Lifestyle Counseling and Medication for Adolescent Weight Management
Phase: PHASE2
Conditions: Obesity, Childhood
Sponsor: University of Minnesota

MEDICAL PROTOCOL LVM-001 
PROTOCOL TITLE: Lifestyle Counseling and Medication for Adolescent Weight Management 
VERSION DATE:  12Mar2025 
 
Page 1 of 61 
 
  
 
ANCILLARY REVIEWS 
 
Which ancillary reviews do I need and when do I need them? 
Refer to HRP-309 for more information about these ancillary reviews. 
Select yes or 
no 
Does your study… 
If yes… 
Impact on 
IRB Review 
☐ Yes 
☒ No 
 
Include Gillette resources, staff 
or locations 
Gillette Scientific review and Gillette 
Research Administration approval is 
required.  Contact: 
research@gillettechildrens.com   
Required 
prior to IRB 
submission 
☒ Yes 
☐ No 
Involve Epic, or Fairview 
patients, staff, locations, or 
resources? 
The Fairview ancillary review will be 
assigned to your study by IRB staff 
Contact: ancillaryreview@Fairview.org 
Approval 
must be 
received 
prior to IRB 
committee/ 
designated 
review.   
 
Consider 
seeking 
approval 
prior to IRB 
submission. 
☒ Yes 
☐ No 
Include evaluation of drugs, 
devices, biologics, tobacco, or 
dietary supplements or data 
subject to FDA inspection? 
The regulatory ancillary review will be 
assigned to your study by IRB staff 
Contact: medreg@umn.edu  
 
See: 
https://policy.umn.edu/research/indide  
☐ Yes 
☒ No 
Require Scientific Review? Not 
sure? See guidance on next 
page. 
 
Documentation of scientific merit must 
be provided.   
Contact: hrpp@umn.edu  
☐ Yes 
☒ No 
Relate to cancer patients, 
cancer treatments, cancer 
screening/prevention, or 
tobacco? 
Complete the CPRC application process.  
Contact: ccprc@umn.edu  
☒ Yes 
☐ No 
Include the use of radiation? 
(x-ray imaging, 
radiopharmaceuticals, external 
beam or brachytherapy) 
Complete the AURPC Human Use 
Application and follow instructions on 
the form for submission to the AURPC 
committee. 
Contact: barmstro@umn.edu  
Approval 
from these 
committees 
must be 
received 
prior to IRB 
approval;  
 
These 
groups 
each have 
their own 
☐ Yes 
☒ No 
Use the Center for Magnetic 
Resonance Research (CMRR) 
as a study location? 
Complete the CMRR pre-IRB ancillary 
review  
Contact: ande2445@umn.edu  
☐ Yes 
☒ No 
Include the use of 
recombinant or synthetic 
nucleic acids, toxins, or 
infectious agents? 
Complete the IBC application via 
eprotocol.umn.edu 
Contact: 

MEDICAL PROTOCOL LVM-001 
PROTOCOL TITLE: Lifestyle Counseling and Medication for Adolescent Weight Management 
VERSION DATE:  12Mar2025 
 
Page 2 of 61 
 
☐ Yes 
☒ No 
Include the use of human fetal 
tissue, human embryos, or 
embryonic stem cells? 
Contact OBAO for submission 
instructions and guidance 
application 
process.  
☒ Yes 
☐ No 
Include PHI or are you 
requesting a HIPAA waiver? 
If yes, HIPCO will conduct a review of 
this protocol. 
Contact: privacy@umn.edu  
☒ Yes 
☐ No 
Use data from the Information 
Exchange (IE)? 
The Information Exchange ancillary 
review will be assigned to your study by 
IRB staff 
Contact: ics@umn.edu  
Approval 
must be 
received 
prior to IRB 
approval. 
 
These 
groups do 
not have a 
separate 
application 
process but 
additional 
information 
from the 
study team 
may be 
required. 
 
☐ Yes 
☒ No 
Use the Biorepository and 
Laboratory Services to collect 
tissue for research? 
The BLS ancillary review will be 
assigned to your study by IRB staff. 
Contact: cdrifka@umn.edu  
☐ Yes 
☒ No 
Have a PI or study team 
member with a conflict of 
interest? 
The CoI ancillary review will be 
assigned to your study by IRB staff 
Contact: becca002@umn.edu  
☒ Yes 
☐ No 
Need to be registered on 
clinicaltrials.gov? 
If you select “No” in ETHOS, the 
clinicaltrials.gov ancillary review will be 
assigned to your study by IRB staff 
Contact: kmmccorm@umn.edu  
☒ Yes 
☐ No 
Require registration in 
OnCore? 
If you select “No” or “I Don’t Know” in 
ETHOS, the OnCore ancillary review will 
be assigned to your study by IRB staff 
Contact: oncore@umn.edu  
Does not 
affect IRB 
approval. 
 
 
 
 

MEDICAL PROTOCOL LVM-001 
PROTOCOL TITLE: Lifestyle Counseling and Medication for Adolescent Weight Management 
VERSION DATE:  12Mar2025 
 
Page 3 of 61 
 
PROTOCOL COVER PAGE 
 
 
 
 
Protocol Title 
Lifestyle Counseling and Medication for Adolescent Weight 
Management 
Principal 
Investigator/Faculty 
Advisor 
Name: Aaron S. Kelly, Ph.D. 
Department: Pediatrics; Center for Pediatric Obesity Medicine 
Telephone Number: (612)626-3492 
Email Address: kelly105@umn.edu 
Student 
Investigator 
Name: N/A 
Current Academic Status (Student, Fellow, Resident): N/A 
  
Department: N/A 
Telephone Number: N/A 
Institutional Email Address: N/A 
Scientific 
Assessment 
Nationally-based, federal funding organizations 
IND/IDE # (if 
applicable) 
158542 
IND/IDE Holder 
Aaron S. Kelly, Ph.D. 
Investigational Drug 
Services # (if 
applicable) 
5875 
Version 
Number/Date: 
Version 21.0, 12Mar2025 
 

MEDICAL PROTOCOL LVM-001 
PROTOCOL TITLE: Lifestyle Counseling and Medication for Adolescent Weight Management 
VERSION DATE:  12Mar2025 
 
Page 4 of 61 
 
 
REVISION HISTORY 
 
Revision # 
Version Date 
Summary of Changes 
Consent Change? 
1 
2.0 
Changes the drug being utilized in 
this study from Liraglutide to 
Semaglutide and revises the 
titration schedule and the 
expected adverse events.  
Modifies the BMI eligibility 
criterion by moving down to the 
95th percentile.  Moved the 
collection of demographic 
information to the screening visit.  
Adds review of GI symptom 
assessment to each visit.  
Reorganizes format of secondary 
outcomes and the statistical 
analysis section for enhanced 
clarity.  Urine pregnancy tests will 
now be conducted only at visits 
where an iDXA will be performed. 
Yes 
2 
3.0 
Revision to trial design: reduction 
of treatment period from two 
years to one year; reduction in 
sample size from 140 to 120.   
Adds details related to safety. 
Yes 
3 
4.0 
Addition of monitoring for effects 
of concomitant oral medications 
No 
4 
5.0 
Revises the recruitment section to 
note the use of social media pages. 
No 
5 
6.0 
Adds in neurobehavioral 
assessments and revises the 
subject compensation for these 
assessments. 
Yes 
6 
7.0 
Adds in information about the 
shortage of semaglutide (Wegovy) 
and our plan to utilize semaglutide 
(Ozempic) in the titration doses of 
0.25, 0.5 and 1.0 mg until the 
shortage has resolved.  There is no 
supply shortage of semaglutide 
(Wegovy) at doses above 1.0 mg; 
No 

MEDICAL PROTOCOL LVM-001 
PROTOCOL TITLE: Lifestyle Counseling and Medication for Adolescent Weight Management 
VERSION DATE:  12Mar2025 
 
Page 5 of 61 
 
therefore, semaglutide (Ozempic) 
will only be used at these lower 
titration doses; participants 
progressing beyond 1.0 mg will 
then utilize our stock of 
semaglutide (Wegovy) for doses 
>1.0 mg. An information sheet for 
parents has been created as well 
as instructions for the use of 
Ozempic. 
7 
8.0 
Updates sections 5.3 and 14.6 of 
the protocol to note Dr. Gross’ 
expanded role in the project now 
that she has received NIH funding 
to perform a neurobehavioral 
substudy that has been embedded 
into this project. 
Yes 
8 
9.0 
Revises the protocol to note how 
long the research records and 
HIPAA records will be retained 
after completion of the research 
Yes 
9 
10.0 
Revises section 14.1 risk to 
participants, revises section 14.5 
definition of serious adverse 
event, adds in section 14.6 
definition of adverse reaction, 
adds in section 14.7 definition of 
serious adverse reaction, adds in 
section 14.8 definition of SUSAR, 
revises section 14.10 to revise the 
reporting of adverse events, 
updates the protocol references. 
No 
10 
11.0 
Notes that the study medication 
has now been approved for use in 
adolescents 12 and older by the 
FDA. 
Yes 
11 
12.0 
Revises Table 3 to update module 
categories and topics and note 
that participants randomized to 
the lifestyle therapy arm will 
receive items to foster eating 
changes. 
Yes 

MEDICAL PROTOCOL LVM-001 
PROTOCOL TITLE: Lifestyle Counseling and Medication for Adolescent Weight Management 
VERSION DATE:  12Mar2025 
 
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12 
13.0 
Corrects the schedule of events 
(pregnancy testing is no longer 
done at screening since protocol 
version 2.0) and updates the 
notifications to include the NIH 
when serious adverse events 
occur. 
 
No 
13 
14.0 
Revises the process for conducting 
the re-consent process. 
No 
14 
15.0 
Revises section 5.1 of the protocol.  
 
Adds a hemoglobinA1c to the 
screening visit.  Updates the 
schedule of events to reflect this 
and section 9.0 of the protocol. 
 
Revises section 12.3 of the 
protocol to note that we are 
working with the medical school 
for a Google ad campaign.  Adds a 
hemoglobin A1c to the screening 
visit We are submitting the ad text 
and pictures that will be utilized.  
Yes 
15 
16.0 
Clarifies the study exclusion 
criteria.  
 
16 
17.0 
Corrects the footer of the schedule 
of events with regard to the 
Hemoglobin A1c 
No 
17 
18.0 
Adds the Accessibility survey to 
the visit at Week 26 
Yes 
18 
19.0 
Revises section 13.1 of the 
protocol to clarify that, in line with 
the intent-to-treat nature of the 
study, participants in the 
medication arm are allowed to 
stop taking study medication but 
remain on study and allowed to re-
start study medication if they 
choose. 
 
Adds in and EDE-Q questionnaire 
to ask about eating behaviors. 
Yes 

MEDICAL PROTOCOL LVM-001 
PROTOCOL TITLE: Lifestyle Counseling and Medication for Adolescent Weight Management 
VERSION DATE:  12Mar2025 
 
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19 
20.0 
Adds in adjusted language about 
suicidal behavior and suicidal 
ideation 
Yes 
20 
21.0 
Revises section 6.0 of the protocol 
with regards to exploratory 
biomarker sampling tests to be 
undertaken.  The study will now 
use biomarker samples to measure 
brain inflammation with a test that 
studies brain derived exomes.  The 
schedule of events has been 
updated to note this and section 
5.3 of the protocol has been 
updated. 
No 
 
 
 

MEDICAL PROTOCOL LVM-001 
PROTOCOL TITLE: Lifestyle Counseling and Medication for Adolescent Weight Management 
VERSION DATE:  12Mar2025 
 
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Table of Contents 
 
1.0 
Objectives 
10 
2.0 
Background 
10 
3.0 
Study Endpoints/Events/Outcomes 
14 
4.0 
Study Intervention(s)/Investigational Agent(s) 
20 
5.0 
Procedures Involved 
25 
6.0 
Data and Specimen Banking 
30 
7.0 
Sharing of Results with Participants 
30 
8.0 
Study Population 
30 
10.0 Local Number of Participants 
37 
11.0 Local Recruitment Methods 
37 
12.0 Withdrawal of Participants 
39 
13.0 Risks to Participants 
39 
14.0 Potential Benefits to Participants 
43 
15.0 Statistical Considerations 
43 
16.0 Health Information and Privacy Compliance 
50 
17.0 Confidentiality 
53 
18.0 Provisions to Monitor the Data to Ensure the Safety of Participants 
53 
19.0 Provisions to Protect the Privacy Interests of Participants 
55 
20.0 Compensation for Research-Related Injury 
55 
21.0 Consent Process 
55 
22.0 Setting 
56 
23.0 Multi-Site Research 
57 
24.0 Coordinating Center Research 
57 
25.0 Resources Available 
57 
26.0 References 
57 
 

MEDICAL PROTOCOL LVM-001 
PROTOCOL TITLE: Lifestyle Counseling and Medication for Adolescent Weight Management 
VERSION DATE:  12Mar2025 
 
Page 9 of 61 
 
ABBREVIATIONS/DEFINITIONS 
AE 
Adverse Event 
AEBQ 
Adult Eating Behavior Questionnaire 
AHC 
Academic Health Center 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BIS/BAS 
Behavioral Avoidance System/Behavioral Approach System Scales 
BMI 
Body mass index 
BRIEF-SR 
Behavior Rating Inventory of Executive Functions-Self Report 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CDC 
Centers for Disease Control 
CEBQ 
Child Eating Behavior Questionnaire 
CI 
Confidence Interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CPOM 
Center for Pediatric Obesity Medicine 
CRF 
Case Report Form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTSI 
Clinical and Translational Science Institute 
DEBQ 
Dutch Eating Behavior Questionnaire 
DCRU 
Delaware Clinical Research Unit 
DHEAS 
Dehydroepiandrosterone Sulfate 
DSMB 
Data and Safety Monitoring Board 
EDE-Q 
Eating Disorder Examination Questionnaire 
FDA 
Food and Drug Administration 
FSH 
Follicular Stimulating Hormone 
GI 
Gastrointestinal 
GLP1-RA 
GLP-1 Receptor Agonist 
HIPAA 
Health Insurance Portability and Accountability Act 
HIPCO 
Health Information Privacy and Compliance Office 
DXA 
Dual Energy X-ray Absorptiometry 
IND 
Investigational New Drug 
ITT 
Intention to Treat 
IWQOL-Kids 
Impact of Weight on Quality of Life-Kids 
LDL 
Low-density Lipoproteins 
LH 
Luteinizing Hormone 
MCMC 
Markov Chain Monte Carlo 
MN-POC 
Minnesota Pediatric Obesity Consortium 
MEN-2 
Multiple Endocrine Neoplasia Type 2 
mSv 
Millisievert 
MTC 
Medullary Thyroid Carcinoma 
NHANES 
National Health and Nutrition Examination Survey 
NIDDK 
National Institute of Diabetes and Digestive and Kidney Diseases 
NIH 
National Institutes of Health 
PAQ-A 
Physical Activity Questionnaire for Adolescents 
Peds QL 
Peds Quality of Life 
PHQ-9 
Peds Health Questionnaire – 9 
PROMIS-29 
Patient-Reported Outcomes Measurement Information System 
QEWP-A 
Questionnaire of Eating and Weight Patterns 
QOL 
Quality of Life 
RED-5 
Reward Based Eating Drive Scale X5 (Hedonic Eating) 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
UPIRTSO 
Unanticipated Problem Involving Risk to Subjects or Others 
TSH 
Thyroid Stimulating Hormone 
U.S. 
United States 
USPSTF 
U.S. Preventive Services Task Force 
WTP 
Willingness to Pay 
 
 
 

MEDICAL PROTOCOL LVM-001 
PROTOCOL TITLE: Lifestyle Counseling and Medication for Adolescent Weight Management 
VERSION DATE:  12Mar2025 
 
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1.0 
Objectives 
The prevalence of adolescent obesity (defined as BMI ≥95th percentile) is at an all-time high in 
the U.S. (~20%),1 and the refractory nature of this disease has led to a serious and challenging 
conundrum in terms of how to provide effective, safe, scalable, and durable treatments without 
placing undue strain on the healthcare system.  Clinical practice guidelines recommend 
behavioral interventions as the primary strategy for all ages and classes of obesity – moderate 
to severe.2,3  In 2017, the U.S. Preventive Services Task Force (USPSTF) released updated 
screening recommendations concluding that comprehensive, intensive behavioral interventions 
with a total of ≥26 contact hours over a period of 2-12 months resulted in weight loss in youth 
with obesity, with ≥52 contact hours leading to even greater weight loss and improvements in 
some cardiometabolic risk factors.4,5    
 
However, the practicality of delivering these types of intensive behavioral services to the 
millions of youth with obesity in the U.S. is debatable not only because of the treatment-
resistant nature of obesity,6-10 but also due to the time-commitment, acceptability, and 
sustainability of this approach for adolescent patients and their families along with the extensive 
resources required to provide these interventions.  Indeed, fewer than 50% of pediatric patients 
referred for weight management services enroll in treatment, and high attrition rates of up to 
50% have been reported in behavioral-based clinical trials and in the clinical setting.6,10-15   
Moreover, adherence to behavioral counseling significantly diminishes over time, which too 
often erodes early weight loss success and ultimately derails durability.16  The reality of what 
most patients/families are able to do and the unique physiological and psychosocial features of 
obesity in adolescence do not seem to align well with the degree of intensity of behavioral 
interventions shown to be effective by the USPSTF.  Therefore, a critical appraisal of the 
feasibility, effectiveness, and sustainability of the USPSTF recommendations among adolescents 
with obesity is warranted.  
 
While behavior change is an indispensable component of any effective weight loss approach, 
adjunctive strategies such as pharmacotherapy may enhance outcomes in adolescents with 
obesity.  Many maladaptive behaviors attributed to obesity are driven by underlying biological 
forces, such as increased appetite and food palatability, that are largely beyond the control of 
the individual.17  Pharmacotherapy can help facilitate behavior change by disrupting core 
pathophysiological processes and restoring homeostasis to the energy regulatory system,18 
therein enabling individuals to sustain healthy behavior change.  Though underexplored as a 
treatment for adolescent obesity, pharmacotherapy along with relatively low-intensity 
behavioral counseling (<26 contact hours) represents a potentially effective, durable, and safe 
treatment strategy.  This approach may be more practical and feasible to implement on a broad 
scale, be preferred by patients/families, utilize fewer healthcare resources, and cost less to 
deliver compared to comprehensive, intensive behavioral interventions. 
 
We will conduct a two-arm, randomized clinical trial in adolescents ages 12 to <18 years old with 
obesity evaluating 56 weeks (one year) of intensive behavioral counseling, aligned with the 

MEDICAL PROTOCOL LVM-001 
PROTOCOL TITLE: Lifestyle Counseling and Medication for Adolescent Weight Management 
VERSION DATE:  12Mar2025 
 
Page 11 of 61 
 
USPSTF recommendations (52 contact hours), vs. 56 weeks of medical management with 
semaglutide 2.4 mg weekly subcutaneous injection (glucagon-like peptide-1 receptor agonist) 
plus relatively low-intensity behavioral counseling (12 contact hours). 
2.0 
Background  
2.1 
Significance of Research Question/Purpose:  
The significance of the proposed work is underscored by: 1) the seriousness and 
prevalence of adolescent obesity; 2) the large treatment gap and paucity of 
effective non-surgical treatment options for this high-risk patient population; 3) 
the need for safe and effective medications to aid in obesity management; and 
4) the pragmatic alternative treatment approach we plan to investigate.4,5  The 
progressive, unrelenting, and recalcitrant nature of obesity demands that 
appropriately-intensive interventions be initiated earlier in life, not later in 
adulthood when adiposity and co-morbidities have become entrenched and 
multisystem physiological decompensation has commenced.  Indeed, excess 
adiposity during childhood is a strong predictor of later development of adverse 
cardiovascular outcomes and type 2 diabetes; however, remission of obesity 
prior to adulthood portends favorable health outcomes.19-23 Moreover, there 
appears to be a narrow window of opportunity in childhood during which BMI 
trajectory can be altered to offer a reasonable opportunity for these youth to 
achieve a healthy BMI in adulthood.24  Early and effective intervention likely 
offers the best chance to improve the long-term health outlook for youth with 
obesity.   
 
There is a need to investigate promising non-surgical treatments that can 
augment the beneficial effects of behavioral counseling and potentially enhance 
durability.  Indeed, one of the conclusions of the evidence review commissioned 
by the USPSTF recommendations stated that: “The clinical significance of the 
small benefit of medication use is unclear.”5  However, in this systematic 
review/meta-analysis, only metformin and orlistat were examined – both of 
which have lower weight loss efficacy as compared to semaglutide.  Hence, the 
rationale and significance of our project, aimed at characterizing the 
effectiveness and safety of pharmacotherapy for youth, is in large part driven by 
a key unanswered question posed by the USPSTF.  Since pharmacotherapy can 
target the underlying biology of obesity (e.g. reduce appetite), we believe the 
rationale for investigating its utility is strong and is consistent with treatment 
approaches for other pediatric chronic diseases.  We expect to observe BMI 
reduction in both groups, but anticipate superior BMI reduction, reasonably 
equivalent safety, and better participant disposition outcomes and cost-
effectiveness in the pharmacotherapy group.    
 
As noted, weight reduction is expected in both groups.  At the same time we 
expect significant heterogeneity in weight loss response and maintenance to 
both treatment options.  Identifying predictors of response would allow for 

MEDICAL PROTOCOL LVM-001 
PROTOCOL TITLE: Lifestyle Counseling and Medication for Adolescent Weight Management 
VERSION DATE:  12Mar2025 
 
Page 12 of 61 
 
matching adolescents to personally effective interventions, thereby optimizing 
outcomes and minimizing unnecessary exposure to potential risks.  Emerging 
evidence in adolescents shows that aspects of executive functioning, including 
inhibition, may improve following behavioral interventions/lifestyle modification 
therapy (LMT) and that enhanced inhibition can predict weight loss response to 
LMT.  Newer anti-obesity medications, such as glucagon-like peptide-1 receptor 
agonists (GLP-1RAs), decrease activation in reward related regions of the brain in 
response to food cutes.  Currently, it is unclear what neurobehavioral factors 
predict weight loss maintenance to LMT or pharmacotherapy, which is the 
ultimate goal of treatment.  Identifying neurobehavioral predictors of initial 
weight loss response and weight loss maintenance will stimulate needed 
progress in the emerging field of precision medicine. 
 
2.2 
Preliminary Data: 
The following studies from our group, along with evidence from the literature, 
provide the background and rationale for our proposed project and have 
informed the design of our clinical trial detailed in this protocol. 
 
Pilot and Feasibility Crossover Trial of GLP-1RA in Adolescents with Severe Obesity 
We conducted a pilot/feasibility trial to evaluate the effects of the GLP-1RA 
exenatide on BMI (primary endpoint), cardiometabolic risk factors, and glucose 
tolerance in adolescents with severe obesity.25 Twelve youth (9-16 years old) 
were enrolled in a six-month, randomized, open-label, crossover, clinical trial 
consisting of two, three-month phases: 1) a control phase of behavioral 
counseling and 2) a medication phase of behavioral counseling plus exenatide.  
Participants were randomized to phase-order (i.e., starting with control or 
medication) then crossed-over to the other treatment.  Outcomes were assessed 
at baseline, three months, and six months.  Results are shown in Table 1.  The 
control-subtracted treatment effect was approximately 5% BMI reduction.  
Compliance with the injection regimen was excellent (≥94%) and exenatide was 
generally well-tolerated.   The most common adverse event was nausea, which 
was experienced in 4/11 (all classified as mild).  Vomiting (3/11) and headache 
(3/11) were the second most common adverse events (all categorized as mild).   
 
 

MEDICAL PROTOCOL LVM-001 
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VERSION DATE:  12Mar2025 
 
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Table 1.  Treatment Effects Within and Between Study Arms (values presented are mean (SD)) 
 
Randomized, Placebo-Controlled Pilot Clinical Trial of GLP-1RA in Adolescents 
with Severe Obesity 
Based on the promising results of our first pilot trial, we performed a larger study 
with a more rigorous design (randomized, double-blind, placebo-controlled trial 
with a three-month open label extension) to evaluate the effects of the GLP-1RA 
exenatide on BMI and cardiometabolic risk factors in adolescents with severe 
obesity.26  Twenty-six adolescents (age 12-19 years) were enrolled.  All patients 
received behavioral counseling and were equally randomized to exenatide or 
placebo injection, twice per day.  The primary endpoint was the mean percent 
change in BMI measured at baseline and three-months.  Twenty-two patients 
completed the trial.  We assessed the medium-term durability of the BMI 
reduction by performing an extension phase during which all participants 
(regardless of initial assignment) were offered open-label exenatide.  BMI 
trajectories are shown in Figure 1.   
 
 
Outcome 
Δ Control 
Δ Exenatide 
Treatment Effect (95% CI) 
P-value 
BMI (kg/m2) 
0.84 (1.28) 
-0.90 (1.22) 
-1.71 (-3.01, -0.42) 
0.010 
Percent Change BMI 
1.72 (4.19) 
-2.57 (3.46) 
-4.92 (-8.61, -1.23) 
0.009 
Weight (kg) 
2.97 (2.88) 
-0.99 (2.90) 
-3.90 (-7.11, -0.69) 
0.017 
Body Fat (%) 
0.92 (2.75) 
-0.36 (3.07) 
-1.28 (-4.66, 2.09) 
0.457 
SBP (mmHg) 
3.10 (8.72) 
-3.11 (8.51) 
-5.31 (-14.89, 4.27) 
0.277 
HDL (mg/dL) 
-0.20 (6.84) 
3.44 (3.40) 
3.25 (-2.47, 8.97) 
0.266 
Triglycerides (mg/dL) 
-4.22 (37.45) 
-9.89 (41.24) 
-12.57 (-59.41, 34.28) 
0.599 
Glucose (mg/dL) 
1.60 (6.40) 
3.22 (5.85) 
1.68 (-3.65, 7.01) 
0.537 
Glucose AUC (per 100) 
11.69 (29.50) 
-17.67 (22.98) 
-27.96 (-56.51, 0.59) 
0.055 
Insulin (mU/L) 
6.00 (5.58) 
-1.62 (8.42) 
-7.54 (-13.71, -1.37) 
0.017 
Insulin AUC (per 100) 
30.29 (98.76) 
-38.95 (73.74) 
-76.01 (-166.30, 14.28) 
0.099 
WBISI/Matsuda 
-2.00 (3.52) 
4.12 (7.10) 
6.13 (1.01, 11.25) 
0.019 
b-Cell Function 
-1.16 (6.33) 
14.50 (26.09) 
17.97 (1.40, 34.54) 
0.034 
 

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PROTOCOL TITLE: Lifestyle Counseling and Medication for Adolescent Weight Management 
VERSION DATE:  12Mar2025 
 
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Figure 1. Percent Change in BMI during the Randomized, Placebo-Controlled and Open Label 
Phase 
 
 
Compared to placebo, GLP-1RA treatment reduced BMI by approximately 3% at 
three months (see Table 2).  Of note, during the open label extension, BMI 
continued to decrease in participants initially randomized to exenatide 
(cumulative BMI reduction of 4%).  Compliance was excellent and ranged from 
85-100% of the required doses; mean = 95%.  The most common adverse events 
(all mild-moderate and transient) were nausea (placebo 31%, exenatide 62%), 
abdominal pain (placebo 23%, exenatide 15%), diarrhea (placebo 31%, exenatide 
8%), headache (placebo 46%, exenatide 23%), and vomiting (placebo 8%, 
exenatide 31%).  The findings of this pilot trial provided additional evidence 
supporting the feasibility, safety, and efficacy of GLP-1RA treatment in 
adolescents with severe obesity. 
 
 

MEDICAL PROTOCOL LVM-001 
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VERSION DATE:  12Mar2025 
 
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Table 2.  Change from Baseline to Three Months for the Primary and Secondary Endpoints 
(values presented are mean (SD)) 
 
 
Large Safety and Efficacy Trial of GLP-1RA in Adolescents with Obesity 
In this randomized, double-blind trial, which consisted of a 56-week treatment 
period and a 26-week follow-up period, adolescents (12 to <18 years 
of age) with obesity and a suboptimal response to lifestyle therapy alone were 
enrolled.27  Participants were randomly assigned (1:1) to receive either liraglutide 
(3.0 mg) or placebo subcutaneously once daily, in addition to lifestyle therapy. 
The primary end point was the change from baseline in the body-mass index 
(BMI; the weight in kilograms divided by the square of the height in meters) 
standard-deviation score at week 56.  A total of 125 participants were assigned 
to the liraglutide group and 126 to the placebo group. BMI and weight-related 
outcomes are shown in Figure 2.  Liraglutide was superior to placebo with regard 
to the change from baseline in the BMI standard-deviation score at week 56 
(estimated difference, −0.22; 95% confidence interval [CI], −0.37 to −0.08; P = 
0.002). A reduction in BMI of at least 5% was observed in 51 of 113 participants 
in the liraglutide group and in 20 of 105 participants in the placebo group 
(estimated percentage, 43.3% vs. 18.7%), and a reduction in BMI of at least 10% 
was observed in 33 and 9, respectively (estimated percentage, 26.1% vs. 8.1%). 
A greater reduction was observed with liraglutide than with placebo for BMI 
(estimated difference, −4.64 percentage points) and for body weight (estimated 
difference, −4.50 kg [for absolute change] and −5.01 percentage points [for 
relative change]). After discontinuation, a greater increase in the BMI standard-
deviation score was observed with liraglutide than with placebo (estimated 
difference, 0.15; 95% CI, 0.07 to 0.23). More participants in the liraglutide group 
than in the placebo group had gastrointestinal adverse events (81 of 125 [64.8%] 
vs. 46 of 126 [36.5%]) and adverse events that led to discontinuation of the trial 
treatment (13 [10.4%] vs. 0). Few participants in either group had serious adverse 
events (3 [2.4%] vs. 5 [4.0%]). One suicide, which occurred in the liraglutide 
Covariate 
N 
Exenatide Δ 
Control Δ 
Estimate (95% CI) 
P-value 
Percent Change BMI 
22 
-2.90 (1.80) 
-0.15 (3.20) 
-2.70 (-5.02, -0.37) 
0.025 
BMI (kg/m2) 
22 
-1.18 (0.67) 
-0.04 (1.23) 
-1.13 (-2.03, -0.24) 
0.015 
Weight (kg) 
22 
-2.93 (2.48) 
0.32 (3.21) 
-3.26 (-5.87, -0.66) 
0.017 
Waist (cm) 
22 
-2.04 (2.62) 
-1.01 (5.57) 
-0.98 (-4.60, 2.64) 
0.579 
Total Tissue Fat (kg) 
15 
-1.69 (2.41) 
-0.65 (2.50) 
-0.72 (-3.66, 2.23) 
0.610 
Visceral Fat Area (cm2) 
14 
-97.00 (191.22) 
-18.17 (178.62) 
-78.15 (-309.55, 153.25) 
0.473 
SBP (mmHg) 
22 
-5.50 (9.13) 
2.00 (13.43) 
-6.36 (-13.46, 0.73) 
0.076 
HDL-cholesterol (mg/dL) 
22 
-0.42 (4.08) 
-3.00 (5.12) 
2.08 (-1.82, 5.99) 
0.278 
Triglycerides (mg/dL) 
22 
2.83 (53.69) 
3.90 (44.41) 
-4.71 (-45.14, 35.72) 
0.810 
Glucose (mg/dL) 
22 
1.17 (8.19) 
4.60 (9.51) 
-3.33 (-9.71, 3.05) 
0.288 
Insulin (mU/L) 
22 
-8.33 (18.81) 
0.67 (7.43) 
-2.91 (-10.91, 5.10) 
0.455 
HbA1c (%) 
22 
-0.12 (0.16) 
-0.01 (0.14) 
-0.11 (-0.23, 0.01) 
0.072 
 

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group, was assessed by the investigator as unlikely to be related to the trial 
treatment.  In adolescents with obesity, the use of liraglutide (3.0 mg) plus 
lifestyle therapy led to a significantly greater reduction in the BMI standard-
deviation score than placebo plus lifestyle therapy. 
 
Figure 2.  BMI and Weight-Related Outcomes with Liraglutide in Adolescents with Obesity 
 
 
Safety and Efficacy of GLP-1RA in Adults 
One of the largest phase III clinical trials of semaglutide 2.4 mg weekly  in adults 
(N=1,961) demonstrated a mean placebo-subtracted body weight reduction of 
12.4% at 68 weeks.28  Figure 3 shows the body weight trajectories and the percent 
achieving 5%, 10%, 15%, and 20% weight loss of the placebo and semaglutide 
groups, both of which received behavioral counseling.   
 
 

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Figure 3.  Weight Outcomes in Adults Treated with Semaglutide 2.4 mg Weekly or Placebo42 
 
 
 
The most frequently-reported adverse events with semaglutide were 
gastrointestinal in nature - mild or moderate nausea and diarrhea were 
predominantly experienced in the up-titration period.28 Serious adverse events 
occurred in 9.8% of the participants receiving semaglutide and 6.4% in those 
receiving placebo.28  These data support our hypothesis that, other than GI 
symptoms, side effects will be similar between groups.   
 
 

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Outcomes of Behavioral Interventions in Youth with Obesity 
In 2017, the USPSTF released updated screening recommendations concluding 
that comprehensive, intensive behavioral interventions with a total of ≥26 
contact hours over a period of 2-12 months resulted in weight loss in youth with 
obesity, with ≥52 contact hours leading to even greater weight loss and 
improvements in some cardiometabolic risk factors.4,5  Figure 4 shows the 
change in BMI in various trials summarized in the USPSTF report.5  Results from 
these trials have informed our anticipated treatment effect estimates presented 
in the statistical analysis plan elsewhere in the protocol.   
 
Figure 4. BMI Reduction with Behavioral Intervention 
 
 
 
Frequency of Contact in Multidisciplinary Pediatric Weight Management 
Programs 
The frequency of contact for the semaglutide plus low-intensity behavioral 
counseling group (12 contact hours) was chosen to reflect what is generally 
considered practical in the real-world clinical setting.  Data collected on program 
profiles from over 30 multidisciplinary pediatric weight management clinics 
throughout the U.S. reported that most (52%) programs offered <25 contact 
hours; only 17% offered contact hours between 25-75 hours.29  Results from the 
large registry study stemming from this collaborative network demonstrated that 
there was a dose-dependent relationship in BMI reduction (expressed as change 
in BMI percent of the 95th percentile) such that outcomes were best in patients 
who received ³7 contact hours.10  Many programs offer approximately monthly 

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provider-patient contact averaging 12 hours per year.  Therefore, we have 
chosen to mimic the approximate number of contact hours that are commonly 
offered in multidisciplinary pediatric weight management programs.   
 
In summary, this portfolio of preliminary work: 1) demonstrates our Center’s 
experience and leadership role in the field of pediatric obesity medicine, and the 
GLP-1RA class in particular; 2) highlights the refractory nature of adolescent 
obesity; 3) demonstrates heterogeneity in treatment response; 4) provides 
evidence of the safety/efficacy of GLP-1RAs in adolescents and in adults; and 5) 
sets the stage for taking this next important step. 
 
3.0 
 
Study Endpoints/Events/Outcomes 
3.1 
Primary Endpoint/Event/Outcome:  
Compare the effectiveness of intensive behavioral counseling vs. medical 
management plus low-intensity behavioral counseling on mean percent change 
in BMI from baseline to 56 weeks of follow-up in adolescents with obesity.  We 
hypothesize that semaglutide 2.4 mg weekly plus low-intensity behavioral 
counseling will elicit superior reductions in BMI (primary efficacy endpoint) 
compared to intensive behavioral counseling at 56 weeks (primary outcome 
assessment timepoint).     
 
3.2 
Secondary Endpoint(s)/Event(s)/Outcome(s):  
3.2.1 Compare the effectiveness of intensive behavioral counseling vs. medical 
management plus low-intensity behavioral counseling on body fat, 
cardiometabolic risk factors, and quality of life in adolescents with 
obesity.  We hypothesize that semaglutide 2.4 mg weekly plus low-
intensity behavioral counseling will elicit superior reductions in body fat 
and greater improvements in cardiometabolic risk factors and quality of 
life compared to intensive behavioral counseling at 56 weeks (primary 
outcome assessment timepoint). 
 
3.2.3 Compare the number of adverse events (AEs) and safety outcomes for 
intensive behavioral counseling vs. medical management plus low-
intensity behavioral counseling in adolescents with obesity.  We 
hypothesize that the number of gastrointestinal-related AEs will be higher 
in those randomized to semaglutide, but that changes in other safety 
outcomes will be approximately equal between the groups. 
 
3.2.4 Evaluate the implementation feasibility of the strategies by assessing 
acceptability, adherence, rate of attrition, and cost-effectiveness.  We 
hypothesize that the semaglutide plus low-intensity behavioral 
counseling will have a higher rate of acceptability and adherence, lower 
rate of attrition, and will be more cost-effective as compared to intensive 
behavioral counseling.   

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3.3 
Tertiary Endpoint(s): Neurobehavioral Predictors of Response 
 
3.3.1 Identify baseline neurobehavioral predictors of weight loss response in 
adolescents with obesity undergoing intervention. 
 
 
3.3.2 For participants achieving >5% BMI reduction at 6 months (i.e., initial 
responders), identify neurobehavioral predictors of weight loss maintenance at 
12 months. 
 
 
3.3.3 Evaluate differences in predictors of response between intensive LMT and 
GLP-1RA therapy. 
 
4.0 
Study Intervention(s)/Investigational Agent(s) 
4.1 Description:  
Behavioral Intervention 
The comprehensive behavioral intervention for both groups (intensive behavior 
group and medication group) will be designed and delivered according to the 
principles and components detailed in the evidence report and systematic review 
commissioned by the USPSTF.5  Participants assigned to the intensive behavioral 
intervention group will engage in weekly sessions for a total of 52 contact hours 
including biweekly (twice per month) in-person group sessions plus bi-weekly 
virtual sessions consisting of a self-paced online module with an accompanying 
individual counseling virtual/phone session,  for a total of one hour of contact every 
week.  Participants assigned to the medication group will also receive behavioral 
counseling, with the same content and structure as that of the intensive group, but 
delivered with lower frequency.  Participants will receive a total of 12 contact hours 
including six in-person group sessions plus six online modules accompanied by an 
individual virtual/phone counseling session, for a total of one hour of contact every 
four weeks.  The rationale for the frequency of contact in both groups is that 
obesity, as a chronic and relapsing disease, necessitates a chronic care model.30, 31     
 
In the spirit of generalizability and in consideration of cost-effectiveness and 
implementation feasibility, almost all in-person sessions will be group-based and 
include only the participants.  It should be noted that the USPSTF 
recommendations encompass both group and individual session strategies (i.e., 
the recommendations apply to either of the two approaches).  In-person sessions 
will 
involve 
the 
adolescent 
participants 
only 
(without 
a 
parent/guardian/caretaker).  However, acknowledging the potential for 
meaningful developmental differences in younger participants, and the variable 
role of parents in creating the proper conditions for aiding in weight management, 
we will encourage all parents/guardians/caretakers for both groups to complete a 
parent-specific self-paced virtual session at the beginning of each module that will 
specifically address how to be supportive with the current topic. All 
parents/guardians/caretakers will also attend the first in-person session with their 

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child at the time of their child’s enrollment and will receive regular communication 
regarding 
programming 
and 
content 
of 
the 
in-person 
sessions. 
Parents/guardians/caretakers will only be required to attend the virtual/phone 
sessions with their child if he/she is 13 years old or younger.  
 
The behavioral program will be based on state-of-the-art interventions conducted 
by members of the study team8, 32-36 and others.37-41  Curriculum will incorporate 
evidence-based behavior change principles, which will include four macro 
components: dietary modification, energy expenditure modification, behavior 
modification, and family involvement and support.  The intervention focuses on: 1) 
dietary intake changes; 2) increases in physical activity and reductions in sedentary 
behavior; and 3) behavior change strategies to facilitate adherence to the diet and 
activity change recommendations. The core intervention is based on a behavioral 
conceptualization of effective weight management that emphasizes: 1) identifying 
behaviors in need of change; 2) setting goals for change; 3) monitoring progress; 4) 
modifying environmental cues to facilitate change; and 5) modifying consequences 
to motivate change. The intervention will incorporate core behavior change 
strategies including self-monitoring, stimulus control, modeling, goal setting, and 
positive reinforcement.  Each session will follow a general format including a review 
of progress, new material, supervised interactive activities, and a summary/plan 
for the upcoming week.  By design, the intensive group will have repetition and 
overlap of curriculum.  Owing to the reduced contact time for the medication 
group, less of the content will be repeated.  Therefore, curriculum for the 
medication group will include the same principles and components as outlined 
below, but will be delivered in a distilled and less-redundant fashion. 
   
Sample details of curriculum components along with the frequency of delivery for 
the intensive group are shown in Table 3.  Although USPSTF recommendations 
were written to encompass all ages, we will tailor session curriculum components 
to address the unique developmental needs of teens.  For example, topics will 
include shared-decision making among parents and adolescents and fostering 
independence with appropriate oversight.  Topics related to social support and 
problem-solving will include examples of maintaining healthy goals and how to 
resist peer pressure. 
 
Participants will be asked to track their food intake and share this information with 
the study staff. 
 
 

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Table 3. Overview of Comprehensive Behavioral Intervention Curriculum 
 
Table 3* 
Intense 
Lifestyle 
ARM 
Meds 
ARM 
Parent 
Module 1: Kickstarter Build Your Knowledge  
WEEK 
TOPIC  
1-wk  
Getting Started, Energy Balance 
In-person Individual 
In-person  
Group 
In-person 
Individual 
 
2-wk 
Keeping Track 
Virtual Session + Call 
3-wk 
Learning About Food 
In-person Individual 
4-wk 
What Should I Eat? 
Virtual Session + Call 
Module 2: Rethink your drink 
5-wk 
What Do You Drink? 
In-person Group 
In-person  
Group 
Virtual Session 
6-wk 
Hydration 
Virtual Session + Call  
7-wk 
Quench Your Thirst, Problem Solving 
In-person Group  
8-wk 
Rethink Your Drink 
Virtual Session + Call  
Module 3: Let’s Be active 
9-wk 
Why Be Active? 
In-person Group 
In-person  
Group 
Virtual Session 
10-wk 
How hard is your body working? 
Virtual Session + Call 
11-wk 
Burn Calories through Exercise 
In-person Group 
12-wk 
What Are you Doing to Be Active?  
Virtual Session + Call  
Module 4: It’s All in the Planning 
13-wk 
Plan Your Day 
In-person Group 
In-person  
Group 
Virtual Session 
14-wk 
Plan What You Need, What’s in Your kitchen 
Virtual Session + Call  
15-wk 
Plan What You Buy 
In-person Group 
16-wk 
Plan How Much You Have 
Virtual Session + Call  
Module 5: High Quality vs Low Quality Foods 
17-wk 
High Quality vs Low Quality Foods  
In-person Group 
Virtual Session + 
Call 
Virtual Session 
18-wk 
You are what you eat 
Virtual Session + Call  
19-wk 
Snacks 
In-person Group 
20-wk 
Food Makeover  
Virtual Session + Call  
Module 6: Mindfulness  
21-wk 
Acceptance of Food-Related Internal Experiences 
In-person Group 
Virtual Session + 
Call 
Virtual Session 
22-wk 
Strategies to Increase Willingness 
Virtual Session + Call  
23-wk 
Mindful-Decision Making 
In-person Group 
24-wk 
Clarification and Commitment to Core Values 
Virtual Session + Call  
Module 7: Let’s be Balanced 
25-wk 
Being Healthy is Being in Balance  
In-person Group 
In-person  
Group 
Virtual Session 
26-wk 
Portion Distortion 
Virtual Session + Call  
27-wk 
After-School Snacks 
In-person Group 
28-wk 
Q and A about sports nutrition, fad diets…  
Virtual Session + Call  
Module: 8 Outside Influences (media, food advertising, food cues, body image, teasing…) 
29-wk 
Effects of Social Media  
In-person Group 
Virtual Session + 
Call 
Virtual Session 
30-wk 
Food Cues (Vignette) 
Virtual Session + Call  
31-wk 
Aaron Kelly: What is research, why is it important + Q&A            
In-person Group 
32-wk 
Influence of advertising: Are you falling for it? (Vignette) 
Virtual Session + Call  
Module 9: Eating Away from Home (fast food, with friends, social support, saying No) 
33-wk 
Eating Away from Home Challenges 
In-person Group 
Virtual Session + 
Call 
Virtual Session 
34-wk 
Social Support 
Virtual Session + Call  
35-wk 
Time Crunch Meal and Snack Ideas 
In-person Group 
36-wk 
Tips and Tricks 
Virtual Session + Call  
Module 10: Boost Your Activity, Lessen Your Sedentary Activity 
37-wk 
Increasing Your Steps  
In-person Group 
In-person  
Group 
Virtual Session 
38-wk 
Move More, Sit Less 
Virtual Session + Call  
39-wk 
Media Messages 
In-person Group 
40-wk 
Activity In a Normal Week 
Virtual Session + Call  
Module 11: Thoughts and Feelings (unhelpful thoughts, emotional eating) 
41-wk 
Learning to Eat When You’re Hungry— and Not When You’re Not 
In-person Group 
Virtual Session + 
Call 
Virtual Session 
42-wk 
Managing Emotions the Healthy Way 
Virtual Session + Call  
43-wk 
Unhelpful Thoughts  
In-person Group 
44-wk 
High Risk Situations 
Virtual Session + Call  
Module 12: Self Care  
45-wk 
Mindful Eating 
In-person Group 
Virtual Session + 
Call 
Virtual Session 
46-wk 
Label Claims (Vignette) 
Virtual Session + Call  

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47-wk 
Amy Gross: Managing Stress 
In-person Group 
48-wk 
Sleep (Vignette) 
Virtual Session + Call  
Module 13: Staying the Course (motivation, overcoming mistakes, focus on positive results, 
tracking, relapse) 
 
 
49-wk 
Motivation 
In-person Group 
In-person  
Group 
Virtual Session 
50-wk 
Building Healthy Habits 
Virtual Session + Call  
51-wk 
Keeping Old, Unhealthy Habits Away 
In-person Group 
52-wk 
Positive Results 
Virtual Session + Call  
*Items to foster change will be distributed during class to intensive lifestyle arm – water bottle, overnight oats kit, crystal light packets, 
portion-control zip-lock bags. 
 
A multidisciplinary team will supervise the delivery of the intervention including a 
researcher with extensive experience in designing and delivering comprehensive 
behavioral interventions (Dr. Sherwood), a pediatrician with specialized training in 
obesity medicine and experience delivering behavioral therapy in the clinical 
setting (Dr. Fox), exercise physiologists (Drs. Kelly and Ryder), registered dietitians 
and/or nutritionist staff members with extensive experience delivering 
comprehensive, intensive behavioral therapy curriculum, behavioral psychologist 
with experience in clinical behavioral management of obesity (Dr. Gross), and 
specially-trained study coordinators that will assist in staffing the sessions.  Dr. 
Marcus, a researcher and clinician with expertise in behavioral interventions for 
youth with severe obesity, will provide consultation regarding the design, 
implementation, and ongoing fidelity monitoring of the behavioral intervention via 
regularly-scheduled conference calls.  Notably, Dr. Marcus was the principal 
investigator of an NIH-funded clinical trial evaluating behavioral therapy for weight 
management in youth with severe obesity and served as an investigator for the 
NIDDK-sponsored TODAY trial, which included an evidence-based, comprehensive 
behavioral therapy component.  She was heavily involved in the development of 
the behavioral curriculum as well as the implementation and fidelity monitoring.  
  
To ensure intervention fidelity and adherence to the delivery of the protocol, a 
manual of operations will be developed for each session that trained staff will 
follow when administering the curriculum.  These session-specific manuals will 
explicitly guide staff to correctly deliver the intervention components.  All 
interventionists will participate in a training phase that will involve review of the 
protocol, intervention materials, and role plays.  Regular quality assurance checks 
will be performed.  Staff will undergo regular training refreshers (quarterly), and 
quality assurance checks will be implemented throughout the project to monitor 
intervention delivery.  
 
Semaglutide Treatment Arm 
Participants assigned to the semaglutide group will initiate treatment with 0.25 mg 
once-weekly dosing via subcutaneous injection and will follow a dose-escalation 
regimen with 4-week dose escalation steps to 0.5, 1.0, 1.7 and 2.4 mg. The goal will 
be to get all participants to the 2.4 mg weekly dose; however, we will not utilize a 
forced-titration strategy meaning that some participants may be treated at a 
maximum tolerated dose lower than 2.4 mg.  Tolerability will include but not be 

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limited to GI side effects and hypoglycemia.  Participants will remain on 
semaglutide for the entire 56-week trial intervention period.    
 
Regulatory Status of Semaglutide  
Semaglutide is approved by the FDA for use in adults (> 18 years old) with obesity.  
In December 2022 the FDA approved semaglutide for use in children (ages 12-17) 
with obesity.  As this study started prior to FDA approval for use in children, an IND 
was obtained for the conduct of this study.    
 
4.2 Drug/Device Handling:  
Semaglutide will be purchased commercially until it receives FDA approval at which 
time product will be donated by the manufacturer, Novo Nordisk.  Trial product will 
be managed by the University of Minnesota Investigational Drug Service Pharmacy 
and will dispensed according to their operating policies.  The IDS office specializes 
in storing and dispensing investigational drugs for clinical trials.  Study physicians 
will write a prescription in order for IDS to dispense the medication.  IDS is in a 
secure facility (behind two locked doors) and maintains refrigerators and freezers 
with temperature tracking to assure that the drugs utilized in this study will 
maintain stability.  IDS will keep detailed records on the receipt of investigational 
product (including lot numbers) and detailed records on the dispensing of product 
to each subject enrolled in the study.  IDS is also equipped to destroy any 
medication that is returned at the end of the study when all drug accountability 
has been completed.  The participant will be taught how to self-administer the 
medication under the supervision of a parent/guardian.  Study staff members will 
inspect used injection pen devices returned by participants and ask participants to 
estimate a percentage of missed doses as additional forms of compliance tracking. 
 
The recent FDA approval of Semaglutide (Wegovy) for adults created high demand 
for the product and has resulted in a widespread shortage of medication at the 
lower titration doses of 0.25, 0.5, and 1.0 mg.  However, the same medication at 
lower doses used for the treatment of type 2 diabetes (marketed under Ozempic) 
is not in short supply.  We will utilize semaglutide (Ozempic) in the 0.25, 0.5 and 
1.0 mg doses until the semaglutide (Wegovy) shortage has eased.  Participants will 
be up-titrated to 1.0 mg using semaglutide (Ozempic) then switch to semaglutide 
(Wegovy) for doses >1.0 mg.  Currently enrolled participants will be provided with 
an information sheet that details this change and we have developed an instruction 
sheet for administering Ozempic as the dosage pen is different than the Wegovy 
dosage pen.   
 
4.3 Biosafety: Not applicable. 
4.4 Stem Cells: Not applicable. 
4.5 Fetal Tissue: Not applicable. 
 

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5.0 
Procedures Involved 
5.1 Study Design:  
This will be a randomized (1:1), head-to-head, 56-week clinical trial examining 
intensive behavioral counseling (52 contact hours) vs. medical management with 
semaglutide 2.4 mg weekly plus low-intensity behavioral counseling (12 contact 
hours) among 120 adolescents with obesity.  All investigators will be blinded to 
treatment condition.  In addition, all personnel responsible for performing data 
collection related to the primary endpoint (BMI) and other secondary physiological 
assessments on participants will be blinded to treatment condition.   
 
Neurobehavioral Predictors of Response:  All participants in both groups will 
complete neurobehavioral assessment at 5 study visits (included in schedule of 
events, Table 4).   
 
The schedule of events section (below, Table 4) shows the data that will be 
collected at each study visit.  All participants will receive reimbursement for 
completing study visit assessments.  Study staff will check in with participants to 
ensure dosing is occurring as outlined in the protocol.    
 
 

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Table 4.  Schedule of Events  
 
 
Screening 
Randomization 
 
1 Year 
Week 4 
Week 8 
Week 12 
Week 16 
Week 26 
Week 39 
Week 56 
Allowable 
window& 
 
± 30d 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
± 15d 
Informed consent, assent 
X 
 
 
 
 
 
 
 
 
Review of eligibility 
X 
 
 
 
 
 
 
 
 
Physical exam and Tanner staging 
X 
 
 
 
 
 
 
 
X 
Baseline demographics 
X 
 
 
 
 
 
 
 
 
Fasting labs: lipids, glucose, insulin, and hemoglobin 
A1c, and storage of blood for batched biomarker 
assessment^@ 
 
X 
 
 
 
 
X 
 
X 
Safety labs: comprehensive metabolic panel, complete 
blood count and hemoglobin A1c$  
X 
 
 
X 
 
X 
 
 
X 
Urine pregnancy test 
 
X 
 
 
 
 
X 
 
X 
BMI/anthropometrics/blood pressure/heart rate 
X 
X 
X 
X 
X 
X 
X 
X 
X 
iDXA (total/regional body fat, BMC) 
 
X 
 
 
 
 
X 
 
X 
PHQ-9 
X 
X 
 
 
 
 
X 
 
X 
C-SSRS 
X 
X 
 
 
 
 
X 
 
X 
Assessment of mood changes and thoughts of self-harm; 
GI symptom assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
Neurobehavioral Assessment 
• 
BRIEF-SR 
• 
NIH Toolbox 
• 
CANTAB 
• 
BIS/BAS Scale 
• 
Kirby Monetary Choice Questionnaire 
• 
Food Choice Task 
 
X 
 
 
X 
 
X 
X 
X 
Eating Behavior, Mood, Quality of Life Questionnaires 
• PROMIS-Anxiety 
• IWQOL-Kids 
• EQ-5D-Y 
• Visual Analog Scale of Self-Reported Appetite and 
Sateity 
• QEWP-! 
• AEBQ 
• RED-5 Hedonic Eating 
• DEBQ 
• Children’s Power of Food Scale 
• PAQ-A 
• EDE-Q 
 
X 
 
 
X 
 
X 
X 
X 
Acceptability questionnaire 
 
 
 
 
 
 
X 
 
X 
Study drug titration and dispensing# 
 
X 
X 
X 
X 
X 
X 
X 
X 
AE assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
Behavioral Program (Intense Arm) 
 
 
ß 52 weekly sessions: 50% in person and 50% 
virtual à 
Behavioral Program (Medication Arm) 
 
 
ß 12 monthly sessions: 50% in-person and 50% 
virtual à 
& 
Allowable window is ± 30 days for the Randomization visit (from Screening), ± 3 days from the Randomization visit for the visits at Weeks 4-56 (with 
exception of week 56 visit, which is 15 days). 
^ 
Batched biomarker collection for an exploratory assessment of brain inflammation via brain derived exomes 
#  
Study drug titration and dispensing will happen only for those participants who are randomized to receive semaglutide. Study drug titration will take place 
over 16 weeks starting at the Randomization visit; additional AE assessments will be done in this group during the titration period 
$ 
Hemoglobin A1c to be done at Screening. 
@ 
Hemoglobin A1c will not be completed as part of the fasting panel at Randomization 
 
 

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5.3 Study Procedures  
 
Anthropometric Measurements and Quantification of Total Body- and Regional-Fat 
Depots  
Height and weight will be measured using a calibrated, wall-mounted stadiometer 
and an electronic scale, respectively.  Measurements will be obtained with 
participants in light clothing, without shoes.  Two consecutive height and weight 
measurements will be obtained and averaged.  If the first two values differ by more 
than 0.5 cm for height and/or 0.3 kg for weight, a third measurement will be 
obtained and the average of three measurements will be calculated.  BMI will be 
calculated as the weight in kilograms divided by the height in meters, squared.  
Waist circumference will be measured at end-expiration midway between the base 
of the rib cage and the superior iliac crest.  Hip circumference will be measured at 
the maximal protuberance of the buttocks.  Total percent body fat, visceral fat, and 
lean mass will be determined by dual energy x-ray absorptiometry.  The scanning 
table accommodates body sizes of up to 204 kg.  Our group has performed much 
of the work regarding the validation of DXA visceral fat in children and adolescents 
demonstrating a high correlation with computed tomography and association with 
cardiometabolic risk factors.41   
 
Pubertal Development, Blood Pressure, and Blood Analyses 
Tanner stage will be determined by trained personnel.  Blood pressure will be 
obtained on the same arm using the same cuff size and equipment according to 
standardized procedures42 and the internal standard operating procedure.   Fasting 
(≥12 hours) blood will be collected for the measurement of lipids, glucose, insulin, 
and hemoglobin A1c (Fairview Diagnostics Laboratories, Minneapolis, MN).  
Additional blood for exploratory biomarkers to measure brain inflammation via 
brain derived exomes will be conducted by the Masonic Institute for the 
Developing Brain (MIDB). 
 
Eating Behavior, Mood, Quality of Life and Acceptability Assessment 
Following an overnight fast of 12 hours, we will obtain ratings on 15-cm visual 
analog scales anchored with “not at all” to “extremely” for appetite.  This method 
has been validated43 and was utilized in a study of adolescents with severe 
obesity.44  Self-reported appetite and satiety will also be measured using the Adult 
Eating Behavior Questionnaire (AEBQ); note: in our experience, the self-report 
version (AEBQ) is more appropriate for adolescents vs. the child version (CEBQ).  
Additional eating behaviors will be address in supplemental questionnaires: Dutch 
Eating Behavior Questionnaire (DEBQ, restrained, emotional, external eating) and 
Reward Based Eating Drive Scale X5 (Red-5, hedonic eating). Binge eating 
behaviors/features will be measured with the Questionnaire of Eating and Weight 
Patterns – Adolescent (QEWP-A); Loss of Control – Eating Disorder Questionnaire 
and the Eating Disorder Examination Questionnaire – 6.2.45 Additional domains are 

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addressed in the AEBQ including emotional overeating and enjoyment of food and 
will be captured in supplemental questionnaires: Dutch Eating Behavior 
Questionnaire, Questionnaire of Eating and Weight Patterns – Adolescent, and 
Children’s Power of Food Scale.  Physical activity will also be assessed via the 
Physical Activity Questionnaire for Adolescents (PAQ-A). 
 
Quality of life will be assessed via the IWQOL-kids (weight-related quality of life), 
the EQ-5D-Y (quality of life).  Anxiety, depression and suicidal ideation will be 
measured with the PROMIS-Anxiety, PHQ-9 and C-SSRS.  Additional assessments 
include the Behavior Rating Inventory on Executive Function-Self Report (BRIEF-SR) 
and the NIH Toolbox (cognition battery.  Acceptability will be assessed in both 
groups using Likert scales addressing degree of satisfaction with the treatment 
intervention (behavioral sessions, and additionally the medication regimen for 
those assigned to this group), perception of the program, and evaluation of the 
scope of topics and usefulness of the behavioral counseling sessions.   
 
Neurobehavioral Assessment 
Neurobehavioral functioning will be assessed using gold standard objective and 
self-report measures of inhibition, cognitive flexibility, working memory and 
reward responsivity.  We selected specific measures based on their 1) validation in 
the adolescent population,46-52 2) test-retest reliability, and 3) ability to be 
administered in a clinical setting (to maximize the potential for translation and 
clinical implementation).  Study staff will administer and/or monitor completion of 
all assessments, per each assessment’s administration guidelines.  In total, 
completing the measures will take participants an estimated 2-2 ½ hours.  
Importantly, many of these assessments can be completed during “down time” of 
the overall study visits.  Inhibition, cognitive flexibility, working memory and 
reward responsivity will be assessed with the NIH Toolbox.46 Cambridge 
Neuropsychological Test Automated Battery (CANTAB) Stop Signal Task and 
Gambling Task49, Behavioral Inhibition Activation System (BIS/BAS) scale53, 
Behavior Rating Inventory of Executive Functions-Self Report (BRIEF-SR)51, Kirby 
Monetary Choice Questionnaire52 and the Food choice Task54.  These items will be 
reviewed and analyzed as part of Dr. Gross’s NIH-funded study. 
 
Additional Health Outcomes, Projected Long-Term Impact, and Cost-Effectiveness 
We plan to develop a decision analytic model (or simulation model) that will 
provide a platform to assess numerous health outcomes and to project the long-
term impact of study findings.  Outcomes will include: quality of life, participant 
preferences (acceptability), and participant and family adherence to the treatment 
plan, which should strongly correlate with the prior two measurements.  Using data 
from the study as the primary source, we will develop a computer-based simulation 
model that depicts or “recreates” the trial.  Projections of estimated benefits, costs, 
and cost-effectiveness in various settings as well as the potential population impact 
of the program implementation will be analyzed.  The development and validation 

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of our model will provide a comprehensive platform to assess economic feasibility 
by varying levels of specific economic and resource constraints.  
 
Safety-Related Assessments 
A comprehensive metabolic panel and complete blood count will be performed at 
selected study visits.  Urine pregnancy tests in females of childbearing potential 
(including females experiencing first menstruation during the study) will be 
conducted before participants undergo an iDXA scan (Randomization, Week 26, 
and Week 56). We will require all females who endorse sexual activity with males 
in the medication group to confirm use of at least two forms of effective 
contraception defined as double barrier methods, stable hormonal contraception 
plus single barrier method, tubal ligation, or abstinence.  We will instruct all 
females who miss a menstrual period or when pregnancy is otherwise suspected 
to perform a pregnancy test.  Semaglutide will be stopped in the event of 
pregnancy.  In all participants we will monitor for potential changes in 
gastrointestinal side effects, the effects of concomitant oral medications (owing to 
the potential for decreased absorption resulting from possibly delayed gastric 
emptying), mood changes including depression and suicidal ideation, self harm and 
injury.  We will educate participants assigned to the medication group (and their 
parents/guardians) on recognition and treatment of hypoglycemia.  Assessments 
of signs/symptoms of hypoglycemia will be performed prior to each dose 
escalation.  Sexual maturation (Tanner stage) and stature will be tracked 
throughout the study.  Additional details of safety-related assessments and 
oversight can be found elsewhere in the protocol.   
 
Depression and Suicide Monitoring 
The PHQ-9 and C-SSRS will measure depression and suicidality and the results will 
be reviewed by a staff member while the participant is still present at the visit.  
Participants (and their parents), if the participant is a minor will be referred to a 
Mental Health Professional (MHP) or to their primary care provider if the subject 
has a PHQ-9 score of > 15, any suicidal behavior, or any suicidal ideation of type 4 
or 5 on the C-SSRS.  They will also be provided with the contact information for the 
nationwide Suicide and Crisis Lifeline (telephone 988 or 988lifeline.org).  If the 
participant endorses current (in that moment), active suicidal ideation with plan 
and intent, they will also be referred to the emergency department.  Participants 
(and their parent) will be asked if they feel safe enough to leave the research clinic 
and with the established plan. 
 
A referral to a MHP or primary care provider should also be made if in the opinion 
of the Investigator it is necessary for the safety of the participant.  If a participant’s 
psychiatric disorder can be adequately treated with psycho- and/or 
pharmacotherapy, then the participant, at the discretion of the MHP or primary 
care provider, can be continued in the trial on randomized therapy. 

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5.4 Study Duration:  
Subjects will be enrolled in the study for 56 weeks (one year).  We anticipate that 
it will take three to four years to meet the trial recruitment goal.   
5.5 Use of radiation:  
This study will consist of four DXA scans, which utilize ionizing radiation.  None of 
the tests done for this study are considered part of standard medical care.  The DXA 
scans each consist of exposure to 0.01 mSv.  The average amount of radiation that 
the average person would receive from the DXA used in this study is less than 1% (3 
mrem) of that received from natural sources of radiation by a Minnesota resident 
in one year (300 mrem). 
 
5.6 Use of Center for Magnetic Resonance Research: Not applicable. 
 
6.0 
Data and Specimen Banking 
Blood samples for lipids (total-, HDL-, and LDL-cholesterol and triglycerides), glucose, 
insulin, and hemoglobin A1c will be sent to the Fairview Diagnostics Laboratory (which 
is CLIA licensed) after collection of the sample.  Additional blood samples for other non-
genetic biomarkers will be sent for an exploratory analysis of brain inflammation to 
look at brain-derived exomes in plasma by the Masonic Institute of the Developing 
Brain (MIDB). 
 
7.0 
Sharing of Results with Participants 
7.1 Participants will receive test results only if deemed clinically-significant or if the 
participant and/or parent/guardian specifically request this information.  
7.2 Sharing of genetic testing:  
Disclosure of results: Biomarker analyses that are conducted will not be returned 
to participants.  
8.0 
Study Population 
8.1 Inclusion Criteria:  
• Obesity (BMI ≥ 95th percentile or BMI ≥30 kg/m2) 
• Age 12 to <18 years old 
 
 

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8.2 Exclusion Criteria:  
• Tanner stage 1 
• Diabetes (type 1 or 2) 
• Current or recent (< six months prior to enrollment) use of anti-obesity 
medication(s) defined as orlistat, phentermine, topiramate, combination 
phentermine/topiramate, liraglutide (or other GLP-1RA), and/or combination 
naltrexone/bupropion (monotherapy use of naltrexone or bupropion is not an 
exclusion) 
• Previous bariatric surgery 
• Any history of treatment with growth hormone 
• Medically-documented history of bulimia nervosa 
• Any history of schizophrenia, psychosis, mania, chemical dependency 
• Unstable depression requiring hospitalization within the previous 6 months 
• Any history of suicide attempt 
• History of suicidal ideation or self-harm within the previous 30 days as 
determined at screening by: 
• PHQ-9 score ³15  
• Suicidal ideation of type 4 or 5 on the C-SSRS  
• Current pregnancy or plans to become pregnant  
• ALT or AST ≥5 times the upper limit of normal 
• Creatinine >1.2 mg/dL 
• Uncontrolled hypertension as determined by the local medical monitor 
• Clinically significant heart disease as determined by the local medical monitor 
• Diagnosed and medically-documented monogenic obesity 
• Medically-documented history of cholelithiasis 
• Untreated thyroid disorder 
• Medically-documented history of pancreatitis 
• Personal or family history of medullary thyroid carcinoma or multiple endocrine 
neoplasia syndrome type 2 
• Personal history of malignant neoplasms within the past five years 
• Hypersensitivity to any component of semaglutide 
 
9.0 
Screening 

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At this visit the subject’s parent/legal guardian and the participant will be taken 
through the consent process and sign the parental consent form and the assent forms 
after they have had the opportunity to learn about the study and ask any questions 
that they may have.  The participant will undergo the following: 
• Review of study eligibility by reviewing medical and medication history 
• Physical examination and Tanner staging 
• Blood collection (approximately 1 teaspoon) for a comprehensive metabolic 
panel, complete blood count and hemoglobin A1c 
• Height, weight, waist and hip measurements will be taken and a BMI will be 
calculated 
• Blood pressure will be measured 
• Heart rate will be measured 
• A PHQ-9 and C-SSRS will be completed by the participant 
 
Randomization Visit: 
• Blood collection (approximately 1 tablespoon) will be drawn for fasting labs, 
and storage for biomarkers 
• Urine will be collected for a urine pregnancy test for females of childbearing 
potential 
• Height, weight, waist and hip measurements will be taken and a BMI will be 
calculated 
• Blood pressure will be measured 
• Heart rate will be measured 
• A PHQ-9 and C-SSRS will be completed by the participant 
• Assessment of mood changes and thoughts of self-harm 
• A GI symptom assessment will be undertaken 
• Participants will be asked to fill out eating behavior, mood, and QOL 
questionnaires 
• Participant will complete neurobehavioral assessments 
• Participants will have a DXA to measure their body fat 
• Participants will be randomized, and study drug will be dispensed to 
participants who are randomized to the medication arm and instructed about 
the dose titration schedule.  Titrations will take place over 16 weeks, with the 
full dose of study medication to be started at Week 17.  Education will be 
offered on recognition and treatment of hypoglycemia. 
• Participants will start their behavioral program, which differs by treatment arm  
 
Week 4: 
• Height, weight, waist and hip measurements will be taken and a BMI will be 
calculated 
• Blood pressure will be measured 
• Heart rate will be measured 

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• Assessment of mood changes and thoughts of self-harm 
• A GI symptom assessment will be undertaken 
• Assessment of effects of concomitant oral medications 
• Adverse events will be reviewed 
• Compliance assessment will be performed for medication group; assessment for 
signs/symptoms of hypoglycemia; and the medication dose will be titrated to 
the next level 
• Participants will continue their behavioral program per their randomization 
schedule 
 
Week 8:  
• Blood collection (approximately 1 teaspoon) for a comprehensive metabolic 
panel, complete blood count 
• Height, weight, waist and hip measurements will be taken and a BMI will be 
calculated 
• Blood pressure will be measured 
• Heart rate will be measured 
• Assessment of mood changes and thoughts of self-harm 
• A GI symptom assessment will be undertaken 
• Assessment of effects of concomitant oral medications 
• Adverse events will be reviewed. 
• Compliance assessment will be performed for medication group; assessment for 
signs/symptoms of hypoglycemia; and the medication dose will be titrated to 
the next level 
• Participants will continue their behavioral program per their randomization 
schedule 
 
Week 12: 
• Height, weight, waist and hip measurements will be taken and a BMI will be 
calculated 
• Blood pressure will be measured 
• Heart rate will be measured 
• Assessment of mood changes and thoughts of self-harm 
• A GI symptom assessment will be undertaken 
• Assessment of effects of concomitant oral medications 
• Adverse events will be reviewed 
• Compliance assessment will be performed for medication group; assessment for 
signs/symptoms of hypoglycemia; and the medication dose will be titrated to 
the next level 
• Participants will be asked to fill out eating behavior, mood, and QOL 
questionnaires. 
• Participant will complete neurobehavioral assessments. 

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• Participants will continue their behavioral program per their randomization 
schedule 
 
Week 16: 
• Blood collection (approximately 1 teaspoon) for a comprehensive metabolic 
panel, complete blood count 
• Height, weight, waist and hip measurements will be taken and a BMI will be 
calculated 
• Adverse events will be reviewed 
• Assessment of mood changes and thoughts of self-harm 
• A GI symptom assessment will be undertaken 
• Assessment of effects of concomitant oral medications 
• Compliance assessment will be performed for medication group; assessment for 
signs/symptoms of hypoglycemia; and the medication dose will be titrated to 
the maximum dose of 2.4 mg/.075 mL 
• Participants will continue their behavioral program per their randomization 
schedule 
 
Week 26: 
• Blood collection (approximately 1 1/3 tablespoon) will be drawn for fasting labs, 
and storage for biomarkers 
• Urine will be collected for a urine pregnancy test for females of childbearing 
potential 
• Height, weight, waist and hip measurements will be taken and a BMI will be 
calculated 
• Blood pressure will be measured 
• Heart rate will be measured 
• A PHQ-9 and C-SSRS will be completed by the participant 
• Assessment of mood changes and thoughts of self-harm 
• Participants will be asked to fill out eating behavior, mood and QOL 
questionnaires. 
• Participant will complete neurobehavioral assessments 
• Participants will be asked to fill out acceptability questionnaire 
• A GI symptom assessment will be undertaken 
• Assessment of effects of concomitant oral medications 
• Participants will be asked to fill out questionnaires 
• Participants will undergo a DXA to measure body fat 
• Participants who are randomized to the medication arm will return their 
medication and have new study drug dispensed 
• Adverse events will be reviewed 
• Compliance assessment will be performed for medication group 

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• Participants will continue their behavioral program per their randomization 
schedule 
 
Week 39: 
• Height, weight, waist and hip measurements will be taken and a BMI will be 
calculated 
• Blood pressure will be measured 
• Heart rate will be measured  
• Participants who are randomized to the medication arm will return their 
medication and have new study drug dispensed 
• Adverse events will be reviewed 
• Assessment of mood changes and thoughts of self-harm 
• Participants will be asked to fill out eating behavior, mood, and QOL 
questionnaires. 
• Participant will complete neurobehavioral assessments 
• A GI symptom assessment will be undertaken 
• Assessment of effects of concomitant oral medications 
• Compliance assessment will be performed for medication group 
• Participants will continue their behavioral program per their randomization 
schedule 
 
Week 56: 
• Participants will undergo a physical examination and Tanner staging (not 
necessary to be repeated if Tanner stage 5 at randomization) 
• Blood collection (approximately 1 1/3 tablespoon) will be drawn for a 
comprehensive metabolic panel, complete blood count, fasting labs, and 
storage for biomarkers 
• Urine will be collected for a urine pregnancy test for females of childbearing 
potential 
• Height, weight, waist and hip measurements will be taken and a BMI will be 
calculated 
• Blood pressure will be measured 
• Heart rate will be measured 
• A PHQ-9 and C-SSRS will be completed by the participant 
• Assessment of mood changes and thoughts of self-harm 
• A GI symptom assessment will be undertaken 
• Assessment of effects of concomitant oral medications 
• Participant will be asked to fill out eating behavior, mood, and QOL 
questionnaires 
• Participant will be asked to complete neurobehavioral assessments 
• Participants will be asked to fill out acceptability questionnaire 
• Participants will undergo a DXA to measure body fat 

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• Participants who are randomized to the medication arm will return their 
medication  
• Adverse events will be reviewed 
• Compliance assessment will be performed for medication group 
 
10.0 Vulnerable Populations 
Participants who are enrolled in this study will be under the age of 18 and will be asked 
to sign an assent form.  At least one parent/guardian will be asked to sign a parental 
consent form.  Parental consent will be obtained before the assent is obtained. Children 
who turn 18 during the course of the study will be asked to sign a consent form and a 
HIPAA form once they reach the age of majority. 
 
10.1 
Vulnerable Populations:  
 
Population / Group 
Identify whether any of the 
following populations will be 
targeted, included (not necessarily 
targeted) or excluded from 
participation in the study.  
Children 
Targeted Population 
Pregnant women/fetuses/neonates 
Excluded from Participation 
Prisoners 
Excluded from Participation 
Adults lacking capacity to consent 
and/or adults with diminished 
capacity to consent, including, but 
not limited to, those with acute 
medical conditions, psychiatric 
disorders, neurologic disorders, 
developmental disorders, and 
behavioral disorders 
Excluded from Participation 
Non-English speakers 
Included/Allowed to Participate 
Those unable to read (illiterate) 
Excluded from Participation 
Employees of the researcher 
Excluded from Participation 
Students of the researcher 
Excluded from Participation 

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Undervalued or disenfranchised 
social group 
Included/Allowed to Participate 
Active members of the military 
(service members), DoD personnel 
(including civilian employees) 
Excluded from Participation 
Individual or group that is 
approached for participation in 
research during a stressful situation 
such as emergency room setting, 
childbirth (labor), etc. 
Excluded from Participation 
Individual or group that is 
disadvantaged in the distribution of 
social goods and services such as 
income, housing, or healthcare. 
Included/Allowed to Participate 
Individual or group with a serious 
health condition for which there are 
no satisfactory standard treatments. 
Included/Allowed to Participate 
Individual or group with a fear of 
negative consequences for not 
participating in the research (e.g. 
institutionalization, deportation, 
disclosure of stigmatizing behavior). 
Included/Allowed to Participate 
Any other circumstance/dynamic 
that could increase vulnerability to 
coercion or exploitation that might 
influence consent to research or 
decision to continue in research. 
Excluded from Participation 
 
10.2 Additional Safeguards: Not applicable. 
 
11.0 Local Number of Participants 
11.1 Local Number of Participants to be Consented: 250 
12.0 Local Recruitment Methods: Within the various health systems in our consortium (MN-
POC), over 10,000 adolescents with obesity are accessible for recruitment to our clinical 
trial.  Our Center has a track record of successfully enrolling and retaining participants in 
pediatric obesity clinical trials.55-57   

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12.1 Recruitment Process: Our recruitment process will be two-fold: we will leverage 
the MN-POC for recruitment.  Member institutions include the University of 
Minnesota, Mayo Clinic, Children’s Hospitals and Clinics of Minnesota, and Park 
Nicollet/HealthPartners, which represent a large portion of the pediatric medical 
care in Minnesota.  We plan on reaching out to physicians in these member 
institutions and letting them know about the study so that they could refer patients 
who come into their clinics.  We may also work with these and other local health 
systems to have them send recruitment letters on our behalf to potentially eligible 
participants.  The second method will be to work with our partner, Fairview 
Research Recruitment Services, to send out recruitment letters and/or emails to 
individuals who are listed in the electronic medical record system, EPIC, that have 
not opted out of being contacted about potential research projects.  Interested 
participants will be asked to contact the study team and up to three follow-up 
phone calls will be made by study staff if the participant leaves a message. 
12.2 Identification of Potential Participants: 
Both the referrals from MN-POC and the recruitment mailings will request that the 
interested parties contact the research staff for additional information.  If the 
interested party and the research staff do not connect on the first try, the research 
staff will attempt to contact the interested parties with up to three follow-up 
phone calls and/or three emails. 
 
12.3 Recruitment Materials:  
A recruitment letter and recruitment flyers will be created for this study and 
approved by the IRB before use.  In addition we will post on social media with a 
photo and a QR code that will take an individual to a landing page where they can 
enter information in order to be contacted by the study team to get information 
about studies that are currently available.  We are also working with the medical 
school to undertake a Google ad campaign.  
 
 
12.4. Payment:  
Participation in this study is time intensive for the subject and their family 
members.  Payment will be made by the Greenphire ClinCard on the following 
schedule: 
• 
Screening visit: $50 
• 
Randomization visit: $150 
• 
Week 12 visit: $50 
• 
Week 26 visit: $250 
• 
Week 39 visit: $50 
• 
Week 56 visit: $250 
 
Parents/guardians attending the randomization, 26-week, and 56-week visits will 
be offered a meal voucher or Greenphire ClinCard for a meal ($10 value) since 
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detailed above, a supplemental completion bonus of $100 can be earned for the 
week 56 visit.  Therefore, participants will be eligible to receive total 
reimbursement/compensation of $350 for the week 56 study visit.  No 
reimbursement will be offered for the in-person or virtual counseling sessions.   
 
13.0 Withdrawal of Participants 
13.1 Withdrawal Circumstances:  
Subjects will be allowed to withdraw from the study at any time.  Subjects may be 
withdrawn from the study at any time based upon investigator judgement.   
 
In the event that a participant has a serious adverse event that is deemed related 
to the study medication and/or procedures by either the external or internal 
medical monitor, the participant will be required to immediately discontinue the 
intervention.   
 
Participants who express interest in stopping study medication but who feel they 
may still benefit from the lifestyle therapy will be allowed to remain in the study 
but off of study medication.  These participants will be analyzed as part of the 
intent-to-treat population but will not be included in the per-protocol analysis.  
Participants who stop study medication but remain in the study to complete 
lifestyle therapy but express an interest in re-starting study medication will be 
allowed to do so as many times as they wish if the PI and medical safety officer 
believe it to be safe for the participant to do so.     
 
13.2 Withdrawal Procedures:  
Any subject who is removed from the study by the principal investigator or who 
requests to be withdrawn from the study will be asked to return for one final visit 
to assess adverse events and to collect any unused study medication and do a final 
study medication compliance. 
 
13.3 Termination Procedures:  
It will be noted in the subject enrollment log that the subject has been discontinued 
from the study and the date of the last study related visit.  No additional data will 
be collected after that time.  Data that has already been collected can be used in 
the study analysis. 
 
14.0 Risks to Participants 
14.1 Foreseeable Risks:  
Risks of blood sampling: There is a minimal risk of bruising, fainting, and infection 
associated with blood draws. 
 

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Risks of exposure to ionizing radiation: The DXA scans involve exposure to a very 
low dose of ionizing radiation.  The average amount of radiation that the average 
person would receive from the DXA used in this study is less than 1% (3 mrem) of 
that received from natural sources of radiation by a Minnesota resident in one year 
(300 mrem).   
 
Expected Adverse Events -Semaglutide:  The US FDA-approved Prescribing 
Information (PI) will be used to assess expectedness.63  The most common adverse 
reactions, reported in greater or equal to 5% are nausea, diarrhea, vomiting, 
constipation, abdominal pain, headache, fatigue, upset stomach, dizziness, feeling 
bloated, burping, decrease in blood sugar (in people with type 2 diabetes), 
flatulence, gastroenteritis, gastroesophageal reflux, and gastritis. Semaglutide like 
other GLP-1 receptor agonists causes thyroid C-cell tumors at clinically relevant 
exposures in both genders of rats and mice.  It is unknown if semaglutide causes 
thyroid C-cell tumors, including medullary thyroid carcinoma (MTC) in humans.  
Therefore, the use of semaglutide is contraindicated in patients with a personal or 
family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome 
type  (MEN2).  Semaglutide may also cause acute kidney injury, hypersensitivity, 
diabetic retinopathy complications in patients with type 2 diabetes, increased 
heart rate, and suicidal behavior and ideation.  Injection site reactions may occur.   
 
Risks of questionnaires and neurobehavioral assessments:  Potential risks related 
to these tests include emotional distress related to thinking about sensitive topics 
and possible “test fatigue.”  Participants always have the option not to respond to 
questions. 
14.2 Reproduction Risks: All female subjects who are sexually active with males must 
agree to use two forms of birth control during their time in the study.  Females of 
childbearing potential will have urine pregnancy tests at each visit requiring a DXA 
scan.  According to the World Health Organization and the United States Center for 
Disease Control and Prevention, the most effective forms of birth control include 
complete abstinence, surgical sterilization (both male and female), intrauterine 
devices (IUDs), and the contraceptive implant.  The next most effective forms of 
birth control include injectables, oral contraceptive pills, the contraceptive ring, or 
the contraceptive patch.  Acceptable, but least effective, methods of birth control 
include male condoms (with or without spermicide) and female condoms.  Any two 
of the methods listed above is acceptable. 
14.3 Risks to Others: Not applicable. 
14.4 Definition of Adverse Events (AE):  An adverse event is any untoward medical 
occurrence in a clinical trial subject that is temporally associated with the use of a 
medicinal product, whether or not it is considered related to the medicinal 
product.  An adverse event can be any unfavorable and unintended sign, including 

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an abnormal laboratory finding, symptom or disease (new or exacerbated) 
temporally associated with the use of a medicinal product. 
14.5 Definition of a Serious Adverse Event (SAE): A serious adverse event is an AE that 
fulfills at least one of the following criteria: 
• Results in death 
• Is life-threatening 
• Requires 
inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization 
• Results in persistent disability/incapacity 
• Is a congenital anomaly/birth defect 
• Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered a Serious Adverse Event when, 
based upon appropriate medical judgement, they may jeopardize the 
patient or subject or require medical or surgical intervention to prevent one 
of the outcomes listed in the definition. 
• Suspicion of transmission of infectious agents must always be considered 
an SAE. 
14.6 Definition of an Adverse Reaction:  An Adverse Reaction is an adverse event for 
which the causal relationship between the product and that Adverse Event is 
suspected. 
14.7 Definition of a Serious Adverse Reaction:  An Adverse event which fulfills both the 
criteria for a Serious Adverse Event and the criteria for an Adverse Reaction. 
14.8 Definition of a Suspected Unexpected Serious Adverse Reaction (SUSAR):  An SAE 
which is unexpected and regarded as possibly or probably related to the 
trial/study product by the investigator. 
14.9 
Classification of an Adverse Event: 
Severity of Event.  The severity of all AEs will be assessed by the study clinician 
using the following grading system: 
• Grade 1: Mild: asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
• Grade 2: Moderate: minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living 
• Grade 3: Severe: medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care activities of daily life 
• Grade 4: Life-threatening: urgent intervention indicated 
• Grade 5: Death related to adverse event 
 
Relationship to Study Intervention: All AEs must have their relationship to study 
intervention assessed by the clinician who examines and evaluates the participant 
based on temporal relationship and his/her clinical judgment.  The degree of 

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certainty about causality will be graded using the categories below.  In a clinical 
trial, the study product must always be suspect. 
• Unrelated: clearly not related to the investigational agent(s) 
• Unlikely: doubtfully related to the investigational agent(s) 
• Possible: may be related to the investigational agent(s) 
• Probable: likely related to the investigational agent(s) 
• Definite: clearly related to the investigational agent(s) 
Expectedness:  The local medical monitor will be responsible for determining 
whether an 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 based on the PI.63  
When an AE involves mental health issues, both the medical monitor and Dr. Amy 
Gross (who is overseeing the NIH-funded neurobehavioral portion of this project) 
will discuss the relationship and expectedness and will ensure that events are 
reported. 
 
14.10 Time Period and Frequency for Event Assessment and Follow-Up:  All AEs 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. 
 
The study staff will record all reportable events with start dates occurring any time 
after informed consent is obtained until the last day of study participation. At each 
study visit, the study staff will inquire about the occurrence of AEs/SAEs since the 
last visit. Events will be followed for outcome information until resolution or 
stabilization. 
 
The PI will notify the IRB, the external medical monitor, NovoNordisk, the NIH,  and 
the FDA of any SAE that meet the definition of SAR or SUSAR.  Notifications will be 
provided within five days of knowledge of the event.  All pregnancies will be 
reported to NovoNordisk and will include the study name, unique subject number, 
subject initials, subject sex, subject age, trial drug, reported causality and outcome. 
 
The DSMB will be provided with AE and SAE information prior to their review 
of the study, at least every six months. 

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15.0 Potential Benefits to Participants 
We believe the potential benefits to the participants outweigh the risks in this study. We 
expect that most, if not all, participants will experience some degree of weight loss. 
Participants randomized to receive medication may benefit further. The side effect 
profile of semaglutide has been demonstrated to be acceptable in adults and the 
proposed tests are not more than minimal risk.  
 
16.0 Statistical Considerations 
16.1 Data Analysis Plan:  
There are 3 analysis populations planned.  Intention-to-treat (ITT) will include any 
participant randomized according to their treatment assignment.  Per-protocol (PP) 
will include those without major protocol violations as determined by the principal 
investigator and documented on protocol deviation case report forms.  The safety 
population will include all who receive treatment, according to treatment received. 
 
16.2 Power Analysis: 
Mean percent change in BMI from baseline to 56 weeks will serve as the primary 
endpoint for which the sample size determination has been based.  We will also 
perform categorical analyses comparing the proportions in each group achieving 
≥5%, ≥10%, 15%, and 20% BMI reduction to address treatment response 
heterogeneity.  Using data reported from clinical trials referenced in the evidence 
review commissioned by the USPSTF to inform the pediatric obesity screening 
recommendations and taking into consideration the refractory nature of 
adolescent obesity, we have liberally projected up to 5% BMI reduction on average 
in the group assigned to the intensive behavioral intervention.  Based on data from 
one of the large phase III clinical trials of semaglutide in adults presented earlier, 
we have conservatively projected approximately 10% BMI reduction on average in 
the group randomized to low-intensity behavioral intervention plus semaglutide.  
This estimate includes the placebo-subtracted efficacy of semaglutide plus the 
effect of the behavioral intervention.  Therefore, we conservatively anticipate a 
difference of at least 5% between the groups in the change in BMI from baseline to 
56 weeks. 
 
We estimate having a dropout rate of no more than 20% (our previous clinical trial 
experience with this population has been 10-15%).  Using BMI variability estimates 
from our previous trials in this population over 12 months suggesting a standard 
deviation of approximately 8.8 and using a conservative correlation between 
baseline and follow-up scores of 0.6, we present in the table below the power 
associated with a very conservative, yet clinically-meaningful control-subtracted 
treatment effect: BMI reduction of 5% based on an overall sample size of 120 (60 
in each treatment arm) and a range of degrees of attrition (including rows reflecting 
scenarios of higher than expected levels). 

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Revised sample size of 120 (60 in each of two arms) 
Power; rho=0.6 
 
 
 
Reduction from baseline 
5% 
Two-sided Unadjusted 
97.1% 
Two-sided with 10% attrition 
95.6% 
Two-sided with 15% attrition 
94.5% 
Two-sided with 20% attrition 
93.2% 
 
Regarding attrition, our group has demonstrated a strong track-record of retention 
success in our clinical trials of adolescent participants with severe obesity.  In an 
ongoing NIDDK-funded (R01) pharmacotherapy clinical trial among adolescents 
with severe obesity, our retention rate following randomization is 88% (53 out of 
60 have either completed the full 12-months of study participation or remain active 
in the trial with most having completed their 6-month visit).  Therefore, based on 
our track-record in this specific patient population, we anticipate having a dropout 
(lost to follow up) rate no higher than 20% for the primary endpoint at 56 weeks 
following randomization.  
 
Tertiary Endpoint(s): Neurobehavioral Predictors of Response 
Because the tertiary aims started after commencement of the overall study, we 
conservatively selected a sample size of N=116 for power calculations.  For tertiary 
aim 1, our power analysis used a regression model with the latent factors as 
primary predictors and 2 potential confounders.  Under these assumptions, we will 
have 80% power to detect an effect size of at least 𝜼 2=0.081 if we used the latent 
factors for two domains (e.g., only inhibition and reward responsivity), or an effect 
size of at least 𝜼2=0.100 if we used the latent factors for all four domains (see 
Future 1).  Prior research showed similar or larger effect sizes (𝜼2=0.091 to 
𝜼2=0.194) in the association between BMI reduction and neurobehavioral 
measures58.  For tertiary aim 2, we anticipate, based on data from the literature59,60 
that approximately half of the study participants in each treatment arm will achieve 
a BMI reduction of at least 5% at 6 months.  We calculated the minimum detectable 
odds ratio for a latent factor for only one domain, assuming that a participant who 
is ”average” in this domain (i.e., when the latent factor is mean-centered across 
study participants) has an equal chance of maintaining or not maintaining BMI 
reduction.  Under these assumptions, we will have 80% power to detect an odds 
ratio of at least OR=2.11. Decreasing the probability of someone with “average” 
neurobehavioral functioning to maintain a BMI reduction to 0.25 increases the 
minimum detectable odds ratio to OR=2.36.  Strong associations (OR=4.191) 
between reward-related decision making and BMI reduction maintenance have 
been previously reported.61  For tertiary aim 3, we expand the models in the power 
analysis from tertiary aim 1 to include a treatment group indicator and an 
interaction term between the treatment group and the latent factor.  Under this 
expanded model, we will have 80% power to detect an effect size for the joint 

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effect of the latent factor, group indicator, and interaction term of at least 𝜼2=0.108 
if we used the latent factors for two domains, or an effect size of at least 𝜼2=0.132 
if we used the latent factors for all four domains.  These minimum detectable effect 
sizes are larger relative to tertiary aim 1 due to the use of more predictors in the 
model, but they are still modest in practice and are similar or smaller in magnitude 
compared to previously reported effect sizes.58 
16.3 Statistical Analysis:  
Descriptive analyses of baseline characteristics and outcomes will include means 
and standard deviations, median and range for continuous variables and 
frequencies for categorical variables.  Treatment compliance will also be evaluated. 
Safety analyses will use the Safety analysis population and will be primarily 
descriptive reporting the number and percentage of adverse events.  All safety 
outcomes will be evaluated and monitored throughout the trial. 
 
Primary Endpoint 
Compare the effectiveness of intensive behavioral counseling vs. medical 
management plus low-intensity behavioral counseling on mean percent change in 
BMI from baseline to 56 weeks of follow-up in adolescents with obesity.  We 
hypothesize that semaglutide 2.4 mg weekly plus low-intensity behavioral 
counseling will elicit superior reductions in BMI (primary efficacy endpoint) 
compared to intensive behavioral counseling at 56 weeks (primary outcome 
assessment timepoint).     
  
The primary analysis will be conducted using the ITT population to compare the 
mean BMI percent change from randomization to 56 weeks of follow-up between 
the treatment groups, adjusted for BMI at randomization for added precision.  
Confidence intervals (CIs) and P-values will be based on robust variance estimation.  
Statistical significance will be considered as p<0.05.  Supportive analyses using the 
PP population will also be conducted along with consideration of adjustment for 
residual imbalances between treatment groups after randomization (e.g., in sex).  
Graphical evaluation will also accompany numerical results, including waterfall 
plots for visual representation of heterogeneity in BMI percent change.   
 
Secondary Endpoints 
We will also evaluate other relevant BMI endpoints including change in absolute 
BMI, BMI percent of the 95th percentile, and BMI percent of the median. In 
addition, we will address the important issue of clinical relevance by describing the 
proportion of participants with ≥5%, ≥10%,  ≥15%, and ≥20% BMI reduction (from 
randomization) at 56 weeks with 95% CIs based on inverting the score test. These 
values will also be compared using the difference in proportions between 
treatment groups accompanied by 95%  CIs and P-values based on the Chi-squared 
test.  We have also identified subgroups for evaluation of heterogeneity of 
treatment effect.  These include sex as a biological variable, age as proxy for 

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cognitive development (12-14 years; 15-17 years), race (Caucasian vs. minority), 
and baseline BMI (<40; 40 and higher).  Each of these will be evaluated by 
incorporating the corresponding indicator and interaction with treatment 
assignment in a linear regression model and presented as point estimates within 
each subgroup. Robust variance estimation will be used for CIs and P-values.  In an 
exploratory fashion, we will also evaluate outcomes by socioeconomic status as 
measured by maternal education, family income, public vs. private insurance 
status, and zip code (geocoding).  These will be evaluated with an interaction term 
in a regression framework and presented as point estimates within each subgroup 
along with CIs and P-values using robust variance estimation. 
 
Compare the effectiveness of intensive behavioral counseling vs. medical 
management 
plus 
low-intensity 
behavioral 
counseling 
on 
body 
fat, 
cardiometabolic risk factors, and quality of life in adolescents with obesity.  We 
hypothesize that semaglutide 2.4 mg weekly plus low-intensity behavioral 
counseling will elicit superior reductions in body fat and greater improvements in 
cardiometabolic risk factors and quality of life compared to intensive behavioral 
counseling at 56 weeks (primary outcome assessment timepoint). 
 
We will evaluate differences in total body- and visceral-fat (absolute mass and 
percent), cardiometabolic risk factors (blood pressure, lipids, glucose), CRP, oxLDL, 
and IWQOL over the full length of follow-up for each time point they are measured.  
The evaluation will be in a similar fashion as the primary outcome wherein analyses 
will be adjusted for values at randomization.  Longitudinal analyses will also be 
conducted, incorporating the multiple time points out to 56 weeks during which 
these measurements will be obtained.  These analyses will allow us to compare the 
durability of comprehensive, intensive behavioral counseling vs. medical 
management plus low-intensity behavioral counseling on mean BMI percent 
change from baseline and mean change from baseline of body fat, cardiometabolic 
risk factors, and quality of life.  Supportive analyses using the PP population for 
each secondary endpoint will also be conducted.  
 
Compare the number of adverse events and safety outcomes for intensive 
behavioral counseling vs. medical management plus low-intensity behavioral 
counseling in adolescents with obesity.  We hypothesize that the number of 
gastrointestinal-related adverse events will be higher in those randomized to 
semaglutide but that changes in other safety outcomes will be approximately equal 
between groups (pubertal development, depression, and suicidal ideation). 
 
The safety analysis will include all participants who receive treatment, according to 
treatment received.  Analyses of adverse events will be primarily descriptive 
reporting the number and percentage of adverse events along with categorizations 
of seriousness, severity, frequency (within a participant), and perceived 

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relatedness to the intervention.  Regarding the safety outcomes, it should be noted 
that many of the measures are continuous and do not have established cut-points 
indicating a specific safety signal.  Therefore, we will evaluate the change from 
randomization to 56 weeks of follow-up for gastrointestinal-related adverse 
events, as well as pubertal development, depression, and suicidal ideation 
between groups, adjusted for each value at randomization.  Confidence intervals 
(CIs) and P-values will be based on robust variance estimation.  
 
Evaluate the implementation feasibility of the two strategies by assessing 
acceptability, adherence, rate of attrition, and cost-effectiveness.  We hypothesize 
that semaglutide plus low-intensity behavioral counseling will have a higher rate of 
acceptability and adherence, lower rate of attrition, and will be more cost-effective 
as compared to intensive behavioral counseling. 
 
Metrics of acceptability, adherence, and rate of attrition will each be evaluated in 
a similar fashion as other secondary endpoints wherein CIs and P-values will use 
robust variance estimation.  Simulation model and cost-effectiveness - the trial will 
serve as the primary source of data for model inputs to inform the construction of 
the initial version of the model as it will mirror or recreate the two study cohorts 
within the two strategy arms in the trial.  The trial results, particularly the BMI 
changes over time, will provide calibration targets, which will be used to validate 
the model.  The results of Aims 1 and 2 will provide additional patient information 
that will inform differences in project intervention impact by specific setting.  
Additional model parameters or inputs necessary to develop a population-level 
model will be derived by and estimated from the literature, such that the model’s 
generalizability can be expanded to include new clinical and geographical settings.  
In addition, baseline prevalence rates and characteristics of youth with obesity in 
different regions of the country will be obtained from the CDC’s National Health 
and Nutrition Examination Survey (NHANES), a nationally representative sample.  
When more granular clinical data regarding patient-level information are not 
available within NHANES, literature searches will provide additional information 
and plausible ranges or estimates for the model.  Cost estimates for the model will 
be derived using individual patient data from the trial, applying microcosting 
techniques, and utilizing published literature estimates including the use of adult 
Medicare reimbursement schedules when pediatric estimates are not available.  
Costs will be adjusted for inflation using the consumer price index for the year of 
the analysis.  Quality of life (QoL) utility scores for obesity related states will be 
derived from published estimates in the literature, using adult values when 
necessary.  Expert opinion will be reserved for circumstances when no published 
estimates are available. 
 
 

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Tertiary Endpoint(s): Neurobehavioral Predictors of Response 
Data will be collected that map to each of following domains: inhibition, cognitive 
flexibility, working memory and reward responsivity. For each domain, we will use 
factor analysis to create a single latent factor that summarizes the information 
within that domain, thereby creating a score for that domain for each participant. 
The latent factors will be created at each of the baseline and the 6-months visits to 
characterize neurobehavioral functioning at those time points. Furthermore, a 
factor analysis on change scores will create latent factors that characterize the 
changes in neurobehavioral functioning. These latent factors will be used as 
predictors in the models described below. Using these latent factors as predictors 
leads to a substantial reduction in dimensionality and multiplicity. The latent factor 
summarizing each domain borrows strength across all measures within that 
domain. Altogether, we expect that using these latent factors will improve 
statistical power in identifying predictors of BMI reduction and maintenance.62  
For tertiary aim 1, identifying baseline neurobehavioral predictors of weight loss 
response in adolescents with obesity undergoing intervention, linear models will be 
used to quantify the association between percent BMI reduction at 6 months (the 
primary outcome) and the latent factors associated with baseline neurobehavioral 
functioning (the primary predictors).  
 
For tertiary aim 2 (i.e., for initial responders, identify neurobehavioral predictors of 
weight loss maintenance at 12 months), analyses will be restricted to the 
participants who experience > 5% BMI reduction at 6 months (the responders). BMI 
reduction at 12 months will be quantified for each responder to determine whether 
they maintained their BMI reduction. Logistic regression will be used with BMI 
reduction maintenance (durability of the initial ³5% BMI reduction) at the 12 
months visit as the primary outcome. We will consider each of the latent factors at 
baseline and the latent factors on the change scores as primary predictors; the 
former quantifies the relationship between the neurobehavioral functioning with 
future BMI reduction maintenance, and the latter quantifies the relationship 
between the change in neurobehavioral functioning with future BMI reduction 
maintenance. Second, we will model BMI reduction maintenance at 12 months 
using generalized linear mixed models (GLMMs). Using the data across all visits 
quantifies how neurobehavioral functioning and change in neurobehavioral 
functioning contribute to within- and between-person variability in BMI reduction 
maintenance.  
 
For tertiary aim 3, evaluating differences in predictors of response between 
intensive LMT and GLP-1RA therapy, we expand on the models in Aim 1 by 
including two terms to each model: i) a group indicator for the treatment arm, 
which will quantify the differences in the primary outcome between treatment 
arms, and ii) an interaction term between the group indicator and the primary 
predictor, which will quantify the differences between treatment arms in the 

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association between the primary predictor with the primary outcome. For 
exploratory analyses to evaluate the differences between predictors of long-term 
maintenance to intensive LMT and GLP-1RA therapy, we will follow a similar 
strategy by expanding the models in Aim 2. 
 
The longitudinal design of the study allows us to conduct supplementary analyses 
to thoroughly explore and identify neurobehavioral predictors of long-term BMI 
reduction response. In particular, we will use the longitudinal trajectory of BMI at 3, 
6, 9, and 12 months as the primary outcome in a linear mixed model (LMM). We 
will use as predictors the latent factors at baseline and the latent factors on the 
change scores, and we will also adjust for time and for BMI at baseline. In tertiary 
aim 2 we focused our analyses only on responders, but here we will look at all 
adolescents so that we can obtain a more complete picture on how BMI, the 
neurobehavioral predictors, and the relationship between the two change over 
time. Furthermore, if we add a group indicator for the treatment arm, its 
interaction with time, and its interaction with the neurobehavioral predictors, we 
can assess how the temporal trajectories of BMI differ across treatment. 
Altogether, these supplementary analyses will complement and expand the scope 
of the primary aims with an eye toward maximizing the overall impact. 
 
The models for each tertiary described above used the latent factors, each of which 
serves as a summary of the measures in one of the domains of interest (inhibition, 
cognitive flexibility, working memory and reward responsivity). Consequently, the 
models lose specificity in which measure is predictive of BMI reduction or BMI 
reduction maintenance. To address this, exploratory analyses will refit each model 
described above, but instead of using the latent factor as a predictor we instead use 
the neurobehavioral measures. This allows us to explore the predictive capability of 
each measure. Due to the large number of statistical tests in these exploratory 
analyses, we will focus on the resulting model fit and predictive capability of each 
measure, which can guide our future research on the relationship between these 
measures and BMI reduction and maintenance. 
 
The tertiary models described above will adjust for potential confounders, namely, 
age, sex as a biological variable, general intellectual functioning, race/ethnicity, and 
socioeconomic status. Residual analyses will be conducted to check for model fit and 
the model assumptions. Model selection criteria that balance model fit with 
complexity, [e.g., the Akaike Information Criterion (AIC)], will be used for model 
selection. 
 
16.4 Data Integrity:  
Validation of the simulation model described in specific aim #3 will be through the 
process of calibration.  The primary calibration target will be the aggregate BMI for 
the cohort.  The BMIs of the individual hypothetical patients in the simulation 

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model will be pooled to determine if model outputs or results match or reproduce 
trial results.  If they do not, model inputs will be revised until there is adequate 
reproduction of trial BMI results. 
 
Sensitivity Analyses - one-way sensitivity analyses will be conducted to investigate 
and explore the effects of changes in model parameters on outcomes across a wide 
range of values, including intervention effect sizes, adherence/participation rates.  
Additionally, probabilistic sensitivity analysis will be performed.  Distributions for 
specific parameters will be assigned and more than 1,000,000 iterations performed 
to gain further insight into the optimal strategy under uncertain conditions within 
our defined willingness to pay (WTP) threshold.  In circumstances where there are 
limited data to inform model projections, best efforts will be used to find and 
integrate available data in a systematic, transparent way. 
 
Missing Data: Despite best efforts, it is possible that some data will be missing, 
which could limit the interpretation and generalizability of results. If the data are 
missing at random, conditioned on measured covariates, then supplementary 
analyses adjusting for these covariates will produce unbiased results.  For potential 
missing data mechanisms beyond measured covariates, we will examine the extent 
to which results may be affected.  Imputation techniques will be considered for 
missing data issues (e.g., multiple imputation).  In particular, for the primary 
analysis we will use multiple imputation techniques for participants on whom we 
do not have a final measurement.  The imputation model will be stratified by 
treatment group and include baseline values at randomization, and change from 
baseline at all interim visits.  Additional variables for inclusion in the model include 
age, race, sex, and tanner stage.  Imputation will be used to estimate treatment 
group differences, 95% confidence intervals, and P values; observed data will be 
used to estimate within treatment group changes.  If the analyses with and without 
multiple imputed values differ substantially, then exploratory analyses will be 
performed to evaluated factors that may have contributed to the differences.  
Secondary endpoints will be handled similarly.   
 
17.0 Health Information and Privacy Compliance 
17.1 
Select which of the following is applicable to your research: 
☐ My research does not require access to individual health information and 
therefore assert HIPAA does not apply.   
 
☒ I am requesting that all research participants sign a HIPCO approved HIPAA 
Disclosure Authorization to participate in the research (either the standalone 
form or the combined consent and HIPAA Authorization). 
☐ I am requesting the IRB to approve a Waiver or an alteration of research 
participant authorization to participate in the research. 

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Appropriate Use for Research:  
☐ An external IRB (e.g. Advarra) is reviewing and we are requesting use of the 
authorization language embedded in the template consent form in lieu of the 
U of M stand-alone HIPAA Authorization.  Note: External IRB must be serving 
as the privacy board for this option. 
 
17.2 
Identify the source of Private Health Information you will be using for your 
research (Check all that apply)   
☒ I will use the Informatics Consulting Services (ICS) available through CTSI 
(also referred to as the University's Information Exchange (IE) or data 
shelter) to pull records for me 
☒ I will collect information directly from research participants. 
☐ I will use University services to access and retrieve records from the Bone 
Marrow Transplant (BMPT) database, also known as the HSCT 
(Hematopoietic Stem Cell Transplant) database. 
☒ I will pull records directly from EPIC. 
☐ I will retrieve record directly from axiUm / MiPACS 
☐ I will receive data from the Center for Medicare/Medicaid Services  
☐ I will receive a limited data set from another institution  
☐ Other. 
 
17.3 
Explain how you will ensure that only records of patients who have agreed to 
have their information used for research will be reviewed. 
We will work with Fairview Research Administration to pull a pool of individuals 
who have agreed, in their electronic medical record, to learn about potential 
research studies.  The data will be placed in the data shelter so that recruitment 
letters and/or emails can be generated and sent to potential participants.  
Individuals who have indicated that they do not want to be contacted about 
research will not be approached. 
 
17.4 
Approximate number of records required for review: >10,000 
 
17.5 
Please describe how you will communicate with research participants during 
the course of this research.  Check all applicable boxes 

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☐ This research involves record review only. There will be no communication 
with research participants. 
☐ Communication with research participants will take place in the course of 
treatment, through MyChart, or other similar forms of communication used 
with patients receiving treatment.  
☒ Communication with research participants will take place outside of 
treatment settings. If this box is selected, please describe the type of 
communication and how it will be received by participants.  
17.6 Explain how the research team has legitimate access to patients/potential 
participants: 
This has been explained in other sections of the protocol. 
17.7 Location(s) of storage, sharing and analysis of research data, including any links to 
research data (check all that apply).   
☒ In the data shelter of the Information Exchange (IE)  
 ☒ Store 
☐ Analyze 
☐ Share 
☐ In the Bone Marrow Transplant (BMT) database, also known as the HSCT 
(Hematopoietic Stem Cell Transplant) Database  
 ☐ Store 
☐ Analyze 
☐ Share 
☐ In REDCap (recap.ahc.umn.edu)  
 ☒ Store 
☐ Analyze 
☐ Share (with DSMB) 
☐ In Qualtrics (qualtrics.umn.edu) 
 ☐ Store 
☐ Analyze 
☐ Share 
☒ In OnCore (oncore.umn.edu)  
 ☒ Store 
☒ Analyze 
☐ Share 
☒ In the University’s Box Secure Storage (box.umn.edu) 
 ☒ Store 
☐ Analyze 
☐ Share 
☐ In an AHC-IS supported server. Provide folder path, location of server and IT 
Support Contact: 
 ☐ Store 
☐ Analyze 
☐ Share 
☒ In an AHC-IS supported desktop or laptop.  
Provide UMN device numbers of all devices:  
 ☒ Store 
☐ Analyze 
☐ Share 
☐ Other. Describe:  

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Indicate if data will be collected, downloaded, accessed, shared or stored using a 
server, desktop, laptop, external drive or mobile device (including a tablet 
computer such as an iPad or a smartform (iPhone or Android devices) that you 
have not already identified in the preceding questions 
☐I will use a server not previously listed to collect/download research data 
☐I will use a desktop or laptop not previously listed 
☐I will use an external hard drive or USB drive (“flash” or “thumb” drives) not 
previously listed  
☐I will use a mobile device such as an tablet or smartphone not previously listed 
 
17.8 Consultants. Vendors. Third Parties. None. 
17.9 Links to identifiable data:  
Absolute confidentiality will be maintained.  All data will be stored in locked 
offices and will not be released without consent of participants.  Blood samples 
that are sent to other laboratories will be identified only by study identification 
number, never by name.  Data to be used in scientific presentations or 
publications will not contain participant identifiers. 
 
17.10 Sharing of Data with Research Team Members.  
Study team members will have access to Box, and OnCore. 
17.11 Storage and Disposal of Paper Documents:  
All data will be stored in locked offices and will not be released without consent 
of participants.  As this study has multiple entities with oversight, records will 
not be destroyed until the latter of the following: 
• NIH:  3 years after the study ends; 
• FDA: 2 years after withdrawal of the IND for this application; 
• HIPAA:  6 years after the date it went into effect. 
18.0 Confidentiality 
Absolute confidentiality will be maintained.  All data will be stored in locked offices and 
will not be released without consent of participant.  Data that is collected will be entered 
into OnCore which is only accessible by the study team.  Blood samples that are sent to 
laboratories will be identified only by study identification number and never by name.  
Data to be used in scientific presentations or publications will not contain participant 
identifiers. 
 
19.0 Provisions to Monitor the Data to Ensure the Safety of Participants 
19.1 Data Integrity Monitoring.  
The study will undergo regular monitoring (at least annually) of the facility, staff, 
and study documents by clinical research associates in the University of Minnesota 

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Clinical Trials Monitoring Service, which specializes in regulatory compliance for 
clinical trials associated with the Food and Drug Administration.  This service 
provides regulatory monitoring of all research-related activities and is offered free 
of charge through the University of Minnesota Clinical and Translational Science 
Institute (CTSI).  Monitoring of fidelity to the protocol (e.g. protocol deviations) will 
be performed at each monitoring visit.  Monitoring staff will present a summary 
report to the PI after each monitoring session.  If necessary, corrective action plans 
will be devised and implemented by the PI to address deficiencies. 
19.2 Data and Safety Monitoring.  
An internal medical monitor will review all adverse events and serious adverse 
events regularly throughout the trial.  In addition, an independent (not involved in 
the trial) external medical monitor will review all serious adverse events regularly 
throughout the trial.  A data and safety monitoring board (DSMB) will be 
established, which will include at least one adult obesity medicine specialist or 
endocrinologist, one pediatric obesity medicine specialist or endocrinologist, and 
one biostatistician.  DSMB members will not be affiliated with the study.  The DSMB 
will meet regularly (frequency to be determined by DSMB members but no less 
than every six months) during the trial to review data and evaluate participant 
safety.  A charter for the DSMB to outline the responsibilities and procedures for 
the conduct of the monitoring board will be developed and approved by its 
members along with a plan for frequency of data review prior to the 
commencement of the trial.  Review materials for the DSMB will be prepared and 
presented by the study biostatistician.  A report from each meeting will be sent to 
the PI, co-investigators, and external medical monitor advising on the continuation 
of the study and any suggestions for trial improvement.  This report will also be 
sent to the assigned NIH Program Director and the IRB.  An important charge of the 
DSMB will be to closely monitor progress and timelines related to recruitment 
goals, fidelity to the protocol (e.g. regularly review the number and types of 
protocol deviations), as well as monitor the quality and integrity of the data.  The 
DSMB will communicate any concerns relevant to these issues of trial conduct to 
the PI and note specific recommendations for improvement in the meeting report.   
 
In the event that a participant has a serious adverse event that is deemed related 
to the study medication and/or procedures by either the internal or external 
medical monitor, the participant will be required to immediately discontinue the 
intervention. The overall study may be stopped at any time at the request of the 
PI, internal or external medical monitor and/or the DSMB.  The main adverse 
effects that we expect to observe with semaglutide are GI-related.  Participants 
may be removed from the study if suicidal ideation is present at any time during 
the trial or if any clinically significant changes (at the discretion of the internal or 
external medical monitor) in mood and/or depression are observed.  If the ratio of 
participants assigned to medication vs. behavioral counseling alone developing a 
serious adverse event (for the medication group, deemed related to study 

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medication) requiring withdrawal exceeds 4:1 (after ≥50% enrollment and a 
minimum of 5 total events, regardless of group assignment), the trial will be 
stopped.  Patients will be instructed that they may withdraw from the study at any 
time and for any reason. 
19.3 Suicidal Behavior and Suicidal Ideation 
Participants (and their parents, if the participant is a minor) will be referred to a 
mental health professional (MHP) or to their primary care provider if the subject 
has a PHQ-9 score of > 15, any suicidal behavior, or any suicidal ideation of type 4 
or 5 on the C-SSRS.  They will also be provided with the contact information for the 
nationwide Suicide and Crisis Lifeline (telephone 988 or 988lifeline.org).  If the 
participant endorses current (in that moment), active suicidal ideation with plan 
and intent, they will also be referred to the emergency department.  Participants 
(and their parent) will be asked if they feel safe enough to leave the research clinic.  
If a participant (and their parent) do not feel safe we can help guide them to the 
emergency department. 
 
20.0 Provisions to Protect the Privacy Interests of Participants 
20.1 Protecting Privacy:  
Please see HIPCO ancillary review 
20.2 Access to Participants:  
Please refer to the recruitment section. 
21.0 Compensation for Research-Related Injury 
21.1 Compensation for Research-Related Injury:  
Treatment for injuries that result from participating in the research activity will be 
available.  Those treatments include first aid, emergency treatment and follow-up 
care as needed.  Care for such injuries will be billed in the ordinary manner, to the 
subject or to their insurance company.  Subjects will be encouraged to contact the 
study team if they think that they have suffered a research related injury. 
21.2 Contract Language:  
Not applicable. 
22.0 Consent Process 
22.1 Consent Process (when consent will be obtained): 
Parental/guardian consent and participant assent will be obtained by a study 
investigator or a designated study coordinator after explaining the study in detail, 
asking the participant and the parents/guardians to explain the purpose, risk and 
benefits, and other details of the study, and giving the participant and 
parents/guardians an opportunity to as questions.  A copy of the signed forms will 
be given to the participants and the parents/guardians. 

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We will make every attempt to conduct parental re-consent and participant re-
assent in a face-to-face manner.  However if this process is not an option for the 
family, we would send the family the revised parental consent and assent forms 
and then set up a time to call them on the phone or Zoom with them to explain the 
revisions to the parental consent and assent and let them ask any questions that 
they might have.  If the parent and child are amenable to the changes, we will ask 
that they sign and return the forms to us for counter signature and we will then 
send them complete executed copies and document in the participant notes the 
reconsent process. 
22.2 Waiver or Alteration of Consent Process (when consent will not be obtained):  
There is no plan to request a waiver or alteration of the consent process. 
22.3 Waiver of Written/Signed Documentation of Consent (when written/signed 
consent will not be obtained): 
There is no plan to request a waiver of written/signed documentation.  
22.4 Non-English Speaking Participants:  
We plan to enroll Spanish speaking participants. Assent and consent documents 
will be translated to Spanish and a Spanish speaking study coordinator will perform 
the consenting process for these individuals.   
22.5 Participants Who Are Not Yet Adults (infants, children, teenagers under 18 years of 
age): 
This study will enroll subject who are under the age of 18 and they will be asked to 
sign and IRB-approved assent form. Their parents/guardians will be asked to sign a 
parental consent form. 
 
Individuals who sign an assent form but turn 18 during the course of the study will 
be asked to sign a consent form and HIPAA to indicate that they are still willing to 
participate in the study once they reach the age of majority.  A copy of the consent 
form will be given to the participant. 
 
22.6 Cognitively Impaired Adults, or adults with fluctuating or diminished capacity to 
consent: 
Not applicable. 
22.7 Adults Unable to Consent: 
Not applicable. 
23.0 Setting 
23.1 Research Sites:  
● 
Center for Pediatric Obesity Medicine (CPOM). 

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● 
Delaware Clinical Research Unit (DCRU). 
● 
M Health Clinics and Surgery Center. 
23.2 International Research: Not applicable.  
24.0 Multi-Site Research 
Not applicable. 
25.0 Coordinating Center Research 
Not applicable.  
 
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