolic 
consequences of obesity.   
Figure 1: BMI at Baseline and Three Years After Adolescent Bariatric Surgery. 
Adapted from [37]. Only 26% achieved BMI <30 kg/m2
To address how best to assist post-bariatric adolescents who continue to have obesity, we 
propose that the use of liraglutide, a glucagon-like peptide-1 (GLP1) agonist be studied in 
adolescent patients (age 12-20y) with BMI ≥30 or BMI ≥95th percentile for age and sex, 1 year 
or more after SG, which is now the most common pediatric bariatric operation in the United 
States.  Results from this drug trial, if positive, may help develop a new pharmacologic option 
for refractory adolescent obesity and an opportunity to investigate the mechanism of action of 
20-24.9
25-29.9
30-34.9
35-39.9
40-49.9
50-59.9
60-69.9
70-89.9
0
10
20
30
40
50
4.6
21.4
19.1
17.9
22.5
8.7
1.2
0
0
0
0.4
1.8
44.7
32.0
16.2
4.8
Body Mass  Index (kg/m2)
Percent (%)
Baseline
3 years


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GLP-1 in treating children and adolescents with obesity post-bariatric surgery, a group uniquely 
resistant to treatment.  
1.5
BACKGROUND 
Liraglutide (Saxenda®) is an acylated human glucagon-like peptide-1 (GLP-1) agonist 
with 97% amino acid sequence homology to endogenous human GLP-1, an incretin hormone 
that activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylate 
cyclase by the stimulatory Gα-protein in pancreatic beta cells and other tissues [42].  Binding of 
liraglutide to pancreatic GLP-1 receptors increases intracellular cyclic AMP leading to protein 
kinase A (PKA) and guanine nucleotide exchange factor II (Epac2) activation. PKA and Epac2 
alter ion channel activity; as a result, beta‐cell ATP‐sensitive potassium (KATP) channels are 
closed, which in turn shifts membrane potential and sensitizes beta cells to glucose [43]. 
Intracellular calcium (Ca2+) concentrations also rise through an elevated release from internal 
stores, resulting in an increase in the number of readily releasable insulin secretory vesicles; 
GLP-1 receptor activation also stimulates insulin gene transcription [44]. Thus, GLP-1 agonists 
lead to greater insulin release from beta cells, but only in the presence of elevated glucose 
concentrations. GLP-1 agonists also decrease glucagon secretion in the fasting state with 
subsequent decrease in hepatic gluconeogenesis [45], and act in the stomach to delay gastric 
emptying, though this latter effect is considered minor because of rapid tachyphylaxis [46].  
Most interestingly, GLP-1 agonists reduce physiological hunger and long-term food intake via 
effects at multiple sites of action including peripheral ascending vagal fibers, neurons in the 
nucleus of the tractus solitarius, ventral tegmental area, the nucleus accumbens, and the 
hypothalamus [47]. These effects make GLP-1 agonists effective tools for the treatment of 
obesity.
Liraglutide is currently approved by the FDA as an adjunct to diet and exercise to 
improve glycemic control in adults with type 2 diabetes mellitus (dose 1.8 mg daily) and as a 
treatment of obesity in adults with a BMI ≥30 kg/m2 or BMI ≥27 kg/m2 with at least one 
weight-related comorbidity (dose 3 mg daily). The largest randomized, double-blind, placebo-
controlled trial showed that among 3731 patients with overweight or obesity, the liraglutide 
group lost an average 8.4 kg of body weight vs. 2.8 kg with placebo at 56 weeks [48].
In children, liraglutide 1.8 mg/d dosing is FDA-approved to treat children 10 years and 
older with type 2 diabetes and the 3 mg/d dose was recently approved for chronic weight 
management in adolescents 12 years and older with body weight above 60 kg and an initial BMI 
≥30 kg/m2 as an adjunct to a reduced-calorie diet and increased physical activity.  Recent data 
from a randomized, double-blind, placebo-controlled phase 3 trial of liraglutide for adolescents 
(n=251, age 12 to <18 years) with obesity (BMI ≥30 kg/m2 and/or ≥95th percentile for age and 
sex) showed that use of liraglutide (3.0 mg) plus lifestyle therapy led to a significantly greater 
reduction in the BMI standard-deviation score (estimated difference -0.22; 95% confidence 
interval, -0.37 to -0.08; P=0.002) (Figure 2), BMI (estimated difference, -4.64 percentage 
points) and body weight (estimated difference, -4.50 kg [for absolute change]) than placebo plus 
lifestyle therapy [32].  Similarly, a randomized, double-blind, placebo-controlled trial including 
24 children with mean age 9.9+/- 1.1 years and mean BMI Z-score of 3.9 showed that short-term 
treatment with liraglutide led to significant reduction in BMI Z-score from baseline to end of 


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treatment at 7-8 weeks (estimated treatment difference in BMI Z score -0.28; P=0.0062) with a 
comparable safety and tolerability profile to trials in adults with obesity with no new safety 
issues [49].
Figure 2: Absolute Change in BMI Standard-Deviation Score in adolescents with obesity who 
were randomized to liraglutide or placebo, Adapted from [32]
There are some relatively small, mostly retrospective studies on the use of anti-obesity 
pharmacotherapy in adult patients with weight regain or inadequate weight loss following MBS 
but none in children and adolescents.  A retrospective review of 319 adults who had undergone 
RYGB (80.9%) or SG (19.1%) at two academic medical centers in the U.S. from 2000-2014 
revealed that many patients who received weight loss medication after bariatric surgery had an 
additional weight loss benefit with mean added weight loss of -7.6% (17.8 lbs.) of total 
postsurgical weight [50].  Among the weight loss medications, topiramate was the most 
commonly prescribed (60.8% of patients) followed by phentermine (37.9%), metformin (38.6%), 
bupropion (23.%), and zonisamide (20.4%) [50].  Another retrospective study showed significant 
weight loss (-6.3 +/- 7.7 kg, P<0.05) among 117 adult patients treated with liraglutide 3.0 mg 
daily over 7.6+/- 7.1 months approximately 8 years post-bariatric surgery regardless of type of 
surgery (45% underwent RYGB , 43% underwent adjustable gastric banding, 12% underwent 
VSG) [51].  Liraglutide was also found to reduce body weight in adults (age 18 years and older) 
with expected weight loss but persistent or recurrent type 2 diabetes after metabolic surgery in 
the GRAVITAS study, a randomized, double-blind, placebo-controlled trial [52]. 80 adults who 
had undergone RYGB or SG at least 1 year before randomization were assigned to either 
liraglutide (1.8 mg daily) or placebo, and there was an estimated weight loss of -4.23 kg from 
0
4
8 12 16 20 24 28 32 36 40 44 48 52 56
-0.30
-0.25
-0.20
-0.15
-0.10
-0.05
0.00
0.05
0.10
Weeks since Randomization
Change from Baseline
BMIz Score
Placebo
Liraglutide


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baseline to week 26 for liraglutide vs. placebo (95% CI 6.81 to -1.64, p=0.0017).  In addition, 
46% of patients in the liraglutide group lost 5% or more of their baseline bodyweight even on 
lower dose liraglutide (1.8 mg instead of 3 mg which is FDA approved dose for obesity 
treatment), compared with only 9% of patients in the placebo group.  Thus, although there is 
retrospective data that suggests weight-loss medications may be beneficial following MBS, there 
are few published data from prospective trials which highlights the importance of research on 
this topic.  
Among the available weight-loss medications, our team is most interested in investigating 
the use of liraglutide for post-bariatric patients because of known changes in GLP-1 and other 
incretin hormone levels like peptide-YY following MBS.  Both RYGB and SG increase 
postprandial GLP1 and peptide-YY via rapid nutrient delivery down the GI tract where 
enteroendocrine L-cells are located [53], with some, though not all, studies finding lesser 
increases in GLP1 after SG than RYGB.  Thus, we hypothesize that liraglutide treatment can 
augment the physiological increase in GLP1 following SG and cause weight loss via appetite 
suppression.  Post-prandial GLP-1 responses appear to remain enhanced following SG up to 1 
year following surgery, but it is unclear whether this effect persists beyond 1 year [54] and if it 
varies among patients with poor weight loss response (<20% BMI reduction) and those with 
typical weight loss (>20% BMI reduction) following MBS.  Thus, it will be important to 
examine if extent of weight loss with liraglutide is impacted by amount of time (i.e. 1 year vs. 
multiple years) since surgery and by pre-treatment post-surgical weight.  
1.6
RISK/BENEFIT ASSESSMENT
1.6.1
Known Potential Risks
1. Risks associated with liraglutide (Saxenda):  
Liraglutide for weight loss is approved by the FDA for use in adults with BMI ≥ 30 kg/m2 or 
adults with BMI 27 kg/m2 or greater in the presence of at least one weight-related comorbid 
condition (e.g. hypertension, type 2 diabetes mellitus, or dyslipidemia) and in adolescents 12 
years and older with body weight above 60 kg and an initial BMI ≥30 kg/m2 as an adjunct to a 
reduced-calorie diet and increased physical activity. Novo Nordisk lists the following most 
common side effects of liraglutide on its package insert [57: nausea, diarrhea, vomiting, 
decreased appetite, indigestion, and constipation [42]. Possible serious side effects include: 
pancreatitis, hypoglycemia when used alone or with other blood glucose lowering medications 
such as insulin and sulfonylurea, kidney failure in patients who have kidney disease, serious 
allergic reaction, and acute gallbladder disease. 
Recent data from a randomized, double-blind, placebo-controlled phase 3 trial of liraglutide (3.0 
mg daily) for adolescents (age 12 to <18 years) with obesity (BMI ≥30 kg/m2 and  ≥95th 
percentile for age and sex) showed that the percentage of patients who reported adverse events 
during the treatment period was similar in the liraglutide group (89%) and the placebo group 
(85%) [32].  However, more participants in the liraglutide group compared to placebo 
complained of gastrointestinal side effects, including nausea, vomiting, and diarrhea (64.8% vs. 
36.5%) and had adverse events that led to discontinuation of trial treatment (10.4% vs. 0%).  


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Saxenda comes with a black box warning for a risk of thyroid C-cell tumors as it causes 
thyroid C-cell tumors at clinically relevant exposures in both sexes of rats and mice.  It is 
unknown whether Saxenda causes thyroid C-cell tumors, including medullary thyroid carcinoma 
in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not 
been determined [42].
2. Blood sampling: 
Peripheral blood draws (venipuncture) performed during this study for research will not exceed 5 
ml/kg in a single day over any 8-week-trial period for pediatric patients (age less than 18 years) 
and will not exceed 10.5 ml/kg or 550 ml< whichever is smaller, over any 8-week-period.  This 
amount falls below the NIH guideline for a safe amount of blood withdrawal. Possible side 
effects from blood draws include faintness, inflammation of the vein, pain, bruising, or bleeding 
at the site of puncture.  There is also a slight possibility of infection. We will offer ELA max 
cream to decrease pain. An area of white or red rash that usually goes away within a few hours 
may be seen after use of ELA max cream. 
3.  Radiation exposure from dual energy absorptiometry (DXA scan):
The DXA scan is a reliable and reproducible method to measure body composition, specifically 
body fat, bone mineral content, and lean body mass.  The patient lies on a flat table with the x-
ray source below the table and the detector above.  For the iDXA scan used in this study, the 
total effective dose of radiation from the two scans performed is 0.00006 rem, which is below the 
guideline of 5 rem (for adults) and 0.5 rem (for children) per year allowed for research subjects 
by the NIH Radiation Safety Committee.  The average person in the United States receives a 
radiation exposure of 0.3 rem per year from natural sources, such as the sun, outer space, and the 
earth’s air and soil.  If participants want to learn more about radiation, they will be given the 
pamphlet: An Introduction to Radiation for NIH Research Subjects.  DXA is not painful but may 
be inconvenient because of the time needed to complete the study.
4.  Oral Glucose Tolerance Test: 
Dextrose solution administration is without known serious risks but may cause mild feelings of 
nausea or rarely lead to vomiting. Patients may develop transiently high blood sugar levels from 
the glucose, but it should normalize within a few hours and should not be clinically significant.
5.  Other body composition methods
Body circumference measurements of the waist will be done with a flexible tape measure; this 
involves no risk and is not painful.  
6.  Accelerometer Testing:
Participants will be asked to wear an accelerometer on their wrist for 2 weeks at a time that 
measures free-living physical activity.  It is an unobtrusive device without known risks and 
requires no maintenance by the user.  It may cause mild inconvenience to the participant as they 
will be instructed to wear the accelerometer during all hours, except when bathing or showering 


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and for contact sports.  If irritation at the site of the wrist strap occurs, the participant will be 
instructed to discontinue the use of the device and contact the research study team.
7.  Questionnaires and interviews
Both questionnaires and interviews involve minimal risk.  However, it is possible that 
participants may experience slight discomfort as a result of being asked to fill out questionnaires 
or respond to queries about stress and mood.  If the wording of a question makes the participant 
uncomfortable, the participant is not required to answer that particular question. Similarly, 
participants will be informed of their right to not complete any test or task during any visit. 
Additionally, questionnaires and interviews may cause inconvenience because of the time 
required for testing.
8.  Pregnancy/Birth control
The effects of liraglutide on the unborn child and on the newborn baby are not known.  Because 
of this, it is important that participants do not participate if pregnant or breast-feeding.  It is also 
important that participants do not become pregnant during the course of the study.  Females with 
child-bearing potential will be required to undergo a pregnancy test prior to starting and 
throughout the study.  Males will also be instructed not to father a child for at least 6 months 
after completion of the study.  Those who are sexually active and not surgically sterile must use 
effective contraception.
9.  The physical examination, body measurements with a tape measure, and vital signs are 
without significant risk, but some subjects may find them inconvenient for time required to 
complete.  A limited physical examination will be performed in a concise but thorough 
manner with appropriate measures taken to provide participant’s privacy.
10.  Urine collections for pregnancy check are without significant risk, but some subjects may 
find them uncomfortable to collect.  
11. Stool samples are also without significant risk, but some subjects may find them 
uncomfortable to collect.  It is possible that we will send subject’s stool to other scientists 
working with us on obesity-related studies, but in this case personal identifiers will be 
removed, and the samples coded or deidentified.  If a subject chooses to withdraw from the 
study, we will keep samples for analysis indefinitely, unless the subject requests that the 
samples be destroyed.  
12.  The surveys and food records (diet log) are also without significant risk but may be 
inconvenient because of the time required to complete.
13.  The buffet meal is without significant risk, but participants may feel uncomfortable if they 
eat too much or too quickly.
Alternatives to participation


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Participation in clinical trials is completely voluntary. Refusal to participate will not affect a 
subject’s ability to participate in other studies at NIH or elsewhere.  The main alternatives to 
treatment include continuing or intensifying behavioral management strategies for obesity, or 
possibly using one of the FDA-approved treatments for obesity in adolescents: orlistat, a lipase 
inhibitor for children ≥12 years and phentermine, a norepinephrine reuptake inhibitor for short-
term use (12 weeks) in adolescents ≥16 years or other medications such as phentermine plus 
topiramate that are approved for those age 17y and older.  It is also possible a provider would 
prescribe liraglutide. None of these medications have been specifically approved by the FDA for 
use in adolescents who have undergone bariatric operations and thus would be considered being 
prescribed off-label.
1.6.2
Known Potential Benefits
This research protocol will investigate the use of liraglutide, a glucagon-like peptide-1 (GLP1) 
agonist in adolescent patients (age 12-20y) who continue to have obesity (BMI ≥30 kg/m2 or 
≥95th percentile for age and sex) 1 year or more after sleeve gastrectomy.  Based on recent data 
from a randomized, double-blind, placebo-controlled phase 3 trial of liraglutide for adolescents 
(age 12 to <18 years) with obesity (BMI ≥30 kg/m2 and  ≥95th percentile for age and sex), use of 
liraglutide (3.0 mg) plus lifestyle therapy is anticipated to have the potential to decrease the BMI 
of enrolled participants [32].
In addition, for enrolled patients with type 2 diabetes taking metformin, liraglutide is expected to 
improve glycemia based on results from the ELLIPSE trial, a 26-week, randomized, double-
blind, parallel-group, placebo-controlled trial in 134 pediatric patients with T2D aged 10 years 
and older [55]. Patients were randomized to liraglutide or placebo once daily in combination 
with metformin, with or without basal insulin.  At Week 26, treatment with liraglutide was 
superior in reducing A1C from baseline vs. placebo with an estimated treatment difference of -
1.06% in A1c reduction from baseline (95% CI: -1.65, -0.46; p<0.001).  In addition, the 
percentage of patients achieving an A1C <7% with liraglutide was 63.7% vs. 36.5% with 
placebo.  
Participants will receive individualized counseling in nutrition from nutrition department staff at 
the NIH Clinical Center at their Screening Visit, but as such counseling is standard of care for 
patients with obesity, it is not considered a benefit of the study.
1.6.3
Assessment of Potential Risks and Benefits
This clinical drug trial and its associated testing will be associated with some risks which we will 
try to minimize as outlined below:
-To minimize the risk for gastrointestinal disturbance, liraglutide dosing will be gradually 
increased over a 5-week period to achieve a maximum dose of 3.0 mg daily.  Participants who 
experience mild to moderate gastrointestinal symptoms will contact the study team and the dose 
of liraglutide will be decreased and maintained at maximum tolerated dose until completion of 
the study.  Participants who experience severe and/or recurrent gastrointestinal symptoms 
including acute gallbladder disease will be withdrawn from the study.  


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-To minimize the risk for hypoglycemia for participants taking liraglutide, we will exclude 
patients on insulin or sulfonylurea therapy.  
-To minimize the risk of pancreatitis in this study from liraglutide treatment, we will exclude 
patients with prior history of more than two episodes of pancreatitis as it may put them at higher 
risk for pancreatitis.  If pancreatitis is clinically suspected (either based on signs/symptoms 
consisting of moderate to severe abdominal pain with nausea or vomiting) the following will take 
place: 1) Patient will be directed to local emergency department where amylase and lipase levels 
will be drawn  2) Abdominal ultrasound will be obtained.   If a diagnosis of pancreatitis is likely 
or confirmed based on labs and/or imaging, the following additional actions will be taken.  1) 
The patient will be recommended for admission for further management or discharged home 
with supportive care depending on clinical severity.  2) Appropriate treatment will be initiated by 
primary medical team (usually, NPO and pain medications) if admitted.  3) The patient will be 
withdrawn from the study.  4) The IRB will be notified per guidelines for serious adverse effects.
-To minimize the risk of kidney failure in this study from liraglutide treatment, we will exclude 
patients with chronic kidney disease (eGFR <60; eGFR calculated using CKD-EPI equation).
-To minimize the risk of thyroid c-cell carcinoma from liraglutide treatment, we will exclude 
patients with a personal or family history of medullary thyroid cancer or multiple endocrine 
neoplasia syndrome type 2 (MEN-2) because use of Saxendais contraindicated in these 
patients.  If a thyroid nodule or neck swelling is observed, further evaluation will be pursued 
with thyroid ultrasound and serum calcitonin measurement.  
-To decrease pain from venipuncture, we will offer ELA max cream to participants.
-To decrease risk of infection from venipuncture, we will place intravenous catheter under sterile 
conditions and observe universal precautions.  
OBJECTIVES AND ENDPOINTS
OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
Primary
1.  To determine the effect 
size for the change in 
BMI of liraglutide 3.0 
mg subcutaneously at 
16 weeks in adolescents 
who have obesity after 
SG
Estimation of required sample 
size for a later RCT through 
calculation of effect size for 
change in body mass index (BMI) 
from baseline to 16 weeks of 
liraglutide.
We will use the 
observed changes to 
determine the sample 
size of a subsequent 
randomized, controlled 
investigation.
Secondary


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OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
1.  To study the effects of 
16 weeks of liraglutide 
3.0 mg subcutaneously 
on change in BMI and 
fat mass in adolescents 
who underwent vertical 
sleeve gastrectomy (SG) 
≥1y prior to study 
initiation but still have 
obesity or have a 
recrudescence of 
obesity after surgery.
2. To compare the effects 
of liraglutide on BMI 
and fat mass in enrolled 
participants who had a 
poor initial response to 
SG (<20% BMI 
reduction at BMI nadir) 
vs. those with a typical 
post-SG weight loss 
(≥20% BMI reduction at 
BMI nadir)
3. Tolerability and Safety 
of 3.0 mg liraglutide
Change from baseline to 16 
weeks in:
1. BMI 
2. Proportion reducing BMI 
by at least 5% and 10%
3. BMI standard deviation 
score for age and sex 
(BMIz)
4. Body weight
Comparison of changes in BMI 
and fat mass after 16 weeks of 
liraglutide in participants who 
had a poor initial response to SG 
(<20% BMI reduction at BMI 
nadir) vs. those with a typical 
post-SG weight loss (≥20% BMI 
reduction at BMI nadir)
Percentage of participants 
reaching the top liraglutide dose 
and all adverse events will be 
recorded.
BMI correlates with 
adiposity and obesity-
related comorbidities 
such as hypertension, 
type 2 diabetes, sleep 
apnea, and 
dyslipidemia.  
Measuring the 
proportion of patients 
reducing their BMI by 
at least 5% and 10% 
will help better 
differentiate degree of 
weight loss with drug 
treatment.
Percentage total body 
fat mass by DXA will 
be measured because 
weight loss with drug 
treatment may be 
associated with changes 
in body composition.  
Tertiary/Exploratory 
1. To examine the effects 
of liraglutide in enrolled 
participants on changes 
in body composition, 
metabolic syndrome 
markers, energy intake, 
glucose tolerance, GI 
hormone 
concentrations, appetite, 
free living physical 
activity, mood, 
1. Percentage total body 
fat mass by DXA
2. Appetite score using 
visual analog scale 
(VAS)
3. Attention bias to 
highly palatable 
images
4. Energy intake at 
buffet meal
Weight loss with drug 
treatment may affect 
obesity-related 
comorbidities/metabolic 
syndrome markers such 
as hypertension, 
dyslipidemia, glucose 
intolerance/diabetes.
We will examine the 
effect of liraglutide on 


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OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
suicidality, weight 
related quality of life, 
self-perception of body 
image, and secretome 
5. Free living physical 
activity by 
accelerometry 
6. Metabolic syndrome 
markers (waist 
circumference, 
systolic and diastolic 
blood pressure, lipids, 
fasting plasma glucose 
level)
7. Fasting plasma insulin 
level and HOMA-IR 
index
8. 2-hour oral glucose 
tolerance test (OGTT) 
insulin and glucose 
measurements
9. Hemoglobin A1C 
10. Plasma GI hormones 
(GLP-1 and PYY) 
during OGTT
11. Weight related quality 
of life (QoL) score
12. Beck Depression 
Inventory total score
13. Body-Esteem Scale 
for Adolescents and 
Adults
14. Secretome analysis
15. Stool microbiome 
analysis
16. Columbia-Suicide 
Severity Rating Scale 
(C-SSR)
energy intake as it is 
known to suppress 
appetite.  We will also 
examine effect of 
liraglutide on attention 
bias to highly palatable 
images as heightened 
attention bias to highly 
palatable images may 
lead to excess energy 
intake. Free-living 
physical activity with 
an accelerometer will 
be measured because 
weight change with 
drug treatment may 
affect energy 
expenditure. Weight 
related quality of life 
score, Beck Depression 
Inventory total score, 
Columbia-Suicide 
Severity Rating Scale, 
and self-perception of 
body image score will 
be measured to examine 
psychological effect of 
weight before and after 
drug treatment


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STUDY DESIGN
1.7
OVERALL DESIGN
This trial will be a multi-site open-label Phase II non-randomized pilot study involving two US 
sites: NIH Clinical Center and CNH. Dr. Evan Nadler and Dr. Nazrat Mirza at CNH will be 
involved in identifying and recruiting potential participants.  They will be involved in answering 
questions about the study from interested patients but will not be screening or obtaining consent 
from participants. They will also be analyzing identifiable information from participants.  All 
study visits will be conducted at a single site (NIH Clinical Center) to investigate the efficacy of 
liraglutide, a glucagon-like peptide-1 (GLP1) analogue to promote weight loss in pediatric 
patients (age 12 to <21y) who continue to have obesity (BMI ≥30 kg/m2 or BMI ≥95th percentile 
for age and sex) 1 year or more after vertical sleeve gastrectomy (SG) over 16 weeks.  
Participants will undergo a telephone screening, followed by a screening visit to assess 
eligibility. Those found eligible will undergo a baseline evaluation to assess their glucose 
tolerance, lipids, levels of plasma GI hormones, appetite, body composition, energy intake, free 
living physical activity (by accelerometry), questionnaire measures, including assessment of 
weight related quality of life, mood, suicidality, and self-perception of body image. The trial will 
be divided into two consecutive periods. Period 1 will consist of 5 weeks of dose titration with 
goal of reaching max dose of 3 mg liraglutide daily with visits every 4 weeks over 16 weeks 
(including the 5 weeks of titration). The treatment period will then be followed by a 12-week 
period off study drug ending at week 28. 
The primary outcome (change in BMI) will be statistically analyzed after participants have been 
treated with 3.0 mg daily liraglutide or max tolerated dose at 16 weeks. Secondary outcomes will 
also be measured at 16 weeks. BMI will be reassessed at follow-up at 28 weeks.  There will be 
no interim analyses.  Randomization will be stratified by birth sex assignment (Male versus 
Female), race (Non-Hispanic Black versus Other), and degree of weight loss after SG (those with 
typical post-SG weight loss, defined as ≥20% BMI reduction versus those with poor post-
surgical weight loss response, defined as <20% BMI reduction post-SG), since expectation of 
benefit might differ in those unable to lose weight with SG.
1.8
SCIENTIFIC RATIONALE FOR STUDY DESIGN
We propose a pilot open-label treatment study to estimate effect sizes and identify potential 
responders for a subsequent larger randomized, double-blind, placebo-controlled trial. Data will 
be compared for patients with poor weight loss response to SG (<20% BMI reduction) vs. those 
with typical post-SG weight loss (>20% BMI reduction) but who have persistent obesity (BMI 
≥30 kg/m2 or ≥95th percentile for age and sex) 1 year or more after SG. These data will allow 
determination of the sample size for a future fully powered randomized controlled trial.
1.9
JUSTIFICATION FOR DOSE
Eligible patients will be treated with daily subcutaneous liraglutide (starting at 0.6 mg daily with 
weekly dose escalations up to 3.0 mg per day or max tolerated dose). This dose is in line with 
liraglutide’s treatment dose for adults with a BMI ≥30 kg/m2 or BMI ≥27 kg/m2 with at least 
one weight-related comorbidity (dose 3 mg daily).  


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In addition, a recent randomized, double-blind, placebo-controlled phase 3 trial of liraglutide for 
adolescents (age 12 to <18 years) with obesity (BMI ≥30 kg/m2 and  ≥95th percentile for age and 
sex) used a treatment dose of  3.0 mg daily [32] and had a comparable safety and tolerability 
profile to trials in adults with obesity with no new safety issues [49]. 
STUDY POPULATION
Adolescents are selected as the study subjects because of the dearth of relevant data for 
adolescents who have undergone SG. All races and ethnicities will be included. Since obesity is 
identified in large percentages among minority groups including Asian Americans, African 
American and Hispanic Americans, we anticipate good representation of all major 
races/ethnicities. It is expected, given our recruitment procedures targeting individuals living in 
the greater metropolitan Washington, D.C. area, that we will recruit rates of minority 
participation in excess of their representation in the Washington, D.C. metropolitan area: 64.2% 
Caucasian, 27.2% African American and 8.6% Hispanic.
Total number of subjects to be studied in the protocol:
50 maximum
Planned number of subjects to be screened in person:
50 maximum
Planned number of subjects to be treated with liraglutide:
43 maximum
Subjects will not be replaced if they withdraw or become ineligible.
 
1.10 INCLUSION CRITERIA
In order to be eligible to participate in this study, an individual must meet all of the 
following criteria:
1. Male or female, 12-20.999 years at screening visit
2. 12 months or more status-post vertical sleeve gastrectomy with a maximum of 10 years 
after surgery
3. BMI 30 kg/m2 or ≥95th percentile for age and sex
4. In good general health as evidenced by medical history 
5. Ability to take subcutaneous medication and be willing to adhere to the daily 
subcutaneous liraglutide regimen
6. Ability to provide consent/assent before any trial-related activities as required per 
protocol
7. Stated availability for the duration of the study 
1.11 EXCLUSION CRITERIA
An individual who meets any of the following criteria will be excluded from participation in this 
study:


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1. Current or recent (within 3 months of start of study drug initiation) use of weight loss 
medications such as phentermine, topiramate, lisdexamfetamine (prescribed specifically 
for weight loss; when prescribed for ADHD and dose is stable for last 3 months this 
medication will be allowed), orlistat, and naltrexone HCl/bupropion HCl, or liraglutide
2. Weight of more than 450 lbs. (because Dual-Energy X-ray Absorptiometry (DXA) 
scanning cannot be done in those exceeding this weight)
3. Current use of insulin or sulfonylurea or other medication affecting insulin secretion or 
GLP1 clearance such as a DPPIV inhibitor
4. Weight loss of more than 3% of body weight in the past 2 months 
5. Current pregnancy, desire to become pregnant within study period, current lactation or, if 
sexually active, not willing to use adequate contraceptive measures
6. History of recurrent pancreatitis (greater than 2 episodes)
7. History of chronic kidney disease (eGFR <60)
8. History of gastroparesis
9. Personal or family history of medullary thyroid carcinoma or multiple endocrine 
neoplasia syndrome type 2 
10. History of prior metabolic and bariatric surgery other than vertical sleeve gastrectomy
11. Current or prior use of any GLP-1 agonist medication during the 6 months before 
screening, including liraglutide.
12. Known or suspected allergy to trial medication, excipients, or related products
13. Treatment with another investigational drug or other experimental intervention within 3 
months prior to enrollment in this trial 
14. Individuals who have current substance abuse or a DSM 5 Axis I psychiatric disorder or 
DSM Axis II Mental Retardation diagnosis that in the opinion of the investigators would 
impede competence, compliance, or participation in the study
15. Suicidal ideation type 4 or 5, history of past suicide attempt, and suicidal behavior in the 
past month
16. Presence of a major medical illness not listed above
1.12 INCLUSION OF VULNERABLE PARTICIPANTS
This study will involve recruitment of adolescents age 12-<21 years as the aim of the clinical 
trial is to determine the efficacy of liraglutide to promote weight loss in adolescent patients, a 
population with limited medical treatment options for moderate to severe obesity.  The study will 
not involve recruitment of other vulnerable populations including pregnant women, prisoners, 
NIH employees, adults who lack consent capacity, including the mentally ill, and cognitively 
impaired participants because they do not meet the inclusion criteria for this study.
1.13 INCLUSION OF PREGNANT WOMEN, FETUSES OR NEONATES
Not Applicable
1.14 LIFESTYLE CONSIDERATIONS
Not Applicable
1.15 SCREEN FAILURES
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of 


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screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE).
Individuals who do not meet the criteria for participation in this trial (screen failure) because of 
use of weight loss medication like phentermine, topiramate, lisdexamfetamine, orlistat, and 
naltrexone HCl/bupropion HCl may be rescreened three months after discontinuing the 
medication.  Rescreened participants should be assigned the same participant number as for the 
initial screening.
1.16 STRATEGIES FOR RECRUITMENT AND RETENTION
Recruitment: A total of at most 50 participants to be screened at the NIH for protocol 
participation will be recruited from Washington, DC and local suburbs in Maryland and Virginia, 
with expected accrual rate of approximately 4 participants per month. Recruitment efforts will 
aim to enroll subjects in proportion to their representation in the population of Maryland. 
Subjects of all racial, ethnic and socio-economic backgrounds will be invited to participate in 
this study. Tools used for the recruitment of subjects will include the posting of the study 
description on the NIH Clinical Trials website. Additionally, flyers will be placed on bulletin 
boards at different buildings throughout the NIH campus and CNH.  Recruitment material will 
be IRB approved prior to dissemination. Potential participants may also be referred by local 
providers responsible for clinical care. This includes providers from CNH’s Bariatric Surgery 
Clinic and CNH’s Obesity Program (multidisciplinary IDEAL Clinic) as well as from other 
community providers to whom we will provide our study information via a physician mailing 
letter and recruitment flyer. If necessary, further subjects will be recruited through newspaper 
advertisements or letter mailings. Advertisements will be submitted to the IRB before use.
Retention: There are incentives for attendance at study visits in terms of compensation for the 
time spent for, and inconvenience of, participation (see Compensation). We have a well-
established track record of success in retaining participants with obesity for pharmacotherapy 
trials in adults and children [56-60]. For example, we recruited 340 adults for a 2-year 
pharmacotherapy RCT, retaining 82% for 1-year and 75% for 2-year study outcome 
measurements.
1.16.1 Costs
The trial drug will be provided at no cost to the patient. All trial related testing will be performed 
at no cost to the patient.
1.16.2 Compensation
Enrolled participants will be financially compensated for participation in this study for attending 
study visits as follows:
Compensation per visit- to be given at the end of each visit
1. Outpatient screening visit:
$50
2. Baseline evaluation visit:
$200
3. Interim Safety Visits (three total @$25 per visit):
$75


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4. Visit 5 
$200
5. Optional stool samples (up to 2 @$25 per sample)
$50
6. Final Visit:
$50
Total=
$575 to $625
Compensation per procedure at Baseline evaluation visit:
1. History and Physical Exam
$20.00
2. OGTT
$50.00
3. DXA
$30.00
4. Accelerometer
$20.00
5. Blood draw
$30.00
6. Questionnaires
$50.00
7. Optional Stool Collection
$25.00
Total
$200 to $225.00
The participants will be compensated for the parts of the study that they have completed.  
Payments will be sent after the visit either by check or direct deposit. If the participant is a 
minor, the guardian will receive the visit payment on behalf of the minor subject.  
Guardians accompanying minors to NIH will be compensated $40 per visit x 7 visits: $280 which 
will be paid as a lump sum at the completion of the study.  
Travel expenses (mileage, Metro, or taxi fare) will also be reimbursed per NICHD guidelines.
STUDY INTERVENTION
1.17 STUDY INTERVENTIONS(S) ADMINISTRATION
1.17.1 Study Intervention Description
The following description is quoted from the FDA-approved package insert [61]: “SAXENDA 
contains liraglutide, an analog of human GLP-1 and acts as a GLP-1 receptor agonist. The 
peptide precursor of liraglutide, produced by a process that includes expression of recombinant 
DNA in Saccharomyces cerevisiae, has been engineered to be 97% homologous to native human 
GLP-1 by substituting arginine for lysine at position 34. Liraglutide is made by attaching a C-16 
fatty acid (palmitic acid) with a glutamic acid spacer on the remaining lysine residue at position 
26 of the peptide precursor. The molecular formula of liraglutide is C172H265N43O51 and the 
molecular weight is 3751.2 Daltons.”
“SAXENDA injection is a sterile, aqueous, clear, colorless or almost colorless solution for 
subcutaneous use. Each 1 mL of SAXENDA solution contains 6 mg of liraglutide and the 
following inactive ingredients: disodium phosphate dihydrate, 1.42 mg; propylene glycol, 14 mg; 
phenol, 5.5 mg; and water for injection. SAXENDA has a pH of approximately 8.15, 
hydrochloric acid or sodium hydroxide may be added to adjust pH. Each prefilled pen contains a 
3 mL solution of SAXENDA equivalent to 18 mg liraglutide (free-base, anhydrous).”
“Liraglutide is an acylated human glucagon-like peptide-1 (GLP-1) receptor agonist with 97% amino 
acid sequence homology to endogenous human GLP-1(7-37). Like endogenous GLP-1, liraglutide 
binds to and activates the GLP-1 receptor, a cell-surface receptor coupled to adenylyl cyclase 


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activation through the stimulatory G-protein, Gs. Endogenous GLP-1 has a half-life of 1.5-2 minutes 
due to degradation by the ubiquitous endogenous enzymes, dipeptidyl peptidase 4 (DPP-4) and 
neutral endopeptidases (NEP). Unlike native GLP-1, liraglutide is stable against metabolic 
degradation by both peptidases and has a plasma half-life of 13 hours after subcutaneous 
administration. The pharmacokinetic profile of liraglutide, which makes it suitable for once-daily 
administration, is a result of self-association that delays absorption, plasma protein binding, and 
stability against metabolic degradation by DPP-4 and NEP.”
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 30-40 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 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 
endogenously 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.”
Liraglutide solution (6 mg/mL, 3 ml) for subcutaneous injection via a pre-filled, multi-dose pen 
that delivers doses of 0.6 mg, 1.2mg, 1.8 mg, 2.4 mg, and 3.0  mg will be used within the 
approved dosing regimens.  Table 1 illustrates the titration schedule for the drug.  The study 
intervention is commercially available and will be purchased.  The intervention dose of 3.0 mg 
daily is approved by the FDA to treat children 12 years and older with body weight above 60 kg 
and an initial BMI ≥30 kg/m2 (or above the International Obesity Task Force BMI Cut-offs for 
Obesity by Sex and Age for Pediatric Patients Aged 12 Years and Older) as an adjunct to a 
reduced-calorie diet and increased physical activity.  
There will be no IND obtained for the use of any of the commercial agents used in this study.  
This study meets the criteria for exemption for an IND as this investigation is not intended to 
support a new indication for use or any other significant change to the labeling; the drugs are 
already approved and marketed and the investigation is not intended to support a significant 


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change in advertising; and the investigation does not involve a route of administration or dosage 
level in use in a patient population or other factor that significantly increases the risks (or 
decreases the acceptability of the risks) associated with the use of the drug product.
We have received an IND exemption for the use of liraglutide (Saxenda) in this study. The 
letter documenting this exemption has been supplied to the IRB. 
1.17.2 Dosing and Administration
1.17.2.1 Dose Escalation
Table 1: Titration Schedule for Liraglutide
Study schedule
Week
Liraglutide (subcutaneous 
injection)
Screening
-1 to 0
-
Baseline visit
0-1
0.6 mg once daily as tolerated
1-2
1.2 mg once daily as tolerated
2-3
1.8 mg once daily as tolerated
3-4
2.4 mg once daily as tolerated
Target study dose 
4-16
3.0 mg once daily as tolerated
The participant will start the study drug at Visit 1 (Baseline Visit) after the History & Physical 
Examination.  The study drug will be titrated to the highest tolerable dose as per Table 1 above.  
1.17.2.2 Dose Limiting Toxicity
Adverse reactions occurring in ≥3% of SAXENDA-treated pediatric patients and more frequent 
than placebo are outlined in the Table below, from the package insert [61]:
Placebo (N=126)
%
SAXENDA (N=125)
%
Nausea
14.3
42.4
Vomiting
4.0
34.4
Diarrhea
14.3
22.4
Hypoglycemia
4.0
15.2


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Gastroenteritis
4.8
12.8
Dizziness
3.2
10.4
Pyrexia
7.1
8.0
Abdominal Discomfort
0.8
4.8
Constipation
2.4
4.8
Dyslipidemia
3.2
4.8
Fatigue
3.2
4.8
Cough
3.2
4.0
Depression
2.4
4.0
Dyspepsia
2.4
4.0
Pain in extremity
2.4
4.0
Injection site pain
3.2
3.2
Flatulence
0
3.2
Increased Blood Creatine Kinase
2.4
3.2
Increased Lipase
0.8
3.2
Rash
0
3.2
Participants on liraglutide may experience gastrointestinal side effects like nausea, diarrhea, 
vomiting, decreased appetite, indigestion, and constipation.  Should a participant find these side 
effect intolerable, their dose will not be escalated (and may be decreased) according to 
tolerability as described below.  In addition to tolerability, dose limiting toxicities are defined in 
the attached Excel file titled “CTCAE_v5.0_2017-11-27 for Liraglutide.”  In order to be dose 
limiting, the AE must be considered to be at least possibly due to the study drug.  
1.17.2.3 Dose Modifications
If intolerable symptoms persist after 3 days at any dose, the liraglutide dosage will be decreased 
by 0.6 mg daily.  If the highest tolerable liraglutide dose is less than 0.6 mg daily, the study drug 
will be discontinued, but the participant will be asked to return for Study Visit 5.
If gastrointestinal symptoms resolve, then at the discretion of the PI, the dose of liraglutide may 
be increased after 3 days to the previous dose.  If participant redevelops GI symptoms on 
previous dose, then they should continue the max tolerated dose for the remainder of the study.  


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If a dose of liraglutide is missed, the study participants will be asked to resume the once daily 
regimen as prescribed with the next scheduled dose.  They will be instructed not to administer an 
extra dose or increase the dose to make up for the missed dose.  
1.17.2.4 Drug Administration
Prior to first use, Saxenda will be stored in a refrigerator between 36 to 46 degrees Fahrenheit as 
recommended on its package insert. Participants or their parent will administer first dose of study 
drug (0.6 mg) subcutaneously at Visit 1 after receiving training from our research team on proper 
injection technique. They will also be given a medication guide (see document titled, “Saxenda 
for patients.”  Subsequent subcutaneous doses will be administered at participants’ home daily at 
a consistent time.  After first use of the Saxenda pen, the pen will be stored at controlled room 
temperature (59 to 86 degrees Fahrenheit) or in a refrigerator (36 to 46 degrees Fahrenheit) with 
the pen cap on.  
If a dose is missed, the participant should make up the missed dose on the same day as soon as 
they remember and take their next daily dose as usual on the following day.  The participant 
should not take an extra dose of the drug or increase their dose on the following day to make up 
for the missed dose.  Any missed doses will be recorded in a patient log.  
Participants will call the research team if they miss their dose of study drug for 3 days or more.  
The study drug dose will be up-titrated as show in Table 1.
1.18 PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Liraglutide (Brand name Saxenda) will be purchased from Novo Nordisk and stored in the NIH 
Clinical Center Pharmacy in its original packaging for use as specified in the Package Insert.  
The NIH Clinical Center Pharmacy will dispense the study medication per study schedule.  
Study medication will be supplied in 30 days’ supply at Visit 1-4.
1.18.1 Acquisition and Accountability
The study drug will be acquired and stored by the NIH Clinical Center Pharmacy.  The 
investigator’s team will pick up the study drug from the NIH CC Pharmacy at each study visit.  
There is no control product in this open label trial.  Empty pens will be returned at Visits 2-5 and 
discharged by the investigator’s team.  The storage of medications will be according to the 
package insert for the study drug.  
1.18.2 Formulation, Appearance, Packaging, and Labeling
Saxenda solution (6 mg/mL, 3 ml) purchased from Novo Nordisk for subcutaneous injection 
via a pre-filled, multi-dose pen will be supplied.  The solution is clear and colorless.  
Participants will be requested to return all used pens as well as any expired or unused medication 
to Study Investigators, who will count used and unused pens and give them to the NIH pharmacy 
for disposal.
1.18.3 Product Storage and Stability
Prior to first use, Saxenda should be stored in a refrigerator between 36 degrees Fahrenheit to 
46 degrees Fahrenheit.  After initial use of the Saxenda pen, the pen can be stored for 30 days 
at controlled room temperature (59F to 86F) or in a refrigerator (36F to 46F).  The pen cap 


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should be kept on when not in use.  Saxenda should be protected from excessive heat and 
sunlight.  The needle should be always removed and safely discarded after each injection [42].
1.18.4 Preparation
No preparation by study staff and/or study participants is required.
1.19 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING
Not applicable as this is an open-label pilot study.
1.20 STUDY INTERVENTION COMPLIANCE
Administration of study intervention will be observed at Visit 1.   Subsequent administration of 
study intervention will be verified by inspecting drug supply at Visits 2-5. One-month supply of 
medication will be dispensed by the NIH pharmacy at Visits 1-4. At each visit, participants will 
be instructed to return all used and unused study medication. The study team will count/record 
the number of unused pens as a measure of medication adherence.
1.21 CONCOMITANT THERAPY
For this protocol, a prescription medication is defined as a medication that can be prescribed only 
by a properly authorized/licensed clinician. Medications to be reported in the Case Report Form 
(CRF) are concomitant prescription medications, over-the-counter medications, and 
supplements.
Participants will be allowed to continue home medications (prescription medications, over-the-
counter medications, and supplements) as long as they are not insulin, sulfonylurea, DPPIV-
inhibitor or weight loss medications such as phentermine, topiramate, lisdexamfetamine, orlistat, 
and naltrexone HCl/bupropion HCl.  All home medications and supplements will be recorded at 
screening and each study visit.    
Liraglutide slows gastric emptying and thereby has the potential to impact the absorption of 
concomitantly administered oral medications.  Thus, caution should be exercised when oral 
medications are concomitantly administered with liraglutide [42] and participants will be 
recommended to take their oral medications separate from liraglutide if possible.
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
1.22 DISCONTINUATION OF STUDY INTERVENTION
Discontinuation from liraglutide does not mean discontinuation from the study, and remaining 
study procedures should be completed as indicated by the study protocol.  If a clinically 
significant finding is identified after enrollment (including, but not limited to changes from 
baseline), the investigator or qualified designee will determine if any change in participant 
management is needed. Any new clinically relevant finding will be reported as an adverse event 
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The data to be collected at the time of study intervention discontinuation will include the 
following:
-History and physical
-Bloodwork per investigator discretion
-The specific underlying reason for discontinuation of study intervention or participant 
discontinuation/withdrawal
Participants are free to withdraw from participation in the study intervention at any time upon 
request. Study medication can be discontinued abruptly without untoward effects from 
medication withdrawal.
An investigator may discontinue or withdraw a participant from the study for the following 
reasons:

Completion of study intervention

If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant

Investigator discretion

Positive pregnancy test or intention of becoming pregnant

Participant unable to receive Liraglutide for 1 week or more

Initiation of obesity or diabetes medications or obesity treatments not permitted during 
the trial
1.23 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY
Prior to removal from study for adverse events, efforts will be made to have all subjects 
complete a safety visit approximately 14 days following the last dose of study therapy and to 
have them return at the scheduled time for Study Visit 5.
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following 
reasons:

Significant study intervention non-compliance 

If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation

Subject has completed the study follow-up period

Death

Screen Failure
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
Withdrawal Case Report Form (CRF). Subjects will be excluded if they have any verified 
abnormality in laboratory values or physical status that cannot be explained by a mild 
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CTCAE 5 grade 3 or greater [62]. Problem-specific stopping rules by CTCAE5 category will be 
prepared in conjunction with this protocol.
Subjects who sign the informed consent form and are scheduled to be treated but do not receive 
the study intervention may be replaced.  Subjects who sign the informed consent form and 
receive the study intervention, and subsequently withdraw, or are withdrawn or discontinued 
from the study will not be replaced.
Investigator error leading to initiation of treatment in an ineligible subject will lead to treatment 
discontinuation as soon as the error is uncovered. Should discontinuation be required for any 
reason, no tapering of liraglutide is necessary; subjects will be requested to return all unused 
medication.
1.24 LOST TO FOLLOW-UP
A participant will be considered lost to follow-up if he or she fails to return for three scheduled 
visits and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site will attempt to contact the participant and reschedule the missed visit within 1-4 
days and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file. 

Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow
STUDY ASSESSMENTS AND PROCEDURES
The specific timing of procedures/evaluations to be done at each study visit are captured in 
Section 1.4, Schedule of Activities (SOA).
1.25 SCREENING PROCEDURES
Potential participants will be mainly referred by providers at CNH who are coinvestigators for 
this study. Dr. Evan Nadler , our research collaborator, is a pediatric surgeon at CNH who 
performs 75-125 cases of laparoscopic sleeve gastrectomy each fiscal year, which should provide 
ample participants. In addition to providers from the CNH Bariatric Surgery Clinic and CNH 
Obesity Clinic, referrals will also be accepted from other community providers to whom we will 
provide information about our study (see recruitment strategies). Interested participants will be 
given our study information and will contact us via the study line or email. Participants will be 
phone screened to determine baseline eligibility and additional study information.  If participants 
are eligible, we will arrange a screening/enrollment visit at the NIH.
If potential participant is a patient at CNH, we will request permission to review medical records 
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Subjects who appear eligible when evaluated during a phone screening intended to assess general 
health and body weight/height (to determine BMI) will attend a screening visit at the NIH 
Clinical Center, during which their eligibility will be determined. History and physical 
examination will be conducted by a licensed practitioner.   Pregnancy testing will be reviewed 
before subjects proceed with protocol related testing and treatment.  
1.25.1 Screening activities performed prior to obtaining informed consent
Initial recruitment and eligibility screening will occur by telephone in response to a message 
from a participant interested in joining the study. Screening will occur on a continuous basis until 
recruitment is complete.  Eligible subjects will then be scheduled for an outpatient visit.  Eligible 
subjects will be mailed or emailed paperwork in advance, including the NIH medical history 
form, as well as the study consent form (s). 
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 

Email, written, in person or telephone communications with prospective subjects. Each 
subject will receive a written explanation of the purposes, procedures, and potential 
hazards of the study (refer to attached consent form).  The scripts used at telephone 
screening are submitted for IRB review. 

Review of existing medical records to include H&P, vital signs measurements, 
laboratory studies, etc.
1.25.2 Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the subject has signed the consent for this 
study. Assessments performed at outside facilities or on another NIH protocol within the 
timeframes below may also be used to determine eligibility once a participant has signed the 
consent.
All screening tests and procedures must be performed within 28 days prior to enrollment.
1.
Protocol review and signing of consent/assent forms.   
2.
Complete medical history and physical exam with weight (in kg) measured while the 
subject wears light clothes, height (in cm) measured in triplicate, and body temperature, 
heart and respiratory rate, and a blood pressure measurement.  Subjects will rest for 5 
minutes in the seated position with the cubital fossa supported at heart level when blood 
pressure measurements are made.  A detailed history will be taken. If a potential subject is 
noted to meet any of the exclusion criteria, that individual will be dismissed without further 
evaluation and referred for any required treatment to their usual physician. 
3.
Fasting blood for complete blood count, HbA1C, electrolytes, glucose, renal, mineral, lipid 
and hepatic profiles, ESR, CRP, 25-OH vitamin D level, urine or serum beta HCG (female 
participants only), and PT/PTT.
Subjects will be counseled that once results of the screening visit are known, they will be 
contacted with information on their eligibility to participate in the full study. 


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Information regarding the key assays used for eligibility criteria and other metabolic syndrome 
components (all measured by the NIH Clinical Center Laboratory Medicine Department):
a.
Glucose: 
 @75mg/dL   
: intraassay CV 2%             interassay CV 3%
 @ 379 mg/dL 
: intraassay CV 1%             interassay CV 2%
Sensitivity: 1 mg/dL
b. Insulin:
@ 24.2 µU/mL   : intraassay CV 1.2%
interassay CV 6.0%
@ 82 µU/mL 
: intraassay CV 1.0%
interassay CV 2.5%
Sensitivity: 0.2uU/mL
c. Triglycerides:
@ 68 mg/dL    
: intraassay CV 3%           
interassay CV 4%
@384 mg/dL   
: intraassay CV 2%           
interassay CV 2%
Sensitivity: 2 mg/dL
d. HDL cholesterol:
@ 26 mg/dL   
: intraassay CV 2.3%           interassay CV 2.7%  
@ 47 mg/dL   
: intraassay CV 1.6%           interassay CV 2.3%  
@ 67 mg /dL  
: intraassay CV 1.9%          
interassay CV 2.1%
Sensitivity: 3 mg/dL
e. Hemoglobin A1c:
@ 5.1%
: intraassay CV 0.4%
interassay 1.11%
@9.9%
: intraassay CV 0.5%
interassay 0.73%
Sensitivity: 4.2%
1.26 EFFICACY ASSESSMENTS
1.26.1 Clinical Evaluations
Physical examination: Participant’s height (on a calibrated stadiometer), weight (on a calibrated 
scale), waist circumference (using a non-stretching tape measure), and vital signs (temperature, 
pulse, respirations, blood pressure) will be measured. A complete physical examination 
(including review of peripheral lymph nodes, head, eyes, ears, nose, mouth and oropharynx, 
neck, heart, lungs, abdomen, musculoskeletal, extremities, neurologic, skin, and Tanner staging) 
will be performed at Visit 1 and 6.  At other visits, a symptom-directed history and physical 
examination will be done. At all visits, participant’s height (in cm), weight (in kg), and vital 


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signs will be measured.  Body mass index (BMI, kg/m2) will be calculated and used to determine 
BMI-SDS according to the Centers for Disease Control standards for age and sex [3]).  Subjects 
will rest for 5 minutes in the seated position with the antecubital fossa supported at heart level 
when blood pressure measurements are made.
Imaging assessment: The participant will undergo a DXA scan at Visit 1 and 5.  The participant 
will lie on a flat table with the x-ray source below the table and the detector above.  Participants 
will undergo DXA scans in the Metabolic Clinical Research Unit (MCRU) using the Lunar 
iDXA (GE Healthcare, Madison, WI, USA) machine. The scan takes approximately 5-10 
minutes. An external standard, simulating bone, fat, and muscle, is scanned once a week to 
validate measurements. This standard allows calculation of total body fat, muscle, and bone 
mass, and percentage of body fat. For the iDXA scan used in this study, the total effective dose 
of radiation from the two scans performed is 0.00006 rem, which is below the guideline of 5 rem 
(for adults) and 0.5 rem (for children) per year allowed for research subjects by the NIH 
Radiation Safety Committee.
Energy intake at buffet meal: Participants will be introduced to a buffet test meal (>10,000 
kcal), varied in macronutrients (54% carbohydrate, 12% protein, 33% fat) and comprised of 
foods that most children like [63] (Appendix 12). Should any participant adhere to a specific 
dietary regimen for religious, ethical reasons or other reasons, if possible, the foods on the buffet 
may be substituted to meet such requirements. The participant will receive a tape-recorded 
instruction to “Let yourself go and eat as much as you want.” Duration of eating is measured 
from the time the experimenter leaves the room until the participant indicates eating is 
completed. All foods are weighed on electronic balance scales in gram weights to the nearest 
gram; foods consumed are determined by subtracting the food weights after the participant’s 
meal from initial weights. Food energy and macronutrient content are calculated using the USDA 
National Nutrient Database for Standard Reference. The energy and macronutrient content of the 
consumed meal is calculated by the ProNutra (Viocare Technologies) program. Nutrition staff 
preparing and measuring food for the buffet have yearly HACCP food safety training that 
focuses upon safe food handling, proper temperatures, hand washing, and using gloves for 
handling foods. All nutritionists also have had training in weighing/processing foods for 
controlled feeding studies to ensure consistency in the method and presentation. Participants will 
complete a brief series of visual analog scales and rating forms to assess appetitive states (e.g., 
hunger, satiety, fullness, nausea, drowsiness, calmness, desire to eat) prior to and after the test 
meal, [64-67]. Participants will also complete the following state mood questionnaires 
immediately before and after the test meal (unless otherwise noted) (Appendix 11):
1. Brunel Mood Scale (BRUMS) [68] is reliable and well-validated [68, 69]. The 
respondent rates his/her mood “right now” on a 5-point Likert scale based on 24 mood 
descriptors.
2. Positive and Negative Affect Schedule, Expanded Version (PANAS-X): The PANAS-X 
captures both negative and positive mood states; for the current study, we will only assess 
guilt using the six-item subscale PANAS-X [70].
3. State-Trait Anxiety Inventory (STAIC) – State Form [71] will be used to measure pre-post 
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4. LOC Severity will only be assessed immediately following the test meal. Comparable to 
the EMA protocol described above, items adapted from the EDE will assess the degree to 
which LOC was experienced during the test meal.
Attention bias to highly palatable images: The Palatable Food Cue Attention Bias Task 
(PFCBT) will examine neural responses during a palatable food cue visual-probe paradigm with 
high and low palatability foods and neutral non-food household items. The same images and task 
protocol were used in our pilot study of food cue attention biases [72]. Similar palatable food 
images have been used effectively in neuroimaging studies of adults with binge eating disorder 
[73, 74] and non-treatment adolescents [75]. Visual-probe paradigms assess attention biases by 
presenting stimulus pairs followed by a probe that requires a response. Each trial will consist of a 
fixation probe in the center of the screen followed by an image pair presentation. Pairs of each 
picture combination (e.g., high palatability food-neutral, low palatability food-neutral, high-low 
palatability food, neutral-neutral) will be presented in randomized order. After the image pair 
disappears, a probe appears in one of the previously occupied photo locations. Youth respond 
with a right or left sided keypress to indicate the orientation of the probe. Youth will be 
instructed to respond as quickly and accurately as possible to the probe. Trials consist of a 
mixture of incongruent trials (when the probe replaces the neutral non-food household items), 
congruent trials (when the probe replaces the food images), and neutral trials (when two identical 
neutral non-food household items appear and the probe location is insignificant). The spatial 
location of images and probes are counter balanced.
Free living physical activity and sleep by accelerometry: Participants will be asked to wear an 
accelerometer on their body that measures free-living physical activity.  The participant will be 
instructed to wear the accelerometer during all hours, except when bathing or showering for 2 
weeks and to return the accelerometer in person or via mail after completion.  We will use the 
ActiGraph GT3X+ activity monitor (ActiGraph, Pensacola, FL), which is worn like a wristwatch 
and delivers 24-hour physical activity and sleep/wake measurements. We have used this device 
successfully in other protocols with adolescents (15-CH-0096) [76, 77]. Outcomes include raw 
acceleration, activity counts, energy expenditure, physical activity intensity, body position, and 
sleep duration. A triaxial accelerometer and integrated ambient light sensor assist with enhancing 
the validity of data collected regarding sleep/wake times. The GT3X+ can store over 40 days of 
raw data, and its rechargeable battery is capable of providing power for 30 days between 
charges. Data will be downloaded and reduced using Actilife software (ActiGraph). In young 
adults, the GT3X+ is a valid and reliable device for detecting sleep/wake diurnal patterns, and 
has demonstrated good concordance with polysomnography [78]. The GT3X+ wrist actigraphy 
has also been used to assess sleep behavior in adolescents [79, 80].
Patient questionnaires: 
Quality of life assessments-
Impact of Weight on Quality of Life-Lite (IWQOL-Lite)[81]
The IWQOL-Lite is a validated 31 item self-report measure of obesity-specific quality of life 
questionnaire.  The IWQOL-Lite provides a total score inclusive of 5 domains: physical 
function, self-esteem, sex life, public distress, and work.  The questionnaire is responsive to 
weight loss and gain, sensitive to treatment seeking status as well as to the degree of obesity.  
The IWQOL-Lite will be conducted in participants ≥18 years of age according to the SOA. 


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The Impact of Weight on Quality of Life (IWQOL)-Kids version for adolescents [82] will be 
used in all patients in this study.
SF-10 Health Questionnaire for Children
The SF-10 Health Survey for Children is a parent-completed survey that contains 10 questions 
adapted from the Child Health Questionnaire.  The SF-10 provide coverage across a wide range 
of domains and is scored to produce physical and psychosocial health summary measures.  The 
SF-10 will be conducted in participants <18 years of age according to the SOA.
Mental Health Assessments-
Beck Depression Inventory (BDI-II)- 
The Beck Depression Inventory (BDI) is a 21-item, self-report rating inventory that measures 
characteristic attitudes and symptoms of depression [83].  BDI-II was revised in 1996 to be more 
consistent with DSMIV criteria for depression in adolescents and adults (age 13-80) [84]. 
Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is a tool used not only to predict suicide attempts but to assess the full range of 
evidence-based ideation and behavior items, with criteria for next steps (e.g., referral to a mental 
health professional [MPH]).  There are 2 versions of the C-SSRS that will be administered 
according to the SOA:
1) The Baseline/Screening version of the scale combines the Baseline and Screening forms 
to assess suicidality in a patient’s lifetime and during a predefined time. This version can 
assess a patient’s lifetime suicidality for data collection purposes as well as eligibility 
based on inclusion/exclusion criteria.
2) The Since Last Visit version of the scale assesses suicidality since the patient’s last visit. 
This version is meant to assess participants who have completed at least one initial C-
SSRS assessment and will be used in every subsequent visit. The ‘Since Last Visit’ 
version of the C-SSRS is asking about any suicidal thoughts or behaviors the 
patient/participant may have had since the last time the C-SSRS was administered.
To be eligible for the study, a patient cannot have a suicidal ideation of type 4 or 5, any lifetime 
history of a suicide attempt, or any suicidal behavior in the last month.
Hollingshead Two Factor Index of Socioeconomic Status [85] will be obtained for the 
parents/guardians of the participant.
Body-Esteem Scale for Adolescents and Adults
The Body-Esteem Scale for Adolescents and Adults is a 23-item measure with subscales of 
general feelings regarding own’s own appearance, one’s perception of others’ evaluation about 
one’s body and appearance, and weight satisfaction [86].  Reponses regarding agreement with 
item statements are provided on a 5-point Likert scale ranging from never (1) to always (5) with 
higher scores indicating more positive body-esteem.  
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Nutritional counseling and monitoring will be performed by nutrition department staff. Nutrition 
department staff will review food log with participants.  
Order of Assessments
When scheduled at the same time point, the order of procedures should be as follows: obtain 
vital signs, perform history and physical examination, perform blood testing (at the specified 
time point, if applicable), perform DXA scan, perform computerized visual probe task of 
sustained attention, have participant answer questionnaires, and eat buffet meal (measure 
appetite score before and after).  Adjustments may be made depending upon specific 
circumstance. 
1.26.2 Biospecimen Evaluations
Blood Sample Collection: As indicated below, the amount of blood that will be obtained from 
adult participants (i.e., those persons 18 years of age or older) for research purposes will not 
exceed 10.5 mL/kg or 550 mL, whichever is smaller, over any eight-week period. For pediatric 
patients, no more than 5 mL/kg will be drawn for research purposes in a single day, and no more 
than 9.5 mL/kg will be drawn over any eight-week period. Approximately 11 mL will be 
collected at screening (CBC, acute care, mineral, hepatic, Vitamin D, CRP, ESR, A1c).  
Oral glucose tolerance test (OGTT):  Participants will undergo a 75 gram oral glucose 
tolerance test with blood samples collection at 0, 15, 30, 60, 90 and 120 minutes for hormones 
and metabolites (including glucose, insulin, glucagon-like-1 peptide, and peptide YY).  It is 
certain that all participants will exceed 43 kg, and thus all will receive the adult dose (75 g) 
rather than require any calculation to determine dose. The homeostatic model assessment of 
insulin resistance (HOMA-IR) will be calculated from fasting (f) insulin (I) and glucose (G): Gf 
(in mg/dL) x If in (µIU/mL/ 405). The Matsuda index (104/([Gf x 18] x If x [mean GOGTTx18] x 
mean IOGTT)0.5) will be calculated from the OGTT values. The diagnosis of impaired fasting 
glucose, impaired glucose tolerance, and diabetes will be made according to standard criteria.
Laboratory evaluations:  The following tests will be drawn in fasting state: plasma glucose, 
lipids, glycosylated hemoglobin A1c.  The lipid profile will include total cholesterol, high 
density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides. Samples to 
save for future research will also be obtained (~20 mL).
1.26.3 Correlative Studies for Research/Pharmacokinetic Studies
Blood samples will be collected for secretome analysis by SomaScan [87] (10 mL at baseline 
and follow-up) and for future research (20 mL). For SomaScan, obtained serum will be 
immediately stored at –80oC until further analysis without being exposed to freeze-thaw cycles.  
Serum proteomic analysis will use the SOMAscan 1.3k Assay (SomaLogic, Boulder, CO).  This 
aptamer-based assay can detect 1305 protein analytes in human serum.[88]  The proteins 
quantified include cytokines, hormones, growth factors, receptors, kinases, proteases, protease 
inhibitors, and structural proteins.  A complete list of analytes measured can be found at 
http://somalogic.com/wp-content/uploads/2017/06/SSM-045-Rev-2-SOMAscan-Assay-1.3k-
Content.pdf.  Concentrations are measured as Relative Fluorescence Units.  The assay will be 
performed according to manufacturer specifications, with data inspection using a web tool, as 
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1.26.4 Samples for Genetic/Genomic Analysis
1.26.4.1 Description of the scope of genetic/genomic analysis

None.
1.26.4.2 Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized

Not Applicable
1.26.4.3 Management of Results

Not Applicable
1.26.4.4 Genetic counseling

Not Applicable
1.27
 SAFETY AND OTHER ASSESSMENTS
Adverse events will be monitored via telephone and at all clinic visits using structured case 
report forms.  If any participant develops any concerning adverse events reported by telephone, 
the individual will be scheduled for an immediate clinic appointment with a trial investigator for 
further work up, as necessary.  Adverse events will also be assessed during the trial via vital 
signs (blood pressure, heart rate, temperature, respiratory rate), interim history, and the 
symptom-directed physical examination, as well as by laboratory studies of electrolytes, hepatic, 
metabolic, and systemic function. There are no EKGs or radiographic assessments for safety.
Physical examination: 
Participant’s height and weight will be measured; a targeted physical examination (including 
cardiac, respiratory, gastrointestinal, and neurological assessment) will be performed as part of 
safety assessment.  
Vital signs:  
Temperature, pulse, respirations, and blood pressure will be measured as part of safety 
assessment.
Questionnaires:
Beck depression survey, C-SSR, and Body Esteem Survey will be scored by research team 
members. The Beck depression survey and C-SSR will be scored on the same day the participant 
completes the questionnaires.  All scores that raise concerns of current suicidality or current 
major depression will be reported on same day of completion/scoring to Dr. Zenno, NP Sheila 
Brady, or Dr. Yanovski who will determine need for follow-up.  
Hollingshead Two Factor Index of Socioeconomic Status [85] will be obtained from the 
participant or parents/guardians of the participant only at baseline.
Injection Site Evaluation and Scoring
Injection sites will be carefully inspected, evaluated, and scored during the study period. The 
injection site evaluation will include identification and measurement of areas of erythema, 


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edema, and induration, as well as the presence of localized pain, tenderness, and itching.  A 
sample injection site evaluation form is included in the Appendix.
In addition, unscheduled evaluations may also be recorded as warranted by clinical conditions, 
including in the interval between scheduled visits.  
Biological specimen collection and laboratory evaluations:  
Safety laboratory tests will include: CBC with platelet count and standard indices, chemistry 
panel (includes sodium, potassium, chloride, CO2, albumin, total protein, glucose, BUN, 
creatinine, uric acid, AST, ALT, GGT, CPK, alkaline phosphatase, total bilirubin, direct 
bilirubin, LDH, calcium, phosphorus).
a.
Screening Visit
All Participants
i. Acute care, mineral, hepatic, 25-OH vitamin D, CRP
3.5 mL
ii. CBC, HbA1c
3.3 x 2 = 6.6 mL
iii. ESR 
1.1 mL
iv. PT/PTT
1 mL
Total
12.2 mL
b. Visit 1
All Participants
i. Acute care, mineral, hepatic, lipid panel,
3.5 mL
25-OH vitamin D, Insulin level, CRP
ii. CBC, HbA1c
3.3 x 2 = 6.6 mL
iii. ESR 
1.1 mL
iv. 2-hour OGTT
6 mL
v. Plasma GI hormones (GLP-1 and PYY)
3 mL
vi. Research Plasma and serum 
16 ml
Total
36.2 mL
c.
Visit 5 (16 weeks)
All participants
i. Acute care, mineral, hepatic, lipid panel,
3.5 mL
25-OH vitamin D, Insulin level, CRP


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ii. CBC, HbA1c
3.3 x 2 = 6.6 mL
iii. ESR 
1.1 mL
iv. 2-hour OGTT
8 mL
v. Plasma GI hormones (GLP-1 and PYY)
3 mL
vi. Research Plasma and serum 
16 ml
Total
38.2 mL
Results of clinical laboratory testing will be provided to participants on request.
1.28 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
 
1.28.1 Definition of Adverse Event
Adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)).
1.28.2 Definition of Serious Adverse Events (SAE)
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse.
1.28.3 Classification of an Adverse Event
1.28.3.1 Severity of Event
All AEs will be assessed by the study clinician using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) 5.0 as the protocol defined grading system.  
For adverse events (AEs) not included in the protocol defined grading system, the following 
guidelines will be used to describe severity. 
•
Mild – asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. Such events do not interfere with the participant’s daily 
activities. 


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•
Moderate – local or non-invasive intervention indicated; limiting age-appropriate ADL 
Such events result in a low level of inconvenience or concern with the therapeutic 
measures.
•
Severe – medically significant but not immediately life-threatening; hospitalization or 
prolonged hospitalization indicated; disabling; limiting self care ADL  Events that 
interrupt a participant’s usual daily activity may require systemic drug therapy or other 
treatment. Severe events are usually potentially life-threatening or incapacitating.  Of 
note, the term “severe” does not necessarily equate to “serious”.
•
1.28.3.2 Relationship to Study Intervention
All adverse events (AEs) must have their relationship to study intervention assessed by the 
investigator who examines and evaluates the participant based on temporal relationship and 
his/her clinical judgment. The degree of certainty about causality will be graded using the 
categories below. In a clinical trial, the study product must always be suspect. 
•
Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study intervention 
administration and cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the study intervention (dechallenge) should be 
clinically plausible. The event must be pharmacologically or phenomenologically 
definitive, with use of a satisfactory rechallenge procedure if necessary.
•
Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs within a reasonable time after administration of the study intervention, is 
unlikely to be attributed to concurrent disease or other drugs or chemicals, and follows a 
clinically reasonable response on withdrawal (dechallenge). Rechallenge information is 
not required to fulfill this definition.
•
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly related” 
soon after discovery, it can be flagged as requiring more information and later be 
upgraded to “probably related” or “definitely related”, as appropriate.
•
Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
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•
Not Related – The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There must 
be an alternative, definitive etiology documented by the clinician.]
1.28.3.3 Expectedness 
Expected adverse reactions are AEs that are known to occur for the study intervention being 
studied and should be collected in a standard, systematic format using a grading scale based on 
functional assessment or magnitude of reaction. The source of the reference safety information 
used to determine the expectedness of the AE will be the package insert (approved labeling) for 
liraglutide approved for adults. Expectedness is assessed based on the awareness of AEs 
previously observed, not on the basis of what might be anticipated from the properties of the 
study intervention. 
The principal investigator will be responsible for determining whether an adverse event (AE) is 
expected or unexpected.  An AE will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the risk information previously described for the 
study intervention.  These determinations will also be reviewed by the study Safety Officer.
Liraglutide administration has known adverse consequences, delineated in the SAXENDA 
package insert [61]. If the rate or severity of these such consequences exceeds the rate or severity 
anticipated in the FDA-approved package insert, the events will be classified and reported as 
Unanticipated Problems, but otherwise will be considered expected events that will be described 
and reported to the IRB and DSMB at each Continuing Review.
We also anticipate that other mild symptoms may occur in the course of participation in the 
protocol unrelated to study drug or participation, with mild signs/symptoms (CTCAE Grade ≤ 2), 
such as rhinorrhea, nasal congestion, watery eyes, cough, lightheadedness, mild wheezing, 
menstrual cramps, muscle weakness, fever blister, mild urinary tract infection, etc., that occur 
infrequently (≤ 20%). These will also be summarized and reported to the IRB and DSMB at the 
time of Continuing Reviews.
1.28.4 Time Period and Frequency for Event Assessment and Follow-Up
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a study participant presenting 
for medical care, or upon review by a study monitor.
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate case report form (CRF). Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution.
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE. 


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Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode.
The principal investigator or associate investigators will record all reportable events with start 
dates occurring any time after informed consent is obtained until 7 (for non-serious AEs) or 30 
days (for SAEs) after the last day of study participation.  At each study visit, the investigator will 
inquire about the occurrence of AE/SAEs since the last visit.  Events will be followed for 
outcome information until resolution or stabilization.
1.28.5 Adverse Event Reporting 
Events occurring during this study will be reported to the NIH IRB per policy 801.
The Safety Officer monitoring this trial and the NICHD Clinical Director will also be sent 
reports of all Reportable Events following the same timelines as required for IRB reporting.
We anticipate that mild symptoms may occur in the course of participation in the protocol 
unrelated to study drug or participation, with mild signs/symptoms (CTCAE Grade ≤ 2), such as 
rhinorrhea, nasal congestion, watery eyes, cough, lightheadedness, mild wheezing, menstrual 
cramps, muscle weakness, fever blister, mild urinary tract infection, etc., that occur infrequently 
(≤ 20%). These will be summarized and reported at Continuing Review.
1.28.6 Serious Adverse Event Reporting 
Events occurring during this study will be reported to the NIH IRB per policy 801.
Each patient must be carefully monitored for the development of any AEs.  This information 
should be obtained in the form of non-leading questions (e.g., “How are you feeling?”) and from 
signs and symptoms detected during each examination, observations of study personnel, and 
spontaneous reports from participants.
All AEs (serious and non-serious) spontaneously reported by the patient and/or in response to an 
open question from study personnel or revealed by observation, physical examination or other 
diagnostic procedures will be recorded on the appropriate CRF.  Any clinically relevant 
deterioration in laboratory assessments or other clinical findings is considered an AE and must 
be recorded on the appropriate CRF.  When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event.
The study Principal Investigator will report to the NICHD Clinical Director any serious adverse 
event, whether or not considered study intervention related, including those listed in the protocol 
or investigator brochure and must include an assessment of whether there is a reasonable 
possibility that the study intervention caused the event within 24 hours from the point in time 
when the Investigator becomes aware of the SAE. Study endpoints that are serious adverse 
events (e.g., all-cause mortality) must be reported in accordance with the protocol unless there is 
evidence suggesting a causal relationship between the study intervention and the event (e.g., 
death from anaphylaxis). 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting 
documentation of the event may be requested by the NICHD Clinical Director and should be 
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The study Principal Investigator will be responsible for notifying the Food and Drug 
Administration (FDA) of any unexpected fatal or life-threatening suspected adverse reaction as 
soon as possible, but in no case later than 7 calendar days after the PI's initial receipt of the 
information.  In addition, the PI must notify FDA and all participating investigators in a safety 
report of potential serious risks, from clinical trials or any other source, as soon as possible, but 
in no case later than 15 calendar days after the PI determines that the information qualifies for 
reporting.
All serious adverse events will be reported by the PI verbally and in writing as soon as possible 
to the NICHD Clinical Director. All adverse events (serious and non-serious, expected and 
unexpected) will be reported annually to the IRB and NICHD Clinical Director for review. 
Electronic data sheets or summary language will be supplied for IRB review of adverse event 
reports at continuing reviews.
The PI (Jack A. Yanovski, MD, PhD) will report adverse events in iRIS, to the IRB and to the 
NICHD Clinical Director in writing.
1.28.7 Events of Special Interest 
None expected.
1.28.8 Reporting of Pregnancy 
The effects of liraglutide on the unborn child and on the newborn baby are not known.  Thus, it is 
important that participants do not become pregnant during the course of the study.  Females with 
child-bearing potential will be required to undergo a pregnancy test prior to starting the study. 
Pregnancy testing will be monitored during the study. Males will also be instructed not to father 
a child for at least 6 months after completion of the study.  Those who are sexually active and not 
surgically sterile must use effective contraception.  If a female participant were to become 
pregnant during the study, she would be instructed to discontinue the study intervention and 
would end study-related visits. We would however contact the participant to ascertain the 
outcome of the pregnancy.  If a male participant were to father a child during the study, the 
mother of his child would be recommended to have close clinical obstetric follow-up.  
1.29 UNANTICIPATED PROBLEMS
1.29.1 Definition of Unanticipated Problems (UP)
Any incident, experience, or outcome that meets all of the following criteria:
•
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; and
•
Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and
•
Suggests that the research places participants or others (which many include research 
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greater risk of harm (including physical, psychological, economic, or social harm) than 
was previously known or expected.
1.29.2  Unanticipated Problem Reporting 
The investigator will report unanticipated problems (UPs) to the NIH Institutional Review Board 
(IRB) as per Policy 801.
1.29.3 NIH Intramural IRB Reporting of IND Safety Reports
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NIH Intramural IRB.
STATISTICAL CONSIDERATIONS
1.30 STATISTICAL HYPOTHESIS

Primary Endpoint: 
The Primary Endpoint is estimation of required sample size for a later RCT through 
calculation of effect size for change in body mass index (BMI) from baseline to 16 weeks 
of liraglutide. The hypothesis is: The data will be sufficient to calculate the effect size for 
change in BMI from baseline to 16 weeks for a 2-group experiment (placebo versus 
liraglutide).

Secondary Endpoint(s):
There are 3 sets of key secondary endpoints:
A. Changes in BMI and fat mass after 16 weeks of liraglutide.  
B. Comparison of changes in BMI and fat mass after 16 weeks liraglutide in participants 
who had a poor initial response to SG (<20% BMI reduction at BMI nadir) vs. those 
with a typical post-SG weight loss (≥20% BMI reduction at BMI nadir)
C. Tolerability and safety of 3.0 mg Liraglutide
Statistical hypothesis A: there will be a statistically significant decrease in BMI and fat 
mass after 16 weeks of liraglutide.
Statistical hypothesis B: there will be a statistically significant greater decrease in BMI 
and fat mass after 16 weeks of liraglutide in participants in who had a typical post-SG 
weight loss vs. those who had a poor initial response to SG.
1.31 SAMPLE SIZE DETERMINATION
As this is a pilot investigation to determine the sample size of a fully powered investigation, no 
formal sample size determination is necessary. That said, the study is powered such that it might 
be able to detect a moderate-to-large difference from treatment. A recent randomized, double-
blind, placebo-controlled phase 3 trial of liraglutide for adolescents (age 12 to <18 years) with 
obesity (BMI ≥30 kg/m2 and ≥95th percentile for age and sex) [32] reported a -1.39 kg/m2 
(SE=0.31, n=125) difference over 1 year of liraglutide treatment. If that effect size is replicated 
and if a similar SD (3.46) is found in the present study, we estimate that a total sample size of 40 
subjects will have 80% power (β) to detect a -1.39 kg/m2 difference in BMI (effect size = -


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0.4017) at level of significance of 0.05 (1-sided, as we are interested only in BMI loss). See 
Table 2.
Table 2, drawn using data obtained using G-Power 3.1.9.2 [90, 91]
We anticipate that virtually all participants who sign consent and are screened will qualify and 
agree to enroll.  We will therefore attempt to recruit and screen in person no more than 50 
adolescents, among whom no more than 43 will be treated with liraglutide in hopes of having 
40 who complete the study. Based on prior studies in adolescents using liraglutide, we 
anticipate few dropouts or withdrawals by week 16. In Kelly et al’s study of adolescents [32], 
119/125 (95%) of those treated with liraglutide remained on-treatment at week 16.
As a pilot investigation, there is no assumption that there will be adequate power for any of the 
secondary outcomes investigated. We will, however, be able to use the data to determine power 
in a future randomized controlled trial for these outcomes.
1.32 POPULATIONS FOR ANALYSES
The following analysis populations will be evaluated and used for presentation and analysis of 
the data:

Screening Analysis Dataset: All participants who have a signed informed consent form.

Intention-to-Treat (ITT) Analysis Dataset: all treated participants. The ITT Population 
will consist of all adolescent subjects who were assigned to treatment regardless of 
whether the subject received treatment or not.  A subject is considered assigned to 
treatment when the Investigator or Investigator’s designee assigns a medication study 
number. For all analyses in the ITT Population, participants will be analyzed as treated, 
whether or not treatment was received.

Safety Analysis Dataset: the subset of participants for whom safety analyses will be 
conducted: Participants who took at least one dose of study medication will be considered 
part of the Safety Analysis Dataset.
0.6
0.7
0.8
0.9
25
30
35
40
45
50
55
60
65
70
t-test - Means: Difference between two dependent means
(matched pairs) Tails = 1,  = 0.05, Effect size dz = 0.4
Power (1- err prob)
Total Sample Size


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
Per Protocol Dataset: Those who complied with the protocol sufficiently to ensure that 
these data would be likely to represent the effects of treatment according to the 
underlying scientific model (i.e., participants who took at least 80% of study intervention 
for 80% of the days within the treatment period).
1.32.1 Evaluable for toxicity 
All participants will be evaluable for toxicity from the time of their first treatment with 
liraglutide. 
1.32.2 Evaluable for objective response 
Not applicable
1.32.3 Evaluable Non-Target Disease Response
Not applicable
1.33 STATISTICAL ANALYSES
1.33.1 General Approach
Tabulations will be produced for appropriate demographic, baseline, efficacy, and safety 
parameters. For categorical variables, summary tabulations of the number and percentage of 
subjects within each category of the parameter will be presented. For continuous variables, the 
number of subjects (N), mean, median, standard deviation (SD), minimum, and maximum 
values will be presented.
Formal statistical hypothesis testing will be performed on endpoints with testing conducted at 
the 1-sided, 5% level of significance. Summary statistics will be presented, as well as 
confidence intervals (Cis), as described in the sections below. Trial success will be based on a 
p-value <0.05.
Covariates to be modeled are pre-specified in the sections below. Results of statistical 
procedures for efficacy outcomes involving covariates will be presented as adjusted means 
(least-squares means) with standard errors.
Checks of assumptions (e.g., normality) underlying statistical procedures will be performed and 
corrective procedures will be applied. It is expected that log transformation will be used for the 
primary outcome and most secondary outcomes. Percentage data will be arcsin (square root 
(value)) transformed for analysis.
Unless otherwise noted, all statistical analyses will be performed using SPSS statistical software 
Version 25 (IBM Corp, Armonk, NY) or higher.
Subject disposition will be tabulated and include the number screened, the number randomized, 
the number treated in total, the number dosed with liraglutide, the number in each subject 
population for analysis, and the number who withdrew prior to completing the study and 
reason(s) for withdrawal.
A by-subject data listing of study completion information including the reason for premature 
study withdrawal, if applicable, will be made available. Subject disposition will include patients 
in the Screening Analysis Dataset.


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1.33.2 Analysis of the Primary Endpoint
The Primary Endpoint is estimation of required sample size for a later RCT through calculation 
of effect size for change in body mass index (BMI) from baseline to 16 weeks of liraglutide. The 
statistical hypothesis is: The data will be sufficient to calculate the effect size for change in BMI 
from baseline to 16 weeks for a 2-group experiment (placebo versus liraglutide). The primary 
outcome could be stated as the percentage of participants who are in the Per Protocol Dataset 
(who complied with the protocol sufficiently to ensure that these data would be likely to 
represent the effects of treatment according to the underlying scientific model (i.e., participants 
who took at least 80% of study intervention for 80% of the days within the treatment period). 
The study will be considered successful if more than 80% complete the trial.
The key variable that will be calculated is the effect size of the investigation. This value will be 
determined using the observed mean change in BMI from baseline to 16 weeks and the standard 
deviation for mean change observed with liraglutide treatment. The effect size (in this case, the 
Standardized Mean Difference (SMD) between two groups) will be calculated using Gpower 
3.1.9.2 [90, 91] assuming the same standard deviation for both liraglutide-treated and control 
groups, a similar sample size for each group, and the observed difference in BMI from baseline 
to 16 weeks as the outcome of interest. Cohen’s d – M1-M2)/SDpooled. A plot will be created 
showing a range of sample sizes required for a between-groups t-test. For example, if we use the 
data from a recent randomized, double-blind, placebo-controlled phase 3 trial of liraglutide for 
adolescents who had not previously undergone bariatric surgery but had obesity [32], the 
liraglutide reduced BMI by -1.39 kg/m2 (SE=0.31, n=125 over 1 year of treatment and the 
placebo group increased BMI by 0.19 kg/m2 (SE=0.33, n=126) over the sample interval. If we 
found a similar reduction in BMI in adolescents who have obesity after bariatric surgery, the 
estimated effect size d=0.4566 (a difference of 1.58 kg/m2 between groups with SD 3.46), a total 
sample size of 120 (60 per group) would be needed for one-sided α=0.05 and power of 0.80 
(Table 1).
Table 1, drawn using data obtained using G-Power 3.1.9.2 [90, 91]
0.6
0.7
0.8
0.9
80
100
120
140
160
180
200
220
t-test - Means: Difference between 2 independent means
(2 groups); Tails = 1, Allocation Ratio N2/N1=1,
 = 0.05, Effect size d = 0.46
Power (1- err prob)
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1.33.3 Analysis of the Secondary Endpoint(s)
There are 2 sets of key secondary endpoints. These analyses are not dependent on findings of the 
primary endpoint. They will be calculated as changes from baseline to 16-week visit in the ITT 
dataset:
1. Changes in BMI and fat mass after 16 weeks of liraglutide.  
2. Comparison of changes in BMI and fat mass after 16 weeks of liraglutide in participants 
who had a poor initial response to SG (<20% BMI reduction at BMI nadir) vs. those with a 
typical post-SG weight loss (≥20% BMI reduction at BMI nadir)
For these analyses, last observation carried forward (LOCF) imputation will be used for missing 
data. The sample is too small to use any other statistical imputation method accurately. A 
sensitivity analysis using baseline observation carried forward (BOCF) will also be conducted.
Changes in BMI and fat mass after 16 weeks of liraglutide will be evaluated using paired t-tests 
of baseline versus 16-week values. Data will be transformed as necessary to meet statistical 
assumptions of normality. 
Comparisons between those who had a poor versus typical post-SG weight loss will be 
conducted with ANCOVAs with change (16-week minus baseline value) as the dependent factor; 
group (poor vs. typical weight loss) as the independent factor; and sex, race, age, and height 
tested as potential covariates.
Tertiary endpoints will be evaluated using similar approaches. For the secretome analysis, paired 
statistical tests will be applied to each analyte (using parametric or nonparametric statistical 
approaches as required by the data) to find significant changes in secretome components. The 
Benjamini-Hochberg procedure will be used to determine the false discovery rate for multiple 
comparisons.
1.33.4 Safety Analyses
Safety endpoints will be analyzed as summary statistics during treatment in the Safety dataset. 
For each safety parameter, the last assessment made prior to the first dose of study drug will be 
used as the baseline for all analyses. AEs will be analyzed based on the drug received.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). A treatment-emergent AE (TEAE) is defined as an AE that starts or worsens at or 
during the time of or after the first study drug administration through the final visit. Each TEAE 
will be counted once only for a given participant. Severity, frequency, and relationship of AEs to 
study intervention will be presented by System Organ Class (SOC). For SAEs, information will 
be reported about start date, stop date, severity, relationship, expectedness, outcome, and 
duration. Adverse events leading to premature discontinuation from the study intervention and 
TEAEs will be presented in a table or a listing.
Clinical Laboratory Evaluations: All numeric laboratory data including chemistry (such as 
acute care panel and hematology tests will be summarized at each visit as well as changes from 
baseline using summary statistics. Laboratory values will be categorized as normal, high, and 
low, based on normal ranges. Shift from baseline will be summarized at each post-baseline visit.


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Vital Signs: Descriptive statistics for resting heart rate, diastolic blood pressure, systolic blood 
pressure, temperature, and the change from baseline to each post-baseline visit.  The change 
from baseline to the minimum and maximum post-baseline values will also be summarized by 
treatment group. Shift tables may also be presented. Clinically significant vital signs will be 
identified in the eCRF and will be listed.
1.33.5 Baseline Descriptive Statistics
Demographics and baseline characteristics will be summarized and presented. Age, height, 
weight, BMI, BMI-SDS, and fat mass percentage at study baseline will be summarized using 
descriptive statistics (N, mean, SD). The number and percentage of subjects in each sex, 
ethnicity, and race category also will be presented. Baseline HOMA-IR, fasting glucose and 
fasting insulin, as well as other measures of metabolism (e.g. cholesterol and triglycerides) will 
be summarized using descriptive statistics (N, mean, SD).
1.33.6 Planned Interim Analyses
No formal interim analyses are planned for safety, futility or efficacy.
1.33.7 Sub-Group Analyses
The sample size is too small to support meaningful sub-group analyses for age, sex, or 
race/ethnicity, and no such analyses will be conducted. 
1.33.8 Tabulation of individual Participant Data
Individual participant data will not be listed by measure and time point.
1.33.9 Exploratory Analyses
Any of the exploratory evaluations that generate quantitative measures will be examined using 
descriptive statistics including confidence intervals when appropriate. Any statistical tests 
(paired t-tests of baseline versus 16-week results) performed for evaluation of exploratory 
objectives will be done without formal adjustment for multiple comparisons, but in the context of 
the number of tests performed.
The following dependent variables will be examined in the dataset:
Change in: BMI standard deviation score for age and sex, body weight, percentage total 
body fat mass by DXA, appetite score using visual analog scale, attention bias to highly 
palatable images, energy intake at buffet meal, free living physical activity by 
accelerometry, hemoglobin A1C, plasma GI hormones (GLP-1 and PYY), weight related 
quality of life score, Beck depression inventory total score, Columbia-Suicide Severity 
Rating Scale, body-esteem scale score for adolescents and adults, HOMA-IR, fasting 
glucose and insulin, triglycerides, LDL- and HDL-cholesterol, OGTT glucose and insulin 
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REGULATORY AND OPERATIONAL CONSIDERATIONS
1.34 INFORMED CONSENT PROCESS
1.34.1 Consent/Assent Procedures and Documentation
In obtaining and documenting informed consent, all study staff will comply with applicable 
regulatory requirements (e.g., 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56) and will adhere 
to ICH GCP.
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Consent and Assent 
forms will be Institutional Review Board (IRB)-approved and the participant (and/or 
parent/guardian) will be asked to read and review the documents. The principal investigator or 
associate investigators with appropriate expertise will obtain written, active consent before the 
Screening Visit or as the first activity conducted at the Screening Visit. The purpose of the 
project, all testing procedures, and study components, and of their rights as research participants, 
will be described in detail in terms suited to the participant’s comprehension. Potential 
participants and their parents will also be informed of the possible risks and inconveniences of 
the study. The investigator will answer any questions that may arise. The investigator will also 
explain the study assent form to minors using appropriate language. Sufficient time and 
opportunity will be given for discussion of the research as well as to answer any questions all 
may have, taking care to minimize or eliminate the perception of coercion or undue influence. 
Participants will have the opportunity to carefully review the written consent form and ask 
questions before signing. The participants will have the opportunity to discuss the study with 
their family or surrogates and given time to think about it prior to agreeing to participate. The 
participant (or parent/guardian) will sign the informed consent document prior to any procedures 
being done specifically for the study. Participants will be informed that participation is voluntary 
and that they may withdraw from the study at any time, without prejudice. The rights and welfare 
of the participants will be protected by emphasizing to them that the quality of their medical care 
will not be adversely affected if they decline to participate in this study. The informed consent 
form (and assent if applicable) will be signed before the participant undergoes any study-specific 
procedures. The investigator-designated research professional obtaining the consent (and assent 
if applicable) must also sign the informed consent and assent form (if applicable). A copy of the 
informed consent/assent documents will be given to the participants for their records. The 
informed consent process will be documented in the medical record (including the date), and the 
original completed forms will be kept in the participant’s medical record with a copy in their 
research chart.
Informed consent documents (and assent documents, if applicable) may be printed to sign and 
date in ink, or the electronic documents may be signed with a hand signature using a finger, 
mouse or stylus via an approved platform. Participants may be asked to complete the consent 
process electronically via iMed and Docusign, which are both 21 CFR Part 11 compliant.  Once 
identity is confirmed, consents can be electronically signed, date-stamped, and routed to the PI 
for electronic signature. Once the PI has logged into the secure site and digitally signed the 
consent, a pdf of the signed consent is created. As is done for forms signed in ink, the participant 
will be provided with a copy of the signed document, and can also contact our study staff to 
obtain a hard copy of the consent at any point in this process.


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For assent of children
All adolescent participants are expected to be able to comprehend and be included in all 
discussions about the trial. Age-appropriate language will be used to describe the procedures and 
tests involved in this study, along with the risks, discomforts, and benefits of participation. All 
child study participants, who will be between age 12 and <18 years will be asked to sign an age 
appropriate assent form. The consent/assent process will be documented in the child’s medical 
record. All children will be contacted after they have reached the age of 18y to determine 
whether they wish to continue participating in the trial; informed consent will be obtained from 
them at that time.
Telephone consent
In certain instances, the PI or designee will obtain informed consent by a telephone or video 
conversation with a protocol-eligible subject who cannot travel to the NIH Clinical Center for a 
considerable period of time.  A parent/guardian will be involved if the subject is <18 years of 
age.  
The informed consent document will be sent to the subject by mail, email, or fax. An explanation 
of the study will be provided over the telephone or other electronic media (via an NIH approved 
remote platform) after the subject has had the opportunity to read the consent form. The 
informed consent form will be signed and dated. 
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was returned.
A fully executed copy will be returned via mail for the subject’s records.
The informed consent process will be documented on a progress note by the consenting 
investigator.
The investigator will confirm that, when required, written legally effective consent has been 
obtained prior to initiating any study interventions.
Telephone assent
The informed consent and assent documents will be sent to the parents/guardian and child. An 
explanation of the study will be provided over the telephone after the parents/guardian and child 
have had the opportunity to read the documents. Age-appropriate language will be used to 
discuss the study with the child. The parents/guardian will sign and date the informed consent. 
The child will sign and date that form. All children will be contacted after they have reached the 
age of 18y to determine whether they wish to continue in the trial and informed consent will be 
obtained from them at that time.
The original signed informed consent and assent documents will be sent back to the consenting 
investigator who will sign and date the consent form with the date the consent was returned.
A fully executed copy will be returned via mail to the subject.
The informed consent and assent process will be documented on a progress note by the 
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1.34.2 Consent for minors when they reach the age of majority 
When a pediatric subject reaches age 18, continued participation (including ongoing interactions 
with the subject or continued analysis of identifiable data) will require that consent be obtained 
from the now adult with the standard protocol consent document to ensure legally effective 
informed consent has been obtained.
If reconsent is not feasible, we request waiver of informed consent to continue to use data and/or 
specimens for those individuals who become lost to follow up or who have been taken off study 
prior to reaching the age of majority.
Requirements for Waiver of Consent consistent with 45 CFR 46.116 (d):
(1) The research involves no more than minimal risk to the subjects.
a.
Analysis of samples and data from this study involves no additional risks to 
subjects.
(2) The research could not practicably be carried out without the waiver or alteration.
a.
Considering the length of time between the minor’s last contact with the 
research team and their age of majority, it will likely be very difficult to locate 
them again. A significant reduction in the number of samples analyzed is 
likely to impact the quality of the research. 
(3) As the research involves using identifiable private information or identifiable 
biospecimens, the research could not practicably be carried out without using such 
information or biospecimens in an identifiable format. 
a.
Though the purpose of future studies cannot yet be known, they often involve 
the correlation of clinical outcomes and clinical interventions with laboratory 
studies.  Such information would be unavailable if access to medical record 
numbers was unavailable. 
(4) The waiver or alteration will not adversely affect the rights and welfare of the 
subjects.
a.
Retention of these samples or data does not affect the welfare of subjects. 
(5) Whenever appropriate, the subjects will be provided with additional pertinent 
information after participation.
a.
We only request a waiver of consent for those subjects who have been lost to 
follow-up or who have been taken off study prior to reaching the age of 
majority.
1.34.3 Consent of Subjects who are, or become, decisionally impaired
Not applicable. Adults unable to provide consent are excluded from enrolling in the protocol. 
However, it is possible that subjects enrolled in the protocol may permanently lose the capacity 
to consent for themselves during the course of this study.  In the event this occurs, the subjects 
will be withdrawn from the study.


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1.35 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigator, funding agency, and regulatory authorities.  If the study is prematurely terminated 
or suspended, the Principal Investigator (PI) will promptly inform study participants, the 
Institutional Review Board (IRB), and NICHD Clinical Director and will provide the reason(s) 
for the termination or suspension.  Study participants will be contacted, as applicable, and be 
informed of changes to study visit schedule.
 Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the NICHD Clinical Director, IRB and, as applicable, the Food and Drug 
Administration (FDA).
1.36 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators 
and their staff. This confidentiality is extended to cover testing of biological samples and genetic 
tests in addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party 
without prior written approval of the Principal Investigator. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the NICHD Clinical Director, 
representatives of the Institutional Review Board (IRB), and/or regulatory agencies may inspect 
all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants 
in this study. The clinical study site will permit access to such records.
The study participant’s contact information will be securely stored for internal use during the 
study. At the end of the study, all records will continue to be kept in a secure location for as long 
a period as dictated by the reviewing IRB, Institutional policies, or NICHD requirements. 
Samples and data will be coded. Human biospecimens will be collected using procedures 
appropriate for the type of biospecimen being collected and will be handled in accordance with 
the U.S. Occupational Safety and Health Administration’s Bloodborne Pathogens Standard for 
Samples. The principal investigator and the co-investigators will have access to identifiable 
participant records. Data will be coded by subject number but will be readily associated with 
identifiable participant records. Records containing personal identifiers will be maintained 
consistent with the security measures required by the NIH. All NIH data will be kept on secure 
computers in the SGO office, whose doors will be locked when staff is not present.  All paper 
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immediately (as described above) NIH will be stored indefinitely in locked freezers by the 
NICHD sample management team supervised by the NICHD Clinical Director and 
tracked/managed through the NICHD Clinical Trials Database (CTDB). Human biospecimens in 
NICHD storage will have a unique identifier, will be labeled with a printed label and will contain 
a barcode. Samples will be tracked using a computer‐based inventory system that records the 
location and detailed information of every specimen in the repository
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored in CTDB. Individual participants and their research 
data will be identified by a unique study identification number. The study data entry and study 
management systems used by research staff will be secured and password protected. 
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.
1.37 FUTURE USE OF STORED SPECIMENS AND DATA
Stored samples, specimens or data may be sent to collaborators for specific measurements or 
analyses. All stored samples, specimens, and data will be coded so that when sent for 
measurements the identity of the volunteer remains confidential. Identification of coded samples 
will be kept in a secure, password-protected database accessible only to investigators, but will be 
identifiable in case specific tests yield clinical information of importance to a particular 
volunteer or samples can be destroyed per volunteer request (see below). Samples will be used 
only for research and not for commercial purposes. Research volunteers will not be informed of 
individual results from analyses performed specifically for research purposes, unless there is 
clear evidence accepted by the medical community that these results would impact the 
volunteer’s individual medical care or future health. Samples will be stored until used and will 
not be destroyed unless specifically requested in writing by the volunteer. 
Additional consent will be obtained to use samples for purposes not already specified if 
participants have requested such consent be obtained (see consent form).  Prior to transfer of 
samples and data to other (additional) non-NIH collaborators, a material transfer agreement 
(MTA) with the outside institution will be established.  The PI will provide the IRB with a listing 
of MTA’s that have been established under these provisions at the time of the Continuing 
Review and include a record of each such collaboration in the study protocol.
Staff will report to the Principal Investigators any destroyed samples, if samples become 
unsalvageable because of environmental factors (ex. Broken freezer or lack of dry ice in a 
shipping container), lost in transit between facilities or misplaced by a researcher. The PI will 
record any loss or unanticipated destruction of samples as a deviation.


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1.38 SAFETY OVERSIGHT
The clinical research team will meet on a weekly basis when participants are being actively 
treated on the trial to discuss progress and adverse events. All data will be collected in a timely 
manner and reviewed by the principal investigator or a lead associate investigator. Adverse 
events will be reported as required above. Events meeting requirements for expedited reporting 
will be submitted within the appropriate timelines.
Safety oversight will be under the direction of a Clinical Safety Officer (CSO) who is a Licensed 
Independent Practitioner (LIP) with relevant clinical experience. The CSO will be independent 
and not otherwise involved in the conduct of the trial. The NICHD Clinical Director and the 
Director of Clinical Research and Compliance, or their designees, will approve the selected CSO. 
The CSO and the PI will jointly determine an interval for routine safety monitoring appropriate 
for the risk level of the trial. This will be included as part of the monitoring plan in the clinical 
study protocol along with appropriate study stopping rules. The PI is responsible for promptly 
notifying the CSO of any emerging safety signals. The CSO will review all Dose-Limiting 
Toxicities (DLTs) considered to be at least possibly related to the study drug, instances of dose 
reductions due to intolerability, as well as any emerging safety signals identified by the PI on an 
ad hoc basis. All Adverse Events, including those that are expected, will be described in the 
routine safety monitoring reports reviewed by the CSO. If there are unresolved differences 
regarding adverse event causality assessment, event reporting, or management, the NICHD 
Clinical Director and the Director of Clinical Research and Compliance, or their designees, will 
be notified and asked to adjudicate. The CSO will provide its input to the Clinical Director of 
NICHD and other staff as appropriate.
For this pilot study of a medication that is FDA-approved for the age group investigated, that is 
performed under an FDA exemption, it is anticipated that the chance of unexpected AEs that 
would lead to study discontinuation is low. Therefore, it is proposed that the routine report that 
the CSO will review that includes all AEs will occur once yearly, at the time of Continuing 
Review. As specified above, SAEs will be reported promptly to the CSO independent of this 
scheduled report.
After half of all anticipated subjects (i.e. at n=20) have had the opportunity to take study 
medication for the 16-week treatment period, the CSO will review the percentage of enrolled 
subjects who continued to take study medication through the 16 week (primary efficacy) 
timepoint. If fewer than 50% remain in the per protocol dataset, the study will be stopped.
The study will also be reviewed to determine if it should be stopped if 3 or more study subjects 
develop unexpected SAEs that are assessed as probably related to study medication or if 6 or 
more study subjects develop expected or unexpected SAEs that are assessed as probably related 
to study medication. 
Individual study subject stopping rules have also been established (see attached file titled, 
“CTCAE_v5.0_2017-11-27 for Liraglutide - revised 2021-FEB-24”. In general, a participant will 
at a minimum reduce the dose and, in most instances, not continue study medication if they 
develop CTCAE 5 grade 3 or greater adverse events, but in some categories lower grades will 
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1.39 CLINICAL MONITORING
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
International Conference on Harmonisation Good Clinical Practice (ICH GCP), and with 
applicable regulatory requirement(s). 
Auditors from the Office of the Clinical Director, NICHD or a designated contracted 
organization will conduct the monitoring on-site. Initial review will occur as soon as possible 
after IRB approval for initial assessment and training. Monitoring will then continue at a 
minimum annually but more frequently if needed, with yearly targeted review of 50% or more of 
participant’s data, for the purpose of verification of primary and secondary endpoint values, 
laboratory safety reports (hematology and chemistry), CRF completeness, consent/assent 
signatures, annual submission of Continuing Review and FDA IND reports, and for accuracy of 
data transcription into the study database. Written outcome letters will be generated in response 
to the monitoring activities and submitted to the Principal investigator and Clinical Director or 
Deputy Clinical Director, NICHD.
1.40 QUALITY ASSURANCE AND QUALITY CONTROL
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation, and completion.  An individualized quality management 
plan will be developed to describe a site’s quality management.
Quality control will be applied at each stage of data handling to ensure that all data are reliable 
and have been processed (e.g., monitoring to review source documents/subject’s charts against 
eCRFs, development of a monitoring plan, data management system with appropriate logic 
checks, quality control review of the database prior to database lock, quality control procedures 
to confirm accurate table, listings, etc.). Quality control (QC) procedures will be implemented 
beginning with the data entry system and data QC checks that will be run on the database will be 
generated. Any missing data or data anomalies will be communicated to the site for 
clarification/resolution.
Audits will be performed as part of implementing quality assurance. Audits will evaluate study 
conduct, data/record integrity, and/or compliance with the protocol, standard operating 
procedures, GCP, and applicable regulatory requirements. Following written Standard Operating 
Procedures (SOPs), the monitors will verify that the clinical trial is conducted and data are 
generated and biological specimens are collected, documented (recorded), and reported in 
compliance with the protocol, International Conference on Harmonisation Good Clinical Practice 
(ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), 
Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the NICHD, and inspection by local 
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1.41 DATA HANDLING AND RECORD KEEPING
1.41.1 Data Collection and Management Responsibilities
Medical and research records for this trial will be maintained in compliance with ICH GCP and 
regulatory and institutional requirements for the protection of confidentiality of participants.  As 
part of participating in a NIH-sponsored study, the site will permit authorized representatives of 
the NIH, NICHD, and regulatory agencies to examine (and when permitted by applicable law, to 
copy) clinical records for the purposes of quality assurance reviews, audits, and evaluation of the 
study safety, progress, and data validity
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported.
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.  
Hard copies of the study visit worksheets will be provided for use as source document 
worksheets for recording data for each participant enrolled in the study. Data recorded in the 
electronic case report form (eCRF) derived from source documents should be consistent with the 
data recorded on the source documents. 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be entered into the NICHD Clinical Trials 
Database, a 21 CFR Part 11-compliant data capture system. The data system includes password 
protection and internal quality checks, such as automatic range checks, to identify data that 
appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the 
source documents. Clinical notes from each visit will also be recorded in the NIH CRIS system.
1.41.2 Study Records Retention
Upon completion of the study Jack A. Yanovski, MD, PhD will retain possession of the 
electronic IND binder and electronic Protocol Binder in a secure location. Study documents 
should be retained for a minimum of 2 years after the last approval of a marketing application in 
an International Conference on Harmonisation (ICH) region and until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed since 
the formal discontinuation of clinical development of the study intervention, and as per the NIH 
Intramural Records Retention Schedule. No records will be destroyed without the written 
consent of the sponsor, if applicable. 
1.42 PROTOCOL DEVIATIONS AND NON-COMPLIANCE
It is the responsibility of the investigator to use continuous vigilance to identify and report 
deviations and/or non-compliance to the NIH Institutional Review Board as per Policy 801.  All 
deviations must be addressed in study source documents, reported to the NICHD Clinical 
Director.  The investigator is responsible for knowing and adhering to the reviewing IRB 
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1.42.1 NIH Definition of Protocol Deviation
A protocol deviation is any changed, divergence, or departure from the IRB-approved research 
protocol. 

Major deviations: Deviations from the IRB approved protocol that have, or may have the 
potential to, negatively impact the rights, welfare or safety of the subject, or to 
substantially negatively impact the scientific integrity or validity of the study.

Minor deviations: Deviations that do not have the potential to negatively impact the 
rights, safety or welfare of subjects or others, or the scientific integrity or validity of the 
study.
1.43 PUBLICATION AND DATA SHARING POLICY
1.43.1 Human Data Sharing Plan
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations:
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final peer-
reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central 
upon acceptance for publication.
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of 
NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results 
Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and 
results information from this trial will be submitted to ClinicalTrials.gov. In addition, every 
attempt will be made to publish results in peer-reviewed journals.  Data from this study may be 
requested from other researchers 1 year after the completion of the primary endpoint by 
contacting Dr. Yanovski.
This study involves the collection of human data in the form of anthropometric (e.g., DXA, 
BMI), metabolic (e.g. blood glucose and insulin), and drug tolerability (e.g., adverse event) data. 
After obtaining consent for data sharing, de-identified data will be made available without cost to 
researchers and analysts through government-supported publicly accessible databases, or a 
similar publicly available databases for which user registration is required. Data will be made 
available proximately following publication of findings that address the main and secondary 
aims of the protocol and will include the relevant phenotypic data. Users must agree to the 
conditions of use governing access to the public release data, including limitation of research to 
investigations consistent with the participants’ consent, restrictions against attempting to identify 
study participants, destruction of the data after analyses are completed, reporting responsibilities, 
restrictions on redistribution of the data to third parties, and proper acknowledgement of the data 
resource.
What data will be shared?

We will share human data generated in this research for future research as follows: 
Coded, linked data in an NIH-funded or approved public repository.
•
Coded, linked data in BTRIS (automatic for activities in the Clinical Center)


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•
Identified or coded, linked data with approved outside collaborators under appropriate 
agreements.
How and where will the data be shared?
Data will be shared through:
•
An NIH-funded or approved public repository: clinicaltrials.gov.
•
BTRIS (automatic for activities in the Clinical Center)
•
Approved outside collaborators under appropriate individual agreements.
•
Publication and/or public presentations
1.43.2  Genomic Data Sharing Plan
Not applicable
1.44 COLLABORATIVE AGREEMENTS 
Not applicable
1.44.1  Agreement Type
Not applicable
1.45 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.  The study leadership in conjunction with the NICHD has 
established policies and procedures for all study group members to disclose all conflicts of 
interest and will establish a mechanism for the management of all reported dualities of interest.
ABBREVIATIONS
AE
Adverse Event
ANCOVA
Analysis of Covariance
BMI
Body Mass Index
BMIz
Body Mass Index Standard Deviation Score for age and sex
BOCF
Baseline Observation Carried Forward
CFR
Code of Federal Regulations
CLIA
Clinical Laboratory Improvement Amendments
CMP
Clinical Monitoring Plan
CNH
Children’s National Hospital
COC
Certificate of Confidentiality
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form
DCC
Data Coordinating Center
DXA
Dual-Energy X-ray Absorptiometry


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DHHS
Department of Health and Human Services
DSMB
Data Safety Monitoring Board
DRE
Disease-Related Event
EC
Ethics Committee
eCRF
Electronic Case Report Forms
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act of 2007
FFR
Federal Financial Report
GI
Gastrointestinal
GCP
Good Clinical Practice
GLP
Good Laboratory Practices
GLP-1
Glucagon-Like Peptide 1
GMP
Good Manufacturing Practices
GWAS
Genome-Wide Association Studies
HIPAA
Health Insurance Portability and Accountability Act 
HOMA-IR
Homeostatic Model Assessment of Insulin Resistance
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation 
ICMJE
International Committee of Medical Journal Editors
IDE
Investigational Device Exemption
IND
Investigational New Drug Application
IRB
Institutional Review Board
ISM
Independent Safety Monitor
ISO
International Organization for Standardization
ITT
Intention-To-Treat
LOCF
Last Observation Carried Forward
LSMEANS
Least-squares Means
MedDRA
Medical Dictionary for Regulatory Activities
MOP
Manual of Procedures
MSDS
Material Safety Data Sheet
NCT
National Clinical Trial
NIH 
National Institutes of Health
NIH IC
NIH Institute or Center
OHRP
Office for Human Research Protections
OGTT
Oral Glucose Tolerance Test
PI
Principal Investigator
PYY
Peptide YY
QA
Quality Assurance
QC 
Quality Control
QoL
Quality of Life
RCT
Randomized Controlled Trial
RYGB
Roux-en-Y gastric bypass
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan


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SG
Sleeve Gastrectomy
SMC
Safety Monitoring Committee
SOA
Schedule of Activities
SOC
System Organ Class
SOP
Standard Operating Procedure
UP
Unanticipated Problem
US
United States
VAS
Visual Analog Scale
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ICF_003.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/10/2022
Page 1 of 17
CC ICF template v. 05.05.20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:  Jack A. Yanovski, MD, PhD
STUDY TITLE: Phase II Trial of Liraglutide (Saxenda(R), Novo Nordisk) in Adolescents with 
Obesity After Sleeve Gastrectomy: A Pilot Open-Label Study 
STUDY SITE: 
NIH Clinical Center
Cohort: Young adults and adolescents with obesity 1 year after sleeve gastrectomy
Consent Version:  11/10/2022
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Sheila M. Brady, F.N.P:
Associate Investigator
SGO, DEMGEO, DIR, NICHD
Hatfield CRC, Room 1-3330 MSC 1103
10 Center Drive, Bethesda, MD 20892
Phone: 301- 451-3783
Fax: 301-480-4291
E-mail: bradys@nih.gov
Jack A. Yanovski, MD, PhD:
Principal Investigator
SGO, DEMGEO, DIR, NICHD, NIH
Hatfield CRC, Room 1-3330 MSC 1103
10 Center Drive, Bethesda, MD 20892
Phone: 301-496-0858
Fax: 301-480-4271
E-mail: jy15i@nih.gov
KEY INFORMATION ABOUT THIS RESEARCH 
This consent form describes a research study and is designed to help you decide if you would 
like to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
This section provides the information we believe is most helpful and important to you in making 
your decision about participating in this study. Additional information that may help you decide 
can be found in other sections of the document. Taking part in research at the NIH is your choice.
We wish to study adolescents (age 12-20.99y) who continue to have obesity after having the 
weight-loss surgery called “vertical sleeve gastrectomy.” Liraglutide is a weight loss promoting 
and glucose lowering medication that is FDA-approved to treat obesity in patients age 12 and 
older and to treat type 2 diabetes in patients 10 years and older, but has not been studied in 
adolescents who have had prior weight loss surgery.  A recent study suggests that use of 
liraglutide plus lifestyle therapy leads to lowering of body-mass-index (BMI) in adolescents. 
We will study the effects of giving liraglutide 3.0 mg once daily for 16 weeks in adolescents 
IRB NUMBER: 000241
IRB APPROVAL DATE: 12/29/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/10/2022
Page 2 of 17
CC ICF template v. 05.05.20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
who continue to have obesity 1 year or more after vertical sleeve gastrectomy.  After a screening 
visit to find out if you/your child can take part, you/your child will undergo baseline studies 
including blood draws and x-rays. Afterwards, you/your child will be taught how to give an 
injection of liraglutide daily under the skin at home. Liraglutide will be started at the lowest 
dose of 0.6 mg daily and then increased slowly over the first several weeks.  The drug  will be 
taken for a total of 16 weeks. Then we will repeat the studies done at baseline to see how weight 
has changed. Liraglutide may cause gastrointestinal side effects like nausea, diarrhea, vomiting, 
decreased appetite, indigestion, and constipation, but for most people, these side effects do not 
make them stop taking liraglutide.  If side effects become too bothersome, we may not increase 
or may even decrease the dose.  While on Liraglutide, we will ask that you/your child not take 
other weight loss medications, insulin, sulfonylureas, or other medications that affect insulin 
secretion or liraglutide clearance.  The effects of liraglutide on the unborn child and on the 
newborn baby are not known.  Because of this, you/your child cannot participate in this study if 
you/your child are pregnant or breast-feeding or become pregnant during the study.    
We will ask you/your child to come to the NIH Clinical Center for outpatient follow-up visits 
that will include a weight check and physical examination.  The final on-medication visit will 
also involve blood work, collection of urine and stool samples, questionnaires, and an imaging 
scan to check body composition.  While at home, we will ask you/your child to take the study 
medicine once a day.
The remaining document will now describe the research study in more detail.  This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information in this document. Some people have personal, religious, or ethical beliefs 
that may limit the kinds of medical or research treatments they would want to receive (such as 
blood transfusions). Take the time you need to ask any questions and discuss this study with NIH 
staff, and with your family, friends, and personal health care providers.
If the individual being enrolled is a minor then the term “you” refers to “you and/or your child” 
throughout the remainder of this document.
Time in weeks
Screening
Visit
~3 hours
Interim Visits
~3 hours
8
Final On-
Medication Visit
~8 hours
1
4
0
12
16
Up to 4 weeks
before baseline
Baseline Visit
~8 hours.
Start study
med
2 3
Weekly dose
increases
as tolerated
28
End Study
Visit
(off medication)
~8 hours
IRB NUMBER: 000241
IRB APPROVAL DATE: 12/29/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/10/2022
Page 3 of 17
CC ICF template v. 05.05.20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
Metabolic Bariatric Surgery, including an operation called “vertical sleeve gastrectomy,” is 
currently the most effective weight loss treatment for severe obesity and its associated diseases 
such as high blood pressure or diabetes. Yet, as many as 75% of adolescents who undergo such 
surgery, even if they have a good initial response, do not achieve a BMI<30 kg/m2 (meaning they 
still have obesity), or subsequently have weight regain after reaching their lowest weight at 
approximately 1 year after surgery that places them at continued risk for the metabolic 
consequences of obesity.  
This is a research study.  The purpose of this research is to find out if a medication called liraglutide 
can help adolescents who continue to have obesity 1 year or more after vertical sleeve gastrectomy 
lose additional weight.  
Liraglutide is a medication that suppresses appetite and helps the body regulate its blood sugar 
level.  Liraglutide has been approved by the U.S. Food and Drug Administration (FDA) to treat 
obesity in children age 12 years or older, to treat type 2 diabetes in patients 10 years and older and 
to treat obesity in adults 18 years and older.  We ask you to join our study so we can find out if 
liraglutide can help teenagers and young adults with obesity after vertical sleeve gastrectomy lose 
more weight.
WHAT WILL HAPPEN DURING THE STUDY?
If you agree to participate and are found to qualify, you will be one of 40 adolescents assigned  to 
take liraglutide once daily for 16 weeks. Liraglutide is administered subcutaneously (an injection 
just under the skin) at a starting dose of 0.6 mg daily. The dose will be increased weekly up to 3.0 
mg per day as tolerated.   
The study consists of seven outpatient visits at the NIH Clinical Center: a screening visit to 
determine eligibility, a baseline visit to study your metabolism, body composition, appetite, and 
mood before you start taking study medicine, three short visits during the time you take liragludie 
to check your weight and how you are feeling, a final on-medication visit to repeat blood tests, 
questionnaires, and body composition scan, and an End Study off-medication final visit 12 weeks 
after you stop taking liraglutide to look for weight change after the intervention. 
Outpatient Screening Visit:
This visit will take about 3 hours to complete. You will be seen on a weekday in the Clinical Center 
at the National Institutes of Health. We ask that you remain fasting for 10 hours before coming to 
the clinic and have nothing to eat or drink except water that morning. During this visit, we will 
perform the following: 
IRB NUMBER: 000241
IRB APPROVAL DATE: 12/29/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/10/2022
Page 4 of 17
CC ICF template v. 05.05.20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
1. Protocol review and signing of consent, and, if needed, assent form. We will go over 
the study in detail and answer any questions. The consent and assent forms will need to be 
signed before you can take part in the study. 
2. Complete medical history and physical exam, with vital signs, weight, and height 
measurements. 
3. Fasting blood tests to ensure that you are in good health. The analysis will examine blood 
cell count, liver and kidney function, cholesterol level, blood sugar level, inflammation 
level, vitamin D level, and coagulation studies.  We will collect about 1 tablespoon of blood 
(~12 mL) at this visit.
4. Urine sample collection for urine analysis and a pregnancy test (for women of 
childbearing age).
5. Nutrition counseling.  You will meet with our nutrition staff who will review how to 
maintain a healthy diet and manage a dietary log.  
6. Testing of how you respond to pictures of appealing foods.  You will be shown a series 
of images and asked to respond to them on a computer.   
7. Wrist accelerometer set-up.  We will set up an accelerometer (a device like a watch) on 
your wrist that will help measure your physical activity.  You will be asked to wear it during 
all hours, except when bathing or showering, contact  sports, or when  swimming.  The at-
home  monitoring  period will last for fourteen (14) consecutive days. You will return this 
accelerometer when you return to the Clinical Center for the Baseline Visit.  
8. Optional stool sample collection set-up. If you agree, we will ask you to obtain stool 
samples to save for future experiments that include sequencing of the DNA from the 
microorganisms in your stool (the “microbiome”). We will send the needed supplies home 
with you at this visit so you can bring the samples back at your next visit. 
Baseline Visit:
If your Screening Visit results suggest you will qualify for participation in the study, you will be 
scheduled for the Baseline Visit. This visit can be done up to 4 weeks later. For the Baseline Visit, 
we ask that you remain fasting for 10 hours before coming to the clinic and have nothing to eat or 
drink except water that morning. You will be seen on a weekday in the Clinical Center at the 
National Institutes of Health, and the visit will take 6- 8 hours to complete. 
During this visit we will perform the following: 
1. Interval medical history and physical exam, with weight, height, waist circumference, 
and blood pressure measurement. You will also complete a few questionnaires that will 
ask about your mood and feelings about your weight. Some will be completed on a 
computer.
2. Urine sample collection as described before.
3. Fasting blood tests to look at your baseline metabolic, inflammatory, glucose, 
cholesterol levels, as well as reserve blood samples to be preserved for additional 
possible research tests. We will insert a small needle into your vein (an intravenous line 
IRB NUMBER: 000241
IRB APPROVAL DATE: 12/29/2022


PATIENT IDENTIFICATION
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or I.V.) to obtain blood samples. We will collect about 2.5 tablespoons of blood (~36 
mL) for these tests.
4. Oral Glucose Tolerance Test (OGTT) is a procedure that tells us a lot about how sugar 
is used by your body, how well your insulin works, and how sensitive your body is to 
insulin. The OGTT study is done while you rest in bed and takes two hours to complete. 
You will be given specific instructions for your diet for the day prior to testing.  Testing 
instructions will be specific to each individual participant.  Generally, the test will 
include the following procedures:
After 10 pm the night before the test and on the morning of the test, you should only drink 
water – no other foods or liquids; this is called “fasting.”
An intravenous (IV) needle and tube will be placed in your arm so that we can do multiple 
blood draws without having to “stick” you each time.  The needle will stay in your arm for 
the entire length of the test.
Then you will be asked to ingest a drink containing 75 grams dextrose, which tastes like a 
very sweet liquid. Blood samples will be drawn at +0, 15, 30, 60, 90, and 120 min after 
you consume the dextrose drink. We will collect less than 1 tablespoon of blood (~10 mL) 
at this visit.
5. Dual energy x-ray absorptiometry (DXA) to look at your body composition (amounts of 
muscle, bone, and fat in the body). The test involves lying still on a padded table while a 
small camera passes over your body. We will do 1 scan of your whole body.  The dose of 
the x-ray is much less than the amount you would get from a normal chest x-ray. The total 
amount of time to do this test will be about 20-30 minutes. 
6. Buffet meal.  You will be invited to eat as much as you want at a lunch buffet meal at the 
NIH Clinical Center.  We will calculate how much food you ate after you are done.  You 
will be asked to assess your appetite and mood before and after the test meal.  
7. Nutrition counseling.  You will meet with our nutrition staff to learn how to maintain a 
healthy diet. 
8. Optional return of stool samples: If you agreed to collect stool samples at home, we 
will ask you to turn in your stool samples.
9. Review of food record. You will go over the record of your diet in person with one of 
the NIH nutrition staff.
10. Check of lab results and final determination of study eligibility. We will review your 
results and let you know if you qualify for the study.
11. Injection teaching: The nurses will teach you how to take the liraglutide study medicine 
by subcutaneous injection. You will need to be comfortable taking the medicine before 
you go home.
12. Dispense study medication. If you are found eligible, we will give you study medication 
for you to take at home. You will be given approximately a 4-week supply of study 
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IRB APPROVAL DATE: 12/29/2022


PATIENT IDENTIFICATION
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File in Section 4: Protocol Consent (1)
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medication to be taken one time per day. The medication can be taken with or without 
food. If you would like, we will help set up a reminder alarm to help you remember when 
to take your medicine. If you forget to take a dose, then take it as soon as you remember. 
But if it is more than 12 hours since you should have taken the medication, just skip the 
missed dose and take your next dose as usual the following day.  We will ask you to call 
the research team if you miss your dose of Liraglutide for 3 days or more.  
At-home dose adjustment:
As long as you are feeling well, we will increase the dose once a week, starting at 0.6 mg per day 
and increasing to 1.2, 1.8, 2.4, and at most 3.0 mg per day. If you do not feel well, you should call 
the study team. We may decide to decrease the dose or not increase it depending on your 
symptoms.
Interim Visits (weeks 4, 8, and 12):
To make sure that you are doing well taking the medication, you will be seen on a weekday in 
the Clinical Center at the National Institutes of Health about 4 weeks, 8 weeks, and 12 weeks 
after you started to take the study medicine. These visits will take about 2 hours to complete. 
During this visit we will perform the following: 
1.
Interval medical history and physical exam, with weight, height, and vital signs 
measurements at each visit.
2.
Urine sample collection with pregnancy test as described before for females at each visit.   
3.
Collection of Used Liraglutide pens.  We will collect your used liraglutide pens from the 
previous 4 weeks and give you a new 1-month supply of medication at each visit.  
4.
Wrist accelerometer set-up (At the 12-week visit only).  We will set up an accelerometer 
on your wrist that will help measure your physical activity, as you did at the Screening 
Visit.  You will be asked to wear it during all hours, except when bathing or showering, 
contact  sports, or when  swimming for fourteen (14) consecutive days.
5.
Repeat testing of how you respond to pictures of appealing foods, the same tests you 
did at your Screening visit will be done at the 12-week visit only.
6.
Nutrition counseling.  You will meet with our nutrition staff to learn about various 
nutrition topics and for measurements at each visit.   
7. Optional stool collection materials (At the 12-week visit only). If you agreed to collect 
stool, we will give you the needed materials to take home and bring the sample back at your 
final visit.
Final On-Medication Visit (16 weeks after starting study medication):
For this visit, we ask that you remain fasting for 10 hours before coming to the clinic and have 
nothing to eat or drink except water that morning. You will be seen on a weekday in the Clinical 
Center at the National Institutes of Health, and the visit will take 6- 8 hours to complete. 
During this visit we will repeat the tests you did at the Baseline Visit: 
IRB NUMBER: 000241
IRB APPROVAL DATE: 12/29/2022


PATIENT IDENTIFICATION
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1. Interval medical history and physical exam, with weight, height, and blood pressure 
measurement. You will also complete a few questionnaires that will ask about your 
mood and feelings about your weight. Some will be completed on a computer.
2.  Urine sample collection as described before.
3. Fasting blood tests to look at your baseline metabolic, inflammatory, glucose, 
cholesterol levels , as well as reserve blood samples to be preserved for additional 
possible research tests. We will insert a small needle into your vein (an intravenous 
line or I.V.) to obtain blood samples. 
4. Oral Glucose Tolerance Test (OGTT). Blood samples will be drawn at +0, 15, 30, 
60, 90, and 120 min after you consume the dextrose drink
5. Dual energy x-ray absorptiometry (DXA) to look at your body composition. 
6. Lunch Buffet meal.
7. Nutrition counseling.  You will meet with our nutrition staff to learn about various 
nutrition topics.   
8. Optional return of stool samples as described before.
9. Review of food intake record. You will go over a 1 week record of your diet in 
person with one of the NIH nutrition staff.
Final Off Medication Visit:
This visit takes place 28 weeks after you started the study medicine. You will be seen on a 
weekday in the Clinical Center at the National Institutes of Health, and the visit will take 1-2 
hours to complete. During this visit we will perform the following: 
1.
Interval medical history and physical exam, with weight, height, waist circumference, 
and blood pressure measurement. If this evaluation suggests any medical problems, blood 
or other tests may be obtained at this visit.
HOW LONG WILL THE STUDY TAKE?
If you agree to take part in this study, your involvement is expected to last for approximately 7 
months. As described above, the 7 required visits last from 2 to 8 hours each.
HOW MANY PEOPLE WILL PARTICIPATE IN THIS STUDY?
We plan to have approximately 50 people participate in this study at the NIH. 
WHAT ARE THE RISKS AND DISCOMFORTS OF BEING IN THE STUDY?
a. Physical examination and measurement of vital signs by a health care provider involves no 
known risk but does take time. A limited physical examination will be performed in a concise 
but thorough manner with appropriate measures taken to provide your privacy.  Body 
circumference measurements of the waist will be done with a flexible tape measure; this involves 
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PATIENT IDENTIFICATION
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no risk and is not painful.  
b. Questionnaires and interviews are also without significant risk but may be inconvenient 
because of the time required to complete.  It is also possible that you may experience slight 
discomfort as a result of being asked to fill out questionnaires or respond to queries about stress 
and mood.  
Procedures:  We will ask you to complete five questionnaires that will take approximately 30-60 
minutes to complete.  The questionnaires will ask you about your general feelings regarding your 
own appearance, your perception of other’s evaluation about your body and appearance, weight 
satisfaction, mood, suicidal ideation, and quality of life.  
Risks:  Some of the questions in the questionnaire may be upsetting or make you feel 
uncomfortable.  You can skip any of the questions you do not want to answer, and you can stop at 
any time.
c.  Surveys and food records 
You will be taught how to keep a log of your dietary intake.  Surveys and food records are 
without significant risk but may be inconvenient because of the time required to complete.
d.  Buffet Meal
You will be asked to eat a lunch buffet meal during your study visit.  The buffet meal is without 
significant risk, but you may feel uncomfortable if you eat too much or too quickly.  
e. Accelerometer testing.  You will be asked to wear an accelerometer on your wrist for 2 weeks 
at a time to measure your physical activity.  It is an unobtrusive device without known risks and 
requires no maintenance by you.  You may find it mildly inconvenient to wear the accelerometer 
during all hours, except when bathing or showering and for contact sports.  If you develop irritation 
at the site of the wrist strap you should take it off and contact the research study team.
f.  DXA scanning.  You will have a DXA (Dual energy X-Ray Absorptiometry) scan to measure 
your bone density.  This procedure will take place at the NIH Clinical Center and will take about 
20 minutes to complete.  During that time, you will need to lie still on a padded table while the 
instrument scans your body.  We will do 1 scan of your whole body at two of your visits.  
g. Blood withdrawals 
Procedures:  You will have a blood drawn from a vein.  This may require a needle stick in your 
arm or hand, or if you already have an IV catheter in place, we may be able to draw through that.  
The amount of blood we will draw is about 1 tablespoon at the screening visit and about 3 
tablespoons at Visits 1 and 5. 
Risks:  Blood draws may cause pain, redness, bruising or infection at the site of the needle stick.  
Rarely some people faint or even throw up.  The study team member may apply numbing cream 
to the area so that the needle stick won’t hurt as much.
Blood withdrawals will remain well within the NIH guideline.This guideline is based upon 
body weight; for adults the maximum amount of blood that can be taken is 10.5 mL/kg or 550 
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PATIENT IDENTIFICATION
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mL, whichever is smaller, over any eight-week period. For children, no more than 5 mL/kg may 
be drawn for research purposes in a single day, and no more than 9.5 mL/kg may be drawn over 
any eight-week period. Any child weighing more than 58 pounds can participate safely in this 
study. 
h. Urine collection for pregnancy testing
For girls and women, urine collections for pregnancy check are without significant risk, but they 
do take time and you may find them uncomfortable to collect.
i.  Stool samples are also without significant risk, but some subjects may find them 
uncomfortable to collect. 
j.  Oral glucose tolerance test (OGTT) 
The only risks from this kind of study are those described for any blood draw, as well as 
developing nausea from the sugar drink. You may develop temporary high blood sugar levels 
from the sugar drink, but it should normalize within a few hours and should not be clinically 
significant.
k.  Liraglutide: the most common side effects of the medication used in this study are nausea, 
diarrhea, vomiting, decreased appetite, indigestion, and constipation.  Possible serious side effects 
include: pancreatitis (swelling and inflammation of the pancreas), hypoglycemia (low blood 
sugar), kidney failure in patients who have kidney disease, serious allergic reaction, and acute 
gallbladder disease, including gallstones. Liraglutide comes with a black box warning for a risk of 
thyroid C-cell tumors as it causes thyroid C-cell tumors at clinically relevant exposures in both 
sexes of rats and mice.  It is unknown whether Liraglutide causes thyroid C-cell tumors, including 
medullary thyroid carcinoma (a rare type of thyroid cancer) in humans, as the human relevance of 
liraglutide-induced rodent thyroid C-cell tumors has not been determined.  If you or a family 
member has a history of medullary thyroid cancer, or a genetic condition called multiple endocrine 
neoplasia type 2 that places you at risk for this cancer, you may not participate in the study.
We will monitor you for all adverse effects. If severe adverse effects develop, we will decrease 
the dose, temporarily stop, or discontinue the medication. If you experience any of the following, 
contact our team right away: 

Severe abdominal pain, diarrhea or vomiting 

Allergic reaction to the medicine that is severe, such as swelling or difficulty breathing
Keep the medication out of the reach of children. 
What are the risks related to pregnancy? 
The effects of liraglutide on the unborn child and on the newborn baby are not known.  Because 
of this, you can not participate in this study if you are pregnant or breast-feeding.  It is also 
important that participants do not become pregnant during the course of the study.  Females with 
child-bearing potential will be required to undergo a pregnancy test prior to starting and at every 
study visit.  Males should not to father a child during the study and for at least 6 months after 
completion of the study.  Those who are sexually active and not surgically sterile must use effective 
contraception.
IRB NUMBER: 000241
IRB APPROVAL DATE: 12/29/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
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File in Section 4: Protocol Consent (1)
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You may not participate in this study if you are pregnant. If you are able to become pregnant, we 
will perform a pregnancy test before exposing you to radiation. You must tell us if you may have 
become pregnant within the previous 14 days because the pregnancy test is unreliable during that 
time.
What are the risks of radiation from being in the study?
DXA scanning is not painful but may be inconvenient because of the time needed to complete the 
study. DXA scanning involves radiation exposure for research purposes only. 
During your participation in this research study, you will be exposed to radiation from two DXA 
scans.  This is considered a low exposure. The risk of this exposure is too low to be reliably 
measured. The amount of radiation you will receive is less than the NIH Radiation Guidelines of 
0.5 rem per year for participants less than 18 years old.
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them.  This type of radiation is called “background radiation”.   No one knows 
for sure whether exposure to these low amounts of radiation is harmful to your body.  The radiation 
you will get by participating in this study is less than the average yearly background radiation in 
the United States.
If you would like more information about radiation and examples of exposure levels from other 
sources, please ask a study member for a copy of the pamphlet called  An Introduction to Radiation 
for NIH Research Subjects.
WHAT ARE THE BENEFITS OF BEING IN THE STUDY?
We are hopeful that your participation in this study will provide evidence as to whether liraglutide 
will help promote additional weight loss in individuals with obesity following vertical sleeve 
gastrectomy. However, you might not benefit directly from participating in this study. Should we 
find abnormalities in any of your test results, you will be notified and receive a copy to assist you 
in seeking further medical evaluation. This information may or may not improve your health. 
Are there any potential benefits to others that might result from the study?
In the future, other people might benefit from this study because if liraglutide reduces body mass 
index of patients with  refractory obesity after vertical sleeve gastrectomy, it might give them a 
new drug option to treat obesity and help reduce the chance of developing complications of obesity.  
WHAT OTHER OPTIONS ARE THERE FOR YOU?
Before you decide whether or not to be in this study, we will discuss other options that are available 
to you. Instead of being in this study, you could continue or intensify behavioral management 
strategies for obesity, or possibly using one of the FDA-approved treatments for obesity in 
adolescents, including liraglutide, the medication we are studying.  Other medications you could 
possibly use are orlistat, approved for those ≥12 years old and phentermine or phentermine plus 
topiramate that are approved for those age 17 years and older.  These medications have not been 
approved by the FDA for use specifically in adolescents who have undergone bariatric operations.  
The other main alternative to this study is not to participate. 
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You may be eligible for other studies at the NIH. You may learn more about them through 
www.clinicaltrials.gov.
DISCUSSION OF FINDINGS
New information about the study
If we find out any new information that may affect your choice to participate in this study, we 
will get in touch with you to explain what we have learned. This may be information we have 
learned while doing this study here at the NIH or information we have learned from other 
scientists doing similar research in other places.
Return of research results
After all participants have completed the study and once the study is fully analyzed, we will let 
you know if liraglutide seemed to help with weight loss and improving metabolic markers of 
obesity. There is no general plan to share your individual test results with you. However, if any 
findings suggest you have a medical issue, we will provide this information to you and your 
primary care provider. You may request a copy of your routine laboratory tests if you desire.
EARLY WITHDRAWAL FROM THE STUDY 
You will be asked to end your participation in the study if you become pregnant, are unable to 
receive liraglutide for 1 week or more, and/or start a different obesity or diabetes medication like 
insulin.  You may also be asked to end your participation in this study at any time if we believe 
that continuation is not in your best medical interest or if you are unable to comply with the 
requirements of the study.  
STORAGE, SHARING AND FUTURE RESEARCH USING YOUR SPECIMENS AND 
DATA
Will your specimens or data be saved for use in other research studies?
As part of this study, we are obtaining specimens and data from you. We will remove all the 
identifiers, such as your name, date of birth, address, or medical record number and label your 
specimens and data with a code so that you cannot easily be identified. However, the code will 
be linked through a key to information that can identify you. We plan to store and use these 
specimens and data for studies other than the ones described in this consent form that are going 
on right now, as well as studies that may be conducted in the future. These studies may provide 
additional information that will be helpful in understanding obesity, or other diseases or 
conditions. This could include studies to develop other research tests, treatments, drugs, or 
devices, that may lead to the development of a commercial product by the NIH and/or its research 
or commercial partners. There are no plans to provide financial compensation to you if this 
happens. Also, it is unlikely that we will learn anything from these studies that may directly 
benefit you.
IRB NUMBER: 000241
IRB APPROVAL DATE: 12/29/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
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File in Section 4: Protocol Consent (1)
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I give permission for my coded specimens and data to be stored and used for future research as 
described above.
_____ Yes
_____ No
Initials
Initials
Will your specimens or data be shared for use in other research studies?
We may share your coded specimens and data with other researchers.  If we do, while we will 
maintain the code key, we will not share it, so the other researchers will not be able to identify 
you.  They may be doing research in areas that are similar to this study or in other unrelated 
areas. These researchers may be at NIH, other research centers and institutions, or commercial 
entities.
I give permission for my coded specimens and data to be shared with other researchers and used 
by these researchers for future research as described above.
_____ Yes 
_____ No
Initials
Initials
If you change your mind and do not want us to store and use your specimens and data for future 
research, you should contact the research team member identified at the top of this document. 
We will do our best to comply with your request but cannot guarantee that we will always be 
able to destroy your specimens and data. For example, if some research with your specimens and 
data has already been completed, the information from that research may still be used. Also, for 
example, if the specimens and data have been shared already with other researchers, it might not 
be possible to withdraw them. 
In addition to the planned use and sharing described above, we might remove all identifiers and 
codes from your specimens and data and use or share them with other researchers for future 
research at the NIH or other places.  When we or the other researchers access your anonymized 
data, there will be no way to link the specimens or data back to you.  We will not contact you to 
ask your permission or otherwise inform you before we do this.  We might do this even if you 
answered "no" to the above questions.  If we do this, we would not be able to remove your 
specimens or data to prevent their use in future research studies, even if you asked, because we 
will not be able to tell which are your specimens or data.
NIH policies require that your clinical and other study data be placed in an internal NIH database 
that is accessible to other NIH researchers for future research. Usually, these researchers will not 
have access to any of your identifiers, such as your name, date of birth, address, or medical 
record number; and your data will be labeled with only a code. We cannot offer you a choice of 
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PATIENT IDENTIFICATION
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whether your data will be placed in this database or not.  If you do not wish to have your data 
placed in this database, you should not enroll in this study.  
How long will your specimens and data be stored by the NIH?
Your specimens and data may be stored by the NIH indefinitely 
Risks of storage and sharing of specimens and data
When we store your specimens and data, we take precautions to protect your information from 
others that should not have access to it. When we share your specimens and data, we will do 
everything we can to protect your identity, for example, when appropriate, we remove information 
that can identify you. Even with the safeguards we put in place, we cannot guarantee that your 
identity will never become known or someone may gain unauthorized access to your information. 
New methods may be created in the future that could make it possible to re-identify your specimens 
and data.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will be compensated for the time and inconvenience associated with participation according 
to NIH research volunteer guidelines. 
Compensation per visit- to be given at the end of each visit
1. Outpatient screening visit:
$50
2. Baseline evaluation visit:
$200
3. Interim Safety Visits (three total):
$75
4. Optional baseline stool collection:
$25
5. Visit 5 
$200
6. Optional end-treatment stool sample
$25
7. Final Visit:
$50
Total=
$575, up to $625
Payments will be sent after the visit either by check or direct deposit.
Guardians accompanying minors will be compensated $40 per visit x 7 visits: $280 which will be 
paid as a lump sum at the completion of the study.  
If you are unable to finish the study, you will receive full compensation for the parts you 
completed.  
With few exceptions, study compensation is considered taxable income that is reportable to the 
Internal Revenue Service (IRS). A “Form 1099-Other Income” will be sent to you if your total 
payments for research participation are $600 or more in a calendar year. If you have unpaid debt 
to the federal government, please be aware that some or all of your compensation may be 
automatically reduced to repay that debt on your behalf.
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
This study does not offer reimbursement for, or payment of, travel, lodging or meals. 
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 
CONFLICT OF INTEREST (COI) 
The NIH reviews NIH staff researchers at least yearly for conflicts of interest.  This process is 
detailed in a COI Guide.  You may ask your research team for a copy of the COI Guide or for more 
information.  Members of the research team who do not work for NIH are expected to follow these 
guidelines or the guidelines of their home institution, but they do not need to report their personal 
finances to the NIH.
No NIH investigator involved in this study receives payments or other benefits from any company 
whose drug, product or device is being tested.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Information on your medical history and laboratory results will be kept in the electronic record 
system (CRIS) of the Clinical Center as well as in special research files in the Section on Growth 
and Obesity. Samples of your blood taken during this study will be kept stored in secure locked 
freezers. Before storing the samples, all identifying information, including your name, date of 
birth and the hospital medical record number, will be removed. The samples will be labeled with 
a code number but no other identifying information. The key to this code along with all other 
private information will be kept confidential and your privacy protected by keeping them in 
secure, locked places. Study documents and pertinent hospital or clinical records may be 
reviewed by qualified monitors within the NICHD quality assurance program. You will be asked 
to supply your social security number in order to be compensated for participation, but your 
social security number is not retained by the protocol study team after it is entered in the NIH 
payment system. You can participate in research but cannot be compensated without supplying 
a social security number.
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:
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PATIENT IDENTIFICATION
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

Qualified representatives from NICHD who audit the study.
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible.  However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons.
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission.  However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections.  
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical information 
that we collect under the authority of the Public Health Service Act.  In some cases, the Privacy 
Act protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy 
IRB NUMBER: 000241
IRB APPROVAL DATE: 12/29/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/10/2022
Page 16 of 17
CC ICF template v. 05.05.20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Act allows release of information from your record without your permission, for example, if it is 
requested by Congress. Information may also be released for certain research purposes with due 
consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting,  to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Jack A. 
Yanovski, MD, PhD; Building 10-CRC Room 1-3330, Telephone: 301-496-0858 Another 
researcher you may call is: Sheila M. Brady, NP, Telephone: 301-451-3783.. You may also call 
the NIH Clinical Center Patient Representative at 301-496-2626, or the NIH Office of IRB 
Operations at 301-402-3713, if you have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 000241
IRB APPROVAL DATE: 12/29/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/10/2022
Page 17 of 17
CC ICF template v. 05.05.20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Parent/Guardian of a Minor Participant: I have read the explanation about this study and have been given 
the opportunity to discuss it and to ask questions. I give permission for my child to take part in this study.
Signature of Parent/Guardian
Print Name of Parent/Guardian
Date
Signature of Parent/Guardian
Print Name of Parent/Guardian
Date
Witness to the oral short-form consent process only: 
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 000241
IRB APPROVAL DATE: 12/29/2022

ICF_004.pdf: 
PATIENT IDENTIFICATION
Assent to Participate in a Clinical Research Study
NIH-2977-1 (7-19)
File in Section 4: Protocol Consent (2)
Version Date: 11/15/2021
Page 1 of 4
CC assent template v. 09.27.19
MEDICAL RECORD
ASSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
Attach to NIH-2977, Consent to Participate in a Clinical Research Study
PRINCIPAL INVESTIGATOR:  Jack A. Yanovski, MD, PhD
STUDY TITLE:  Phase II Trial of Liraglutide (Saxenda(R), Novo Nordisk) in Adolescents with 
Obesity After Sleeve Gastrectomy: A Pilot Open-Label Study 
STUDY SITE: NIH Clinical Center
Cohort: Assent 
Assent Version:  11/15/2021
WHY ARE YOU HERE?
We are asking you to take part in a research study of a study drug.  This is because you still have 
a high body weight after you had sleeve gastrectomy surgery to help reduce your weight.   High 
body weight can cause complications like diabetes (high blood sugar), high blood pressure, and 
high cholesterol level 
Before you decide if you want to be in this study, we want to tell you about what is involved.  
This is so you can ask questions.
Read this paper and ask us questions about anything you do not understand. If you want to read 
more about the study, ask for a copy of the form that your parent will read and sign.
WHY IS THE STUDY BEING DONE?
The study is being done to see how safe the study drug is and how well it works.  The study drug 
is called liraglutide and it is given as a once-a-day subcutaneous injection. Liraglutide is approved 
to treat obesity in patients 12 years and older and to treat type 2 diabetes in patients 10 years and 
older, but it has not yet been studied as a treatment for obesity in teenagers who have had prior 
weight loss surgery.  
WHAT WILL I BE ASKED TO DO?
This study lasts about 28 weeks (7 months). You will need to come to the NIH Clinical Center up 
to 7 times. It starts with a screening visit to find out if you can take part followed by 5 monthly 
visits to check your weight and see how you are feeling.  
Time in weeks
Screening
Visit
~3 hours
Interim Visits
~3 hours
8
Final On-
Medication Visit
~8 hours
1
4
0
12
16
Up to 4 weeks
before baseline
Baseline Visit
~8 hours.
Start study
med
2 3
Weekly dose
increases
as tolerated
28
End Study
Visit
(off medication)
~8 hours
IRB NUMBER: 000241
IRB APPROVAL DATE: 11/19/2021


PATIENT IDENTIFICATION
Assent to Participate in a Clinical Research Study
NIH-2977-1 (7-19)
File in Section 4: Protocol Consent (2)
Version Date: 11/15/2021
Page 2 of 4
CC assent template v. 09.27.19
MEDICAL RECORD
ASSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
Attach to NIH-2977, Consent to Participate in a Clinical Research Study
Below is a list of activities that will occur during your visits:

You will have a fasting blood draw at screening visit, baseline visit, and the final on-
medication visit. Fasting means you can have water but can’t eat or drinking anything 
else for at least 8 hours, but preferably for 10-12 hours, before the blood draw. At two 
visits, you will be asked to drink a sweet drink and have more blood draws (Baseline and 
final on-medication visit).

At all Visits, you will have a medical history and physical exam. The first one will be 
very complete, the rest much shorter, where if you have complaints about your body then 
the study doctor will check that area of your body.

Your vital signs, including blood pressure, heart rate, temperature, and breathing rate will 
be checked at every visit. 

Your weight will be measured at every visit.

The study doctor will ask you questions about your health, appetite, habits, physical 
activity, and sleep patterns at every visit. Some tests about hunger and food will be done 
on the computer.

On two occasions, you will be asked to wear a small watch-like device called an 
accelerometer on your wrist for 2 weeks, except when taking a bath or a shower or when 
taking part in a contact sport. The accelerometer will need to be returned to the team. 

If you are a girl and can get pregnant, you will be asked to take a urine pregnancy test at 
every visit. If your urine test shows you are pregnant then you will have a blood test to 
confirm you are pregnant.

If you want, you might also bring a little bit of your stool or poop with you to two of your 
visits. If you want to do this, we will give you everything you need to get the stool here to 
NIH.

You will have a DXA X-ray test that measures your body muscle and body fat and your 
height will be measured (at Screening or at Baseline Visit and also at Visit 5).

You will be instructed to inject the study drug every day using a small needle just 
under the skin (subcutaneously). This is the way people with diabetes take insulin. Most 
people get used to taking these shots without any problem. If you forget to take the study 
drug, we will ask you not to take the medicine if more than 12 hours have passed since 
you were supposed to take it. Just continue the once daily regimen as prescribed with the 
next scheduled dose.  We will ask that you not take an extra dose or increase the dose to 
make up for the missed dose.  
If you want to do our study, we will give you give you $50 for the Screening and  End Study 
visits, $200 for the Baseline and Final End-Medication visits, and $75 for each of the interim 
visits. If you want to give us a little bit of your stool (poop), we will give you $25 for each of the 
two samples.
You and your caregiver will be asked questions about how you are feeling, your behavior and 
habits during the study.
Girls in this study should not get pregnant.  If you are a girl and you have ever had your period, 
your doctor will discuss this with you.  You will be tested to see if you are pregnant during this 
IRB NUMBER: 000241
IRB APPROVAL DATE: 11/19/2021


PATIENT IDENTIFICATION
Assent to Participate in a Clinical Research Study
NIH-2977-1 (7-19)
File in Section 4: Protocol Consent (2)
Version Date: 11/15/2021
Page 3 of 4
CC assent template v. 09.27.19
MEDICAL RECORD
ASSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
Attach to NIH-2977, Consent to Participate in a Clinical Research Study
study.  If you are pregnant, your doctor may tell your parents.  You should not take part in this 
study if you don’t want a pregnancy test.
CAN BAD THINGS HAPPEN TO ME FROM BEING IN THE STUDY?
You may have new feelings or problems that you have not had before.  Tell your parents and tell 
your study doctor or study site staff if you feel sick during the study.  Tell them if you no longer 
want to be in this study.
Some people who have taken this study medicine before had the following side effects.  You too 
may have these side effects:

You may find that you may have an upset stomach, feel like throwing up, or have trouble 
having a bowel movement. 
You may also have bad effects from some of the study tests:

You may feel a little bit uncomfortable when we measure your blood pressure with a 
tight armband.

It may feel a little uncomfortable to not have anything to eat or drink for at least 10 hours 
before a visit.

You may feel a little bit uncomfortable when you need to lie down on a table to have a 
scan of your body.

When a needle is put in your arm to collect blood, it may hurt, cause a bruise, make you 
feel dizzy, or cause an infection (very rarely).  A numbing cream can be used to lessen 
the pain.

The study doctor or nurse will be asking you questions about how you are feeling.  You 
may not enjoy answering these questions.

You may find wearing the wrist accelerometer inconvenient. If irritation at the site of the 
wrist strap occurs, stop wearing it and contact us.

Other tests may be slightly inconvenient but are not risky – these include giving urine and 
stool samples, having body measurements with a tape measure, filling out diet surveys, 
and eating a meal. You may feel too full or even need to throw up after you eat the meal, 
especially if you eat too quickly.
You may feel other bad effects not listed. You must tell your parents or legal guardian and the 
study doctor if you feel sick or have bad effects.
There is a small amount of radiation used in the X-ray scan of your body.  This is what the 
doctor does to look at your body muscle and body fat. We do not know if this has any effect on 
your health.  The scan does not hurt. For the test, you will lie down on a table while the scanner 
directs X-ray energy towards your body.  This will take 15-20 minutes. Lying on the table may 
feel a little uncomfortable.
WILL BEING IN THE STUDY HELP ME?
IRB NUMBER: 000241
IRB APPROVAL DATE: 11/19/2021


PATIENT IDENTIFICATION
Assent to Participate in a Clinical Research Study
NIH-2977-1 (7-19)
File in Section 4: Protocol Consent (2)
Version Date: 11/15/2021
Page 4 of 4
CC assent template v. 09.27.19
MEDICAL RECORD
ASSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
Attach to NIH-2977, Consent to Participate in a Clinical Research Study

We do not know if being in this study will help you.

The study drug may help reduce your body weight.  
WHO WILL KNOW ABOUT THIS STUDY?
The study is private.  What the study doctor learns about you will be shared with your parents or 
legal guardian.  Scientists working on the study and the part of the government that makes rules 
about medicine will need to see what is learned, but they are not allowed to tell anyone about you.
If any bad effects happen during the study, those effects will be reported to the United States 
government.
DO I HAVE TO BE IN THE STUDY?
You do not have to be in the study if you do not want to.  You can stop at any time and no one will 
be upset with you or your parents.  If you stop being in the study, this will not change the way your 
doctor treats you.
Tell your parents, study doctor or nurse about any parts of the study that make you feel bad.  
The study doctor or nurse will answer any questions you have.
I have had this study explained to me in a way that I understand, I have been given the opportunity 
to discuss it, and I have had the chance to ask questions. I agree to take part in this study.
Assent of Participant: 
________________________________   __________________________   _________________
Signature of Participant                               Print Name of Participant               Date
Investigator: 
________________________________   __________________________   _________________
Signature of Investigator                            Print Name of Investigator            Date
IRB NUMBER: 000241
IRB APPROVAL DATE: 11/19/2021