Enhancing Weight Loss Maintenance With GLP-1RA (BYDUREON™) in Adolescents With Severe Obesity
Phase: PHASE2
Conditions: Severe Obesity
Sponsor: University of Minnesota

 
University of Minnesota 
 
 
Enhancing Weight Loss with Medication in Adolescents 
 
 
Regulatory Sponsor: 
University of Minnesota 
Funding Sponsor: 
National Institutes of Health (NIH) 
National Institute of Diabetes and Digestive and Kidney 
Diseases (NIDDK) 
Study Product: 
Exenatide extended-release for injectable suspension 
(BYDUREONTM)  
IND Number: 
126745 
Principal Investigator: 
Aaron S. Kelly, Ph.D. 
Medical Officer/Co-
Investigator: 
Claudia K. Fox, M.D., M.P.H. 
Co-Investigators: 
Kyle D. Rudser, Ph.D. 
Brandon M. Nathan, M.D. 
Amy Gross, Ph.D., L.P. 
Muna Sunni, M.B.B.Ch. 
Charles Billington, M.D. 
M. Jennifer Abuzzahab, M.D. 
Seema Kumar, M.D. 
Betsy Schwartz, M.D. 
Justin R. Ryder, Ph.D. 
Donald R. Dengel, Ph.D. 
Megan Oberle, M.D. 
Version Date: 
Version 7, 13 November 2019 

 
 
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Protocol Change History: 
Version 1: 13 May 2015 
Version 2: 18 August 2015: Addition of FDA stipulated safety 
measures 
Version 3: 15 October 2015: Addition of Fairview stipulated 
recruitment language 
Version 4: 11 April 2016: duration of Phase 1 reduced to 8 
weeks (from 12 weeks) 
Version 5: 07 December 2017: clarifications regarding 
baseline lab, exclusion criteria; removal of vascular 
measures; substance abuse and neuromuscular disorder 
exclusion  
Version 6: 25 June 2019: Corrects a typographical error 
regarding the number of subjects to be enrolled.  
Version 7: 13 November 2019: Adds the PHQ-2 as a safety 
measure to be done at every in-person visit.  The PHQ-2 was 
developed to help identify depressed mood and anhedonia, 
and following changes in depression could be helpful in this 
population.  The protocol also adds in an action plan for 
individuals who have a score of 3 or greater. 
 
 
 
 
 
 
 
CONFIDENTIAL 
 
This document is confidential and the property of the University of Minnesota.  No part of 
it may be transmitted, reproduced, published, or used by other persons without prior 
written authorization from the study sponsor. 

 
 
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Table of Contents 
STUDY SUMMARY........................................................................................................................................................... 1 
1 INTRODUCTION/SUMMARY ..................................................................................................................................... 3 
1.1 
BACKGROUND AND RATIONALE ................................................................................................................. 3 
1.2 
INVESTIGATIONAL AGENT .......................................................................................................................... 5 
1.3 
CLINICAL DATA TO DATE .......................................................................................................................... 5 
1.4 
DOSE RATIONALE AND RISK/BENEFITS – USE IN THE PEDIATRIC POPULATION ............................................. 9 
2 
STUDY OBJECTIVES .......................................................................................................................................... 10 
2.1 
PRIMARY OBJECTIVE ............................................................................................................................... 10 
2.2 
SECONDARY OBJECTIVES ......................................................................................................................... 10 
3 
STUDY DESIGN .................................................................................................................................................... 10 
3.1 
GENERAL DESIGN .................................................................................................................................... 10 
3.2 
PRIMARY AND SECONDARY STUDY ENDPOINTS ........................................................................................ 11 
4 
SUBJECT SELECTION AND WITHDRAWAL .............................................................................................. 11 
4.1 
INCLUSION CRITERIA ............................................................................................................................... 11 
4.2 
EXCLUSION CRITERIA .............................................................................................................................. 11 
4.3 
EARLY WITHDRAWAL OF PARTICIPANTS .................................................................................................. 12 
4.3.1 
When and How to Withdraw Participants .................................................................................. 12 
4.3.2 
Data Collection and Follow-up for Withdrawn Participants ...................................................... 13 
5 
STUDY DRUG ........................................................................................................................................................ 13 
5.1 
TREATMENT REGIMEN ............................................................................................................................. 13 
5.2 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS .................................................................... 13 
5.3 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ............................................................................. 13 
5.4 
PARTICIPANT COMPLIANCE MONITORING ................................................................................................. 13 
5.5 
PRIOR AND CONCOMITANT THERAPY ....................................................................................................... 13 
5.6 
PACKAGING ............................................................................................................................................. 13 
5.7 
RECEIVING, STORAGE, DISPENSING AND RETURN ..................................................................................... 13 
5.7.1 
Receipt of Drug Supplies ............................................................................................................ 13 
5.7.2 
Storage......................................................................................................................................... 14 
5.7.3 
Dispensing of Study Drug ........................................................................................................... 14 
5.7.4 
Destruction of Study Drug .......................................................................................................... 14 
6 
STUDY PROCEDURES ....................................................................................................................................... 14 
6.1 
SCREENING VISIT OR PHONE CALL ........................................................................................................... 15 
6.2 
BASELINE VISIT ....................................................................................................................................... 15 
6.3 
4-WEEK, 6-WEEK, AND 8-WEEK MEAL REPLACEMENT PHASE VISITS ....................................................... 17 
6.4 
RANDOMIZATION VISIT – STUDY MEDICATION PHASE .............................................................................. 17 
6.5 
4-WEEK FOLLOW-UP VISIT ...................................................................................................................... 18 
6.6 
12-WEEK FOLLOW-UP VISIT .................................................................................................................... 18 
6.7 
26-WEEK FOLLOW-UP VISIT .................................................................................................................... 19 
6.8 
39-WEEK FOLLOW-UP VISIT .................................................................................................................... 20 
6.9 
52-WEEK FOLLOW-UP VISIT .................................................................................................................... 20 
6.10 
PHONE CALLS – WEEKS 8, 16, 20, 30, 34, 43, AND 47............................................................................ 21 
6.11 
DETAILED STUDY PROCEDURES ........................................................................................................... 21 
6.11.1 Anthropometric Measurements and Assessment of Pubertal Status ...................................... 21 
6.11.2 Blood Pressure and Heart Rate ................................................................................................. 22 
6.11.3 Blood Analyses ............................................................................................................................ 22 
6.11.4 Lifestyle/Behavioral Modification Counseling ............................................................................ 22 
6.11.5 Meal Replacement Induction Period .......................................................................................... 23 
6.11.6 Questionnaires ............................................................................................................................ 23 
6.11.7 Standardized Meal Test .............................................................................................................. 23 

 
 
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6.11.8 Measurement of Energy Expenditure ........................................................................................ 24 
7 
STATISTICAL PLAN ............................................................................................................................................ 24 
7.1 
PARTICIPANT POPULATIONS FOR ANALYSIS .............................................................................................. 24 
7.2 
SAMPLE SIZE DETERMINATION................................................................................................................. 24 
7.3 
STATISTICAL METHODS ........................................................................................................................... 25 
7.3.1 
Primary Endpoint ......................................................................................................................... 25 
7.3.2 
Secondary Endpoints .................................................................................................................. 25 
7.3.3 
Safety Analyses ........................................................................................................................... 26 
7.3.4 
Exploratory Analyses .................................................................................................................. 26 
7.4      MISSING DATA ........................................................................................................................................ 26 
8 
SAFETY AND ADVERSE EVENTS .................................................................................................................. 27 
8.1 
POTENTIAL RISKS .................................................................................................................................... 27 
8.1.1 
Dual-energy X-ray Absorptiometry (iDXA) Scan ....................................................................... 27 
8.1.2 
Blood Sampling ........................................................................................................................... 27 
8.1.3 
Medication.................................................................................................................................... 27 
8.1.4 
Questionnaires ............................................................................................................................ 27 
8.2 
DEFINITIONS............................................................................................................................................ 27 
8.2.1 
Adverse Event ............................................................................................................................. 27 
8.2.2 
Serious Adverse Event ............................................................................................................... 28 
8.2.3 
Adverse Event Reporting Period ................................................................................................ 28 
8.2.4 
Preexisting Condition .................................................................................................................. 28 
8.2.5 
General Physical Examination Findings .................................................................................... 28 
8.2.6 
Post-study Adverse Event .......................................................................................................... 29 
8.2.7 
Abnormal Laboratory Values ...................................................................................................... 29 
8.2.8 
Hospitalization, Prolonged Hospitalization or Surgery ............................................................. 29 
8.3 
RECORDING OF ADVERSE EVENTS ............................................................................................................ 29 
8.4 
REPORTING OF SERIOUS ADVERSE EVENTS ............................................................................................... 30 
8.4.1 
IRB Notification by Investigator .................................................................................................. 30 
8.4.2 
FDA Notification by Sponsor ...................................................................................................... 30 
8.5 
UN-BLINDING PROCEDURES ..................................................................................................................... 30 
8.6 
STOPPING RULES ..................................................................................................................................... 30 
8.7 
MEDICAL MONITORING ........................................................................................................................... 30 
8.8 
DATA AND SAFETY MONITORING BOARD ............................................................................................ 31 
9 
DATA HANDLING AND RECORD KEEPING ............................................................................................... 31 
9.1 
CONFIDENTIALITY ................................................................................................................................... 31 
9.2 
SOURCE DOCUMENTS AND CASE REPORT FORMS ...................................................................................... 31 
9.3 
RECORDS RETENTION .............................................................................................................................. 31 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ............................................................................. 31 
10.1 
STUDY MONITORING PLAN .................................................................................................................. 31 
10.2 
AUDITING AND INSPECTING ................................................................................................................. 32 
11   ETHICAL CONSIDERATIONS ............................................................................................................................ 32 
11.1 
HUMAN SUBJECTS INVOLVEMENT AND CHARACTERISTICS ................................................................... 33 
11.2 
SOURCE OF RESEARCH MATERIALS...................................................................................................... 33 
11.3 
RECRUITMENT AND INFORMED CONSENT ............................................................................................. 33 
11.4 
POTENTIAL RISKS TO SUBJECTS ........................................................................................................... 33 
11.5 
PROTECTIONS AGAINST RISK ............................................................................................................... 34 
11.6 
POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO THE SUBJECTS AND OTHERS ............................. 35 
11.7 
IMPORTANCE OF THE KNOWLEDGE TO BE GAINED ................................................................................ 35 
11.8 
DATA AND REGULATORY MONITORING PLAN ...................................................................................... 35 
12   STUDY FINANCES ................................................................................................................................................. 36 

 
 
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12.1 
FUNDING SOURCE ............................................................................................................................... 36 
12.2 
CONFLICT OF INTEREST ....................................................................................................................... 36 
12.3 
SUBJECT STIPENDS OR PAYMENTS ....................................................................................................... 36 
13 
PUBLICATION PLAN.......................................................................................................................................... 36 
 

 
 
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List of Abbreviations 
 
 
AE 
 
Adverse Event 
AEBQ  
Adult Eating Behavior Questionnaire 
ALT 
 
Alanine Transaminase 
AST 
 
Aspartate Aminotransferase  
AUC 
 
Area-under-the-curve 
BMI 
 
Body mass index 
CEBQ  
Child Eating Behavior Questionnaire 
CES-DC 
Depression Scale for Children 
CFR 
 
Code of Federal Regulations 
CIs  
 
Confidence intervals  
CLIA  
Clinical Laboratory Improvement Amendments  
CPAP  
Continuous Positive Airway Pressure 
BIPAP  
Bilevel Positive Airway Pressure 
CRF 
 
Case Report Form 
CTSI  
Clinical Translational Science Institute 
DSMB  
Data safety and monitoring board 
ECG 
 
Electrocardiogram 
FDA 
 
Food and Drug Administration 
GCP 
 
Good Clinical Practice 
GIP 
 
Glucose-dependent insulinotropic polypeptide 
GLP-1RA 
Glucagon-like peptide-1 receptor agonist 
HDL 
 
High density lipoprotein 
IDS 
 
Investigational Drug Services Pharmacy 
iDXA  
i Dual Energy X-ray Absorptiometry  
IND 
 
Investigational New Drug 
IRB 
 
Institutional Review Board 
ITT  
 
Intent to Treat 
LDL 
 
Low density lipoprotein 
PHI 
 
Personal Health Information 
PHQ-2  
Patient Health Questionnaire-2 
REPA  
Report of External Professional Activities  
SAE 
 
Serious Adverse Event 
UPIRTSO 
Unanticipated problems involving risk to subjects or others 

 
 
Page 1 
 
Study Summary 
Title 
Enhancing Weight Loss with Medication in Adolescents 
Phase 
Phase 3 
Methodology 
Randomized, double-blind, placebo-controlled clinical trial 
Study Duration 
5 Years 
Study Center 
University of Minnesota in collaboration with the Minnesota Pediatric 
Obesity Consortium (MN-POC) 
Objective & 
Hypothesis 
Primary Objective: Evaluate the effect of glucagon-like peptide-1 
receptor agonist (GLP-1RA) treatment on the maintenance of 
weight loss and durability of cardiometabolic risk factor 
improvements among adolescents with severe obesity following a 
meal replacement induction period.  We hypothesize that adolescents 
with severe obesity receiving GLP-1RA treatment following a short-term 
meal 
replacement 
induction 
period 
will 
demonstrate 
superior 
maintenance of initial BMI reduction 52 weeks following randomization 
compared to those assigned to placebo (primary endpoint) and that a 
higher proportion of those assigned to GLP-1RA treatment vs. placebo 
will maintain ≥5% BMI reduction from baseline to the 52-week time point 
(secondary endpoint).  Moreover, GLP-1RA treatment will result in 
superior maintenance of initial reductions of body fat (total, visceral, and 
subcutaneous), blood pressure, triglycerides/HDL ratio, inflammation, 
oxidative 
stress, 
postprandial 
glucose-insulin 
response, 
insulin 
resistance, and β cell dysfunction at 52 weeks. 
 
Secondary Objectives: Investigate the mechanisms by which GLP-
1RA treatment facilitates weight loss maintenance and identify 
predictors of response to treatment.  We hypothesize that compared 
to placebo, GLP-1RA treatment following a period of meal replacement 
will reduce appetite (and related hormones) and gastric emptying rate, 
and will increase satiety (and related hormones) and resting energy 
expenditure at 26- and 52 weeks following randomization.  Moreover, 
based on our preliminary work, we hypothesize that appetite (and 
appetite-related hormones) following the meal replacement period and 
female gender will be associated with superior weight loss maintenance 
with GLP-1RA treatment. 
Number of Subjects 
We anticipate having to consent/screen up to 250 subjects. 
Diagnosis and Main 
Inclusion Criteria 
Diagnosis: Severe obesity 
Main Inclusion Criteria: 
• 
BMI ≥1.2 times the 95th percentile (based on sex and age) or 
BMI ≥35 kg/m2 
• 
Age 12-17 years 

 
 
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Study Product, 
Dose, Route, 
Regimen 
Study Product (dose and route) 
Exenatide extended-release for injectable suspension (BYDUREON™) 
2.0 mg weekly 
 
Regimen 
After achieving ≥5% BMI reduction during a run-in period of up to 8 
weeks of meal replacement therapy, participants will be randomly 
assigned to exenatide or matching placebo for a subsequent period of 
52 weeks.  
Statistical 
Methodology 
The primary analysis will be conducted using the intent-to-treat 
population to compare the mean BMI percent change from 
randomization to 52 weeks of follow-up between exenatide and placebo 
groups, adjusted for randomization values of BMI. Confidence intervals 
and P-values will be based on robust variance estimation.  Statistical 
significance will be considered as p<0.05.   
 

 
 
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1 Introduction/Summary 
 
Long-term weight loss maintenance is seldom achieved by individuals with obesity owing to 
numerous biological adaptations involving appetite, satiety, and energy expenditure in the post- 
weight loss setting.  Following a loss in body weight, peripheral and central mechanisms convey 
a sense that energy reserves have dwindled, activating a strong counter response to increase 
caloric intake.  Adolescents with severe obesity are not immune to the vexing issue of weight 
regain.  Indeed, only 2% are able to achieve and maintain clinically-meaningful weight loss with 
lifestyle modification therapy.  Therefore, novel treatment paradigms focused on long-term 
weight loss maintenance are urgently needed.  Pharmacotherapy has the potential to prevent 
weight regain by targeting specific counter-regulatory mechanisms in the post- weight loss 
setting.  One of the most promising candidates is the glucagon like peptide-1 receptor agonist 
(GLP-1RA) class, which greatly enhanced weight loss maintenance following a short-term low 
calorie diet among adults with obesity.  The rationale for focusing on GLP-1RA treatment to 
prevent weight regain is supported by the multiple central and peripheral mechanisms of action 
targeted by this class of drug; many of which specifically address the biological adaptations 
known to induce relapse.  We have strong preliminary data demonstrating that GLP-1RA 
treatment reduces BMI in adolescents with severe obesity.  Moreover, we and others have 
shown that although meal replacement therapy (structured meals of known caloric content) can 
elicit robust short-term weight loss among adolescents with severe obesity, weight regain is a 
pervasive problem.  Therefore, in this clinical trial, our innovative approach will utilize GLP-1RA 
treatment to target weight regain following short-term meal replacement therapy in youth with 
severe obesity.  Participants who achieve ≥5% BMI reduction during the meal replacement 
phase will be randomized to GLP-1RA treatment or placebo for an additional 52 weeks while 
simultaneously engaging in lifestyle modification therapy.  Importantly, this study will also allow 
us to examine the extent to which GLP-1RA treatment addresses mechanisms of weight regain, 
investigate other pleiotropic benefits of GLP-1RA, and identify predictors of weight loss 
response. 
 
1.1 
Background and Rationale 
Obesity is a chronic disease requiring lifelong management.  Long-term weight loss 
maintenance is seldom achieved by individuals with obesity owing to numerous biological 
adaptations involving appetite, satiety, and energy expenditure in the post- weight loss setting.1-
3  Following a loss in body weight, peripheral and central mechanisms convey a sense that 
energy reserves have dwindled, activating a strong counter response to increase caloric intake.2  
Moreover, resting and non-resting energy expenditure decreases, further compounding the 
propensity for weight rebound.1  Adolescents with severe obesity (BMI ≥1.2 times the 95th 
percentile or BMI ≥35 kg/m2) are not immune to the vexing issue of weight regain as evidenced 
by the poor outcomes of interventions using lifestyle modification alone.4-7  Indeed, only 2% of 
adolescents with severe obesity are able to achieve and maintain clinically-meaningful weight 
loss with lifestyle modification therapy.4  These findings are sobering considering the relatively 
high prevalence of pediatric severe obesity (8% in the United States), the rate at which it is 
increasing (fastest growing category of obesity), and the serious immediate- and long-term 
medical and psychosocial consequences of the disease.8, 9  
 
The number and levels of cardiovascular risk factors are considerably higher in severe pediatric 
obesity compared to those associated with milder forms of obesity.  Approximately 85% of 
children and adolescents with severe obesity have at least one cardiovascular risk factor and 
60% have two or more.10  Subclinical atherosclerosis and arterial stiffening in the carotid artery 
is present in youth with severe obesity at levels similar to peers with type 2 diabetes.11  

 
 
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Compared to overweight and obese peers, youth with severe obesity have higher levels of 
inflammation and oxidative stress,12 an adverse adipokine profile,13 and arterial endothelial 
activation.14  Moreover, longitudinal data uniformly implicate obesity in childhood as a strong 
predictor of future risk factor clustering and sub-clinical atherosclerosis in adulthood.15-17  Risk of 
developing type 2 diabetes is high in youth with severe obesity.18-26  The prevalence of impaired 
glucose tolerance in children and adolescents with severe obesity is notable, with estimates 
ranging from 4.5%-25%.27-29  Perhaps most alarming is the poor prognosis for youth afflicted 
with severe obesity.  Approximately 90% will have a BMI ≥35 kg/m2 in adulthood;10 and severe 
obesity in adulthood reduces life expectancy by 7-14 years.30  Considering the serious nature of 
the disease, the poor efficacy of lifestyle modification approaches when used alone, and the 
higher level of risk associated with bariatric surgery, a new direction must be taken in the 
treatment of severe obesity in adolescents.  If the field is to move forward, novel treatment 
paradigms focused on long-term weight loss maintenance and the incorporation of 
pharmacotherapy need to be explored.   
 
Pharmacotherapy has the potential to prevent weight regain by targeting specific counter-
regulatory mechanisms in the post- weight loss setting, and various agents have improved long-
term weight loss durability in studies of adults.31-34  One of the most promising strategies 
involves the use of the GLP-1RA class of medication, which was originally approved by the FDA 
for use in adults with type 2 diabetes to improve glycemic control (weight loss is a beneficial 
“side effect”) and was recently approved for a weight loss indication.  Recently, GLP-1RA 
treatment was shown to greatly enhance weight loss maintenance (and produced additional 
weight loss) following a short-term low calorie diet among adults with obesity.34  Over 80% of 
those treated with GLP-1RA maintained ≥5% weight loss at one year.34  The rationale for 
specifically focusing on the GLP-1RA class to prevent weight regain is the multiple central and 
peripheral mechanisms of action addressed by the drug, which target many of the post- weight 
loss counter-regulatory biological adaptations known to induce relapse by: 1) reducing appetite 
through activation of GLP-1 receptors in the hypothalamus; 2) enhancing satiety by slowing 
gastric emptying and bolstering the vagal afferent signaling of gastric distension to the nucleus 
tractus solitarius portion of the hind brain; 3) beneficially altering insulin and leptin signaling in 
the hypothalamus and amygdala and inhibiting the reward pathways associated with hedonic 
eating behaviors; and 4) increasing energy expenditure.34-46  Through these various 
mechanisms, sustained weight loss has been achieved in the long-term (at least two years) 
using GLP-1RA treatment in adults.47  Additional justification for using this specific class of 
medication in adolescents with severe obesity includes recent evidence showing that GLP-1 
levels are reduced in the context of pediatric obesity,48 indicating a potentially maladaptive 
response in some individuals.  Moreover, GLP-1RAs, via weight loss dependent- and -
independent mechanisms, improve many obesity-associated risk factors and co-morbidities 
such as impaired glucose tolerance, insulin resistance, hypertension, vascular dysfunction, and 
inflammation.49-53  
 
We have preliminary data demonstrating that GLP-1RA treatment reduces BMI and improves 
cardiometabolic risk factors in adolescents with severe obesity.50, 54  Moreover, we and others55 
have shown that although short-term meal replacement therapy (structured meals of known 
caloric content) results in clinically-meaningful weight loss (6% BMI reduction) among 
adolescents with severe obesity, weight regain is experienced by the vast majority of individuals 
and long-term weight loss maintenance is poor.  The proposed clinical trial will take the next 
step and evaluate the weight loss-maintenance effectiveness of GLP-1RA treatment instituted 
immediately following a short-term meal replacement induction period among adolescents with 
severe obesity.  Importantly, this study will also allow us to: 1) examine the extent to which GLP-
1RA treatment targets the various mechanisms responsible for weight regain (including tracking 

 
 
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serial changes in a panel of appetite and satiety hormones), 2) investigate additional pleiotropic 
(weight loss-dependent and -independent) benefits of GLP-1RA therapy, and 3) identify 
predictors of successful weight loss maintenance with GLP-1RA treatment among adolescents 
with severe obesity. 
1.2 
Investigational Agent  
Exenatide  
Exenatide is a 39-amino acid synthetic peptide amide with an empirical formula of 
C184H282N50O60S and a molecular weight of 4186.6 Daltons.  The amino acid sequence for 
exenatide is shown below. 
 
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-  
Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-  
Pro-Ser-NH2 
1.3 
Clinical Data to Date 
Significance and Preliminary Work 
The significance of the proposed work lies in the seriousness and prevalence of the disease 
being targeted (pediatric severe obesity) and the improved outcomes that we hope to deliver 
(durable weight loss and risk factor management) in this population in need of safe, effective, 
and durable treatments.  The nature of severe obesity demands that appropriately-intensive 
interventions be initiated earlier in life, not later in adulthood when adiposity and co-morbidities 
have become entrenched.  Therefore, investigation into promising non-surgical treatments for 
pediatric severe obesity is desperately needed, considering the risks of surgery are not 
inconsequential56 and most will be unwilling to undergo this extreme treatment.  Weight regain 
continues to be a major hurdle in the field of obesity medicine. 
 
Study #1: Pilot and Feasibility Trial of GLP-1RA Treatment in Severe Pediatric Obesity50 
We conducted a pilot and 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.50  Twelve adolescents (ages 9-16 years old) were recruited from MN-POC sites 
and enrolled in a 6-month, randomized, open-label, crossover, clinical trial consisting of two, 3-
month phases: 1) a control phase of lifestyle modification and 2) a drug phase of lifestyle 
modification plus exenatide.  Participants were randomized to phase-order (i.e., starting with 
control or drug therapy) then crossed-over to the other treatment.  Outcomes were assessed at 
baseline, 3-, and 6-months.  Results are shown in Table 1.  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).  The encouraging preliminary findings (BMI reduction of 5% and improvements in glucose 
tolerance, insulin sensitivity, and beta cell function) prompted our group to conduct a follow up 
trial (see “Study #2”, below). 
 
 

 
 
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Table 1. Three-Month Treatment Effects Within and Between Study Arms 
 
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 
Values presented are mean (SD). 
 
Study #2: Randomized, Placebo-Controlled, Multicenter Trial of GLP-1RA Treatment in 
Adolescents with Severe Obesity54 
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 exenatide on 
BMI and cardiometabolic risk factors in adolescents with severe obesity.54  Twenty-six 
adolescents (age 12-19 years) were enrolled.  All patients received lifestyle modification 
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.  Results are shown in Figure 1 and Table 2.   
 
Figure 1. Percent Change in BMI during the 
Randomized, Placebo-Controlled and Open 
Label Phase 
 
Of note, during the open label extension, BMI 
was further reduced in those 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 
provide additional evidence supporting the feasibility, safety, and efficacy of GLP-1RA treatment 
in adolescents with severe obesity. 
 
 

 
 
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Table 2. Change from Baseline to Three-Month Follow-up for Primary and Secondary 
Endpoints 
 
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 
Values presented are mean (SD). 
 
Study #3: Predictors of BMI Response with GLP-1RA Treatment in Adolescents with Severe 
Obesity (unpublished data) 
We pooled data from our previously-described pilot trials and evaluated whether specific factors 
would predict BMI reduction at 3 months.  Data from the 29 participants who had a 3-month BMI 
measurement (mean age 14.5 ± 2.0 years; 66% female; mean BMI 40.2 ± 5.7 kg/m2) were 
included.  The primary predictor variables of interest were appetite and satiety at baseline from 
a validated questionnaire (Child Eating Behavior Questionnaire: CEBQ) modified to a self-report 
format for adolescents.  Appetite (or “Food Responsiveness” from the CEBQ) and satiety (or 
“Satiety Responsiveness” from the CEBQ) were classified as high or low based upon a cut-point 
of 2.5 on the scale of 1-5 which ranges from “never” to “always” for each item mean.  Additional 
exploratory predictor variables assessed included: baseline BMI, gender, age, early incidence (1 
month) of nausea, GI symptom frequency, and BMI percent change at 1 month.     
 
 

 
 
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Figure 2. Predictors of BMI Response with GLP-1 RA Treatment 
 
Mean differences in percent 
change in BMI from baseline to 
3 months between predictor 
groups were estimated.  The 
treatment effects and 
corresponding P-values 
represent the comparison of 
exenatide vs. placebo within 
each sub-group (i.e. the 
placebo-subtracted treatment 
effect) (Figure 2).  Interaction P-
values are also shown.  Each 
dot represents the mean 
percent BMI reduction at 3 
months within each sub-group, 
along with 95% confidence 
intervals.  As can be 
appreciated from Figure 2, the 
clearest separations for percent 
change in BMI are for gender and baseline appetite.  While other factors will be investigated in 
our proposed trial, we will focus primarily on gender and appetite as predictors of weight loss 
response. 
 
Study #4: Short-Term Weight Loss with Meal Replacements in Adolescents with Severe Obesity 
The use of meal replacements (structured meals consisting of liquid shakes and frozen entrees 
of known caloric content) represents one promising treatment approach for obesity.  A meta-
analysis of studies among obese adults has shown that meal replacements reduce body weight 
to a greater extent than conventional dieting alone.57  The rationale for the use of meal 
replacements is that individuals with obesity, including adolescents,58 often under-estimate 
caloric intake and that adherence to a strict, pre-determined meal regimen removes the “guess-
work” from eating.  The use of meal replacements is relatively new in the context of pediatric 
obesity management but a recent study by Berkowitz et al.55 demonstrated promising short-term 
weight loss efficacy (BMI reduction of approximately 6%) in adolescents with severe obesity 
using meal replacements for a period of 4 months.  However, weight loss maintenance was 
hampered by poor long-term compliance and weight regain ensued.55   
 
 

 
 
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Figure 3. Trajectory of BMI Reduction with Short-Term Meal Replacements in 
Adolescents 
 
We are currently conducting a clinical 
trial that includes a one-month meal 
replacement induction period and have 
observed promising BMI reduction 
among adolescents with severe obesity 
(N=17).  Mean BMI reduction was 3.4% 
in only four weeks (Figure 3); 
participants in the proposed trial will 
have up to 12 weeks of meal 
replacements.  Should this trajectory 
continue, we expect the majority would 
achieve ≥5% BMI reduction within 12 
weeks.  Therefore, based upon results 
from Berkowitz et al.55 and our pilot 
data, we believe the proposed approach is feasible and the BMI goal is attainable. 
 
In summary, our extensive portfolio of preliminary work: 1) demonstrates our group’s leadership 
role in, and commitment to, the field of pediatric obesity medicine; 2) provides initial evidence 
regarding the safety and efficacy of GLP-1RA treatment in adolescents with severe obesity; 3) 
highlights the benefits (short-term weight loss) and limitations (long-term weight regain) of meal 
replacement therapy; and 4) sets the stage for taking the next important step toward developing 
comprehensive and appropriately-intensive treatment strategies for teens afflicted with severe 
obesity.  The logical extension of our previous work is to evaluate the most promising aspect of 
meal replacement therapy (short-term weight loss) in combination with pharmacotherapy aimed 
at weight loss maintenance. 
1.4 
Dose Rationale and Risk/Benefits – Use in the Pediatric Population 
We will utilize the once-weekly, extended-release formulation of exenatide, a long-acting GLP-
1RA.  The frequency and intensity of GI side effects, such as nausea and vomiting, are lower 
with long-acting GLP-1RA agents, which should be associated with better tolerability (a prime 
consideration in pediatric medicine).  The newly-approved injection device for extended-release 
exenatide is easy-to-use and similar to the short-acting devices.  Despite a lower incidence of 
nausea, weight reduction with extended-release exenatide is similar to the twice per day 
formulation.59-62  Extended-release exenatide is administered one time per week by 
subcutaneous injection in the upper arm, abdomen, or thigh.  Exenatide will be initiated and 
maintained at a dose of 2.0 mg per week.  The 2.0 mg dose was shown to achieve plasma 
concentrations similar to the maximum concentration achieved with a single injection of 10 mcg 
exenatide and was demonstrated to be the most efficacious dose for weight loss.62  Exenatide 
and matching placebo will be donated by Astra Zeneca Pharmaceuticals.  Placebo/exenatide 
devices will be indistinguishable.  Study drug and placebo will be managed by the University of 
Minnesota Investigational Drug Service Pharmacy.  Education will be provided by a trained 
study coordinator and/or physician.  Subjects will be instructed to administer the medication 
under the supervision of a parent/guardian, and will be required to complete a study medication 
log. 

 
 
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2 
Study Objectives 
2.1 
Primary Objective 
Evaluate the effect of GLP-1RA treatment on the maintenance of weight loss and durability of 
cardiometabolic risk factor improvements among adolescents with severe obesity following a 
meal replacement induction period.  We hypothesize that adolescents with severe obesity 
receiving GLP-1RA treatment following a short-term meal replacement induction period will 
demonstrate superior maintenance of initial BMI reduction 52 weeks following randomization 
compared to those assigned to placebo (primary endpoint) and that a higher proportion of those 
assigned to GLP-1RA treatment vs. placebo will maintain ≥5% BMI reduction from baseline to 
the 52-week time point (secondary endpoint).  Moreover, GLP-1RA treatment will result in 
superior maintenance of initial reductions of body fat (total, visceral, and subcutaneous), blood 
pressure, triglycerides/HDL ratio, inflammation, oxidative stress, postprandial glucose-insulin 
response, insulin resistance, and β cell dysfunction at 52 weeks. 
2.2 
Secondary Objectives 
Investigate the mechanisms by which GLP-1RA treatment facilitates weight loss maintenance 
and identify predictors of response to treatment.  We hypothesize that compared to placebo, 
GLP-1RA treatment following a period of meal replacement will reduce appetite (and related 
hormones) and gastric emptying rate, and will increase satiety (and related hormones) and 
resting energy expenditure at 26- and 52 weeks following randomization.  Moreover, based on 
our preliminary work, we hypothesize that appetite (and appetite-related hormones) following 
the meal replacement period and female gender will be associated with superior weight loss 
maintenance with GLP-1RA treatment. 
3 
Study Design 
3.1 
General Design 
This will be a randomized, double-blind, placebo-controlled clinical trial specifically designed to 
evaluate the effectiveness of GLP-1RA treatment to improve weight loss maintenance following 
a short-term (up to 8 weeks) meal replacement induction period among up to 100 adolescents 
with severe obesity.  Because the trial is designed to evaluate weight loss maintenance, 
participants must achieve at least 5% BMI reduction during the meal replacement induction 
period in order to be randomized.  Weight checks will be performed regularly (week 4 and 8 with 
an optional week 6 weight check) during the induction period, and randomization will occur as 
soon as the 5% BMI reduction benchmark has been achieved (i.e., it may not take the full 8 
weeks for some participants to be randomized – it could occur at week 4, 6 or 8).  Participants 
who do not achieve the 5% BMI reduction benchmark will not continue in the trial.  However, 
these participants (i.e. those who experienced a reduction in BMI but did not quite achieve the 
5% benchmark) will be given the option to undergo reassessment of some of the procedures 
performed at baseline to evaluate whether BMI reduction less than 5% can improve 
cardiometabolic risk factors.  This will be considered an ancillary study and individuals who 
agree to participate, and their parents, will sign a separate assent and consent form, 
respectively.  After achieving the 5% BMI reduction benchmark, participants will be randomized 
(1:1) to either exenatide or placebo for a subsequent period of 52 weeks.  During the meal 
replacement induction period, all participants will engage in a meal replacement therapy 
protocol designed to achieve BMI reduction of at least 5% in a maximum timeframe of 8 weeks.  
We believe the goal of 5% BMI reduction over a period of 8 weeks is realistically achievable for 
most individuals based on the study by Berkowitz et al.55 and on our unpublished data 

 
 
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demonstrating a mean BMI reduction of 3.4% with only 4 weeks of meal replacement therapy in 
17 participants.   
3.2 
Primary and Secondary Study Endpoints 
The primary analysis will compare the mean BMI percent change from randomization to 52 
weeks of follow-up between GLP-1RA and placebo groups, adjusted for randomization values of 
BMI. Confidence intervals (CIs) and P-values will be based on robust variance estimation.  
Statistical significance will be considered as p<0.05.  Adjustment for residual imbalances may 
be made between treatment groups after randomization (e.g., in sex).  We will also evaluate 
differences in the proportion of subjects able to maintain ≥5% reduction from baseline with CIs 
and P-values based on the Chi-squared test. 
 
Secondary endpoints of body fat (total body-, visceral-, and subcutaneous fat), triglycerides/HDL 
ratio, blood pressure, inflammation, oxidative stress, postprandial glucose and insulin response, 
insulin resistance, and beta cell dysfunction will be characterized 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 randomization values.  Longitudinal analyses will 
also be conducted, incorporating the multiple time points these features are measured. 
 
Mechanism of action metrics of appetite and satiety at 52 weeks follow-up will each be 
evaluated in a similar fashion as other secondary endpoints wherein analyses will be adjusted 
for values at randomization and CIs and P-values will use robust variance estimation.  Potential 
effect modifiers of appetite at randomization (high vs. low, based on CEBQ cutoff and area-
under-the-curve for visual analog scale and meal test hormones) and gender will each be 
evaluated separately for estimates of treatment effect within each subgroup along with a test of 
interaction. 
4 
Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
• 
BMI ≥1.2 times the 95th percentile (based on sex and age) or BMI ≥35 kg/m2 
• 
12-17 years old 
4.2 
Exclusion Criteria 
• 
Tanner stage <2 
• 
Type 1 or 2 diabetes mellitus 
• 
Previous (within 6 months) or current use of medication(s) prescribed primarily for weight 
loss (refer to appendix material for comprehensive list) 
• 
If currently using weight altering drug(s) for non-obesity indication(s) (refer to appendix 
material for comprehensive list), any change in drug(s) or dose within the previous 6 
months 
• 
Previous bariatric surgery 
• 
If currently using anti-hypertensive medication(s), lipid medication(s), and/or 
medication(s) to treat insulin resistance (refer to appendix material for comprehensive 
list), any change in drug(s) or dose within the previous 6 months 
• 
If currently using CPAP/BIPAP (for sleep apnea), change in frequency of use or settings 
within the previous 6 months 
• 
History of treatment with growth hormone 

 
 
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• 
Neurodevelopmental disorder severe enough to impair ability to comply with study 
protocol 
• 
Clinical diagnosis of bipolar illness, schizophrenia, and/or conduct disorder  
• 
Substance abuse 
• 
Females: currently pregnant, planning to become pregnant, or unwilling to use 2 or more 
acceptable methods of contraception when engaging in sexual activity throughout the 
study 
• 
Tobacco use 
• 
Liver/renal dysfunction 
• 
ALT or AST >2 times the upper limit of normal (Note: Non-alcoholic fatty liver disease is 
highly prevalent in the target population and is NOT an exclusionary criterion.  Thus, if 
non-alcoholic fatty liver disease is suspected as the cause of elevated ALT or AST, it is 
at the discretion of the medical safety officer to order a liver ultrasound and relevant labs 
to rule out other potential causes of liver enzyme elevation.  If other causes are ruled out 
based on results of the work up, participant may be enrolled in the trial, again at the 
discretion of the medical safety officer.) 
• 
Bicarbonate <18 mmol/L 
• 
Creatinine >1.2 mg/dL 
• 
History of pancreatitis 
• 
Personal- and/or family history of medullary thyroid carcinoma 
• 
Personal- and/or family history of multiple endocrine neoplasia type 2 
• 
Calcitonin level >50 ng/L 
• 
Bulimia nervosa 
• 
Neuromuscular disorder 
• 
Hypothalamic obesity 
• 
Obesity associated with genetic disorder (monogenetic obesity) 
• 
Hyperthyroidism or uncontrolled hypothyroidism 
• 
History of suicide attempt 
• 
History of suicidal ideation or self-harm within the past year 
• 
History of cholelithiasis 
 
Patients will be recruited from the Pediatric Weight Management Clinic at the University of 
Minnesota Masonic Children’s Hospital and referred from the MN-POC member institutions.  
Additional recruitment strategies may include advertisements, study-specific recruitment letters 
sent to potentially-eligible patients in the respective health systems of the MN-POC (Fairview for 
the University of Minnesota), and word of mouth.  Appropriate designees will discuss study 
participation with interested participants and their parents at which time the initial consent and 
assent discussion will be conducted.  
4.3 
Early Withdrawal of Participants 
 
4.3.1 When and How to Withdraw Participants 
Participants may withdraw from the trial at any time.  The study may also be stopped at 
any time by the principal investigator, medical officer, IRB, or the FDA for any reason.  
Participants who discontinue participation and withdraw consent/assent will not complete 
follow-up visits.  However, participants who are not fully compliant with the medication 
regimen and/or who choose to stop the medication altogether but do not withdraw 
consent will remain in the study for follow-up in order to preserve the ability to perform 

 
 
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an ITT analysis.  Upon completion of the trial or upon complete withdrawal from the trial, 
participants will be referred back to their primary care physician, if applicable. 
 
4.3.2 Data Collection and Follow-up for Withdrawn Participants 
If a participant withdraws consent to participate in the trial, attempts will be made to 
obtain permission to record follow-up data.  Attempts to follow up will include three 
phone calls to the participant.  A participant will be considered lost to follow-up if no 
response is obtained after three attempts.   
5 
Study Drug  
5.1 
Treatment Regimen 
Following the meal replacement induction period, and if successful in achieving ≥5% BMI 
reduction, participants will be randomized (1:1) to either exenatide or placebo.  Extended-
release exenatide will be initiated and maintained at a dose of 2.0 mg per week.  
5.2 
Method for Assigning Subjects to Treatment Groups 
Each participant will be randomly assigned (1:1) to active drug or placebo using permuted 
blocks of size 2, 4, or 6.  For eligible participants who are randomized, a randomization number 
will be assigned starting with R001 and numbered sequentially.  Randomization codes will be 
maintained at the University of Minnesota Investigational Drug Service Pharmacy. The medical 
officer and PI will be responsible for determining when individual treatment assignments should 
be un-blinded (e.g., safety issues).   
5.3 
Preparation and Administration of Study Drug 
Study drug and placebo will be obtained, managed, dispensed, and tracked by the IDS 
pharmacy at the University of Minnesota.  
5.4 
Participant Compliance Monitoring 
Study drug compliance will be assessed at all follow up visits.  Participants will be given a 
medication journal in which they will be required to track when medication is administered as 
well as any symptoms experienced while taking the medication.  Participants will be required to 
bring study medication/placebo to all visits for compliance assessment. 
5.5 
Prior and Concomitant Therapy 
Concomitant medication(s) status will be collected at the baseline visit.  Changes in concomitant 
medication(s) will be assessed during follow-up visits.    
5.6 
Packaging 
Drug/placebo will be blinded and dispensed by the University of Minnesota IDS Pharmacy.  
Astra Zeneca Pharmaceuticals will send study supplies directly to the University of Minnesota 
IDS Pharmacy, which will be responsible for tracking and handling the material. 
5.7 
Receiving, Storage, Dispensing and Return 
 
5.7.1 Receipt of Drug Supplies 
Upon receipt of the study medication and supplies, an inventory will be performed and a 
drug receipt log completed and signed by IDS staff.  IDS staff will count and verify that 
the shipment contains all the items noted in the shipment inventory.  Any damaged or 

 
 
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unusable study drug in a given shipment will be documented in the study files.  IDS staff 
will notify the investigator of any damaged or unusable study drug.  A chain of custody 
will be maintained by IDS staff.   
 
5.7.2 Storage 
Study medication will be stored in a temperature-controlled and locked room in IDS 
Pharmacy with minimum access and controlled environmental conditions.   
 
5.7.3 Dispensing of Study Drug 
Study drug/placebo will be dispensed from the IDS.  Study drug reconciliation/chain of 
custody will be performed on a regular basis to document drug assigned, drug 
consumed, and drug remaining.  This reconciliation will be logged on the drug 
dispensation case report form.   
 
5.7.4 Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug consumed and 
drug remaining.  This reconciliation will be logged on the drug reconciliation form, signed 
and dated.  Any discrepancies noted will be investigated, resolved, and documented 
prior to the destruction of unused study drug.  Drug destroyed on site will be 
documented in the study files and completed per the IDS standard operating 
procedures.  
6 
Study Procedures 
Participants will be asked to administer trial medication/placebo but withhold all other 
concomitant medication(s), if applicable, for study visits.  Table 3 shows the procedures to be 
performed and data to be collected at each study visit (please refer to the detailed breakdown of 
visits following the table for comprehensive list of assessments/procedures).  All participants will 
receive reimbursement payments for completing study visit assessments.  Note: 6- and 8-week 
meal replacement visits may be unnecessary for some participants (those who achieve 5% BMI 
reduction early) and the 6-week weight check visit is optional. 
 
 

 
 
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Table 3.  Measured Variables by Visit 
 
 
Baseline 
4 
Weeks  
Meal 
Repl. 
6 
Weeks 
Meal 
Repl. 
8 
Weeks  
Meal 
Repl. 
Randomization 
4 
Weeks 
12 
Weeks 
26 
Weeks 
39 
Weeks 
52  
Weeks 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
Tanner Staging 
X 
 
 
 
X 
 
 
X 
 
X 
Safety Labs 
X 
 
 
 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
X 
 
 
X 
 
X 
Bone Age X-Ray 
X 
 
 
 
X 
 
 
 
 
X 
Fasting labs and 
blood biomarkers 
X 
 
 
 
X 
 
 
 
 
X 
BMI/anthropometrics 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
iDXA scan 
X 
 
 
 
X 
 
 
X 
 
X 
Metabolic Rate 
X 
 
 
 
X 
 
 
X 
 
X 
Blood Pressure 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Questionnaires* 
X 
 
 
 
X 
 
 
X 
 
X 
PHQ-2 questionnaire 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Meal Test 
X 
 
 
 
X 
 
 
X 
 
X 
AE assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Compliance assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lifestyle Counseling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
* Questionnaires include PedsQL (Young Adult Quality of Life Inventory), Child and Parent Questionnaire, PEDSQL Gastrointestinal Symptoms 
Scale, Impact of Weight on Quality of Life (IWQOL-KIDS), Children’s Power of Food Scale, Adult Eating Behavior Questionnaire (AEBQ), Dutch 
Eating Behavior Questionnaire, Questionnaire of Eating and Weight Patterns-Adolescent (QWEP), Depression Scale for Children (CES-DC), 
Screen for Child Anxiety Related Disorders (SCARED), Physical activity patterns questionnaire, and (if applicable), questionnaires examining 
dietary habits, quality of life and physical activity patterns 
 
6.1 
Screening Visit or Phone Call 
• 
Informed consent/assent 
• 
Medical record review 
• 
Evaluation against inclusion and exclusion criteria 
• 
Remind participant to fast for 8 hours prior to baseline visit 
 
6.2 
Baseline Visit 
(Visit completed following an 8-hour fast and confirmation that all medications have been 
withheld on the morning of the study visit) 
 
Screening and baseline visit may be completed on the same visit day. 
 
• 
Informed consent/assent, if not previously obtained 
• 
Interim medical history review (if screening visit occurred previously) 
• 
Vital signs (heart rate and blood pressure) 
• 
Concomitant medications  
• 
Anthropometric measurements (height, weight, hip/waist circumference, 
body mass index, iDXA) 
• 
Physical exam with Tanner (pubertal) stage determination (note: if Tanner 
5, exam does not need to be repeated at subsequent visits)  
• 
Urine pregnancy test for all female subjects  
• 
Questionnaires: 
• 
PedsQL™ (Young Adult Quality of Life Inventory) Child and Parent 
Questionnaire 
• 
PedsQL™ Gastrointestinal Symptoms Scale 
• 
Impact of Weight on Quality of Life: IWQOL-Kids 
• 
Children’s Power of Food Scale 

 
 
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• 
Adult Eating Behavior Questionnaire (AEBQ) 
• 
Dutch Eating Behavior Questionnaire  
• 
Questionnaire of Eating and Weight Patterns-Adolescent (QEWP) 
• 
Depression Scale for Children (CES-DC) 
• 
Screen for Child Anxiety Related Disorders (SCARED) 
• 
Physical activity patterns questionnaire 
• 
PHQ-2  
• 
If applicable, additional questionnaires examining dietary habits, 
quality of life, and physical activity patterns 
• 
Fasting blood draw: complete metabolic panel, lipid profile (total 
cholesterol, LDL cholesterol, HDL cholesterol, triglycerides), insulin, 
hemoglobin A1c, calcitonin, amylase, lipase, prolactin, TSH, FSH, LH, 
testosterone, estradiol, dehydroepiandrosterone sulfate (DHEAS), and 
carcinoembryonic antigen (CEA) – Note: the safety labs drawn at this visit 
will serve as the screening labs for trial eligibility and qualification to receive 
study drug/placebo 
• 
ECG 
• 
Bone age x-ray 
• 
Blood draw for frozen plasma and serum storage  
• 
Resting metabolic rate assessment 
• 
Meal test 
• 
Urine sample collection for frozen storage 
• 
Meal replacement instructions (including food journaling to track 
compliance) 
• 
Lifestyle/behavioral modification counseling 
• 
For all female subjects, contraceptive counseling and confirmation of use of 
2 acceptable forms of contraception when engaging in sexual activity 
throughout the study (acceptable methods are described in the counseling 
tool document, which will be given to subjects and discussed at each visit 
and phone call) 
• 
Dispensation of meal replacement shakes and entrees (or order placement 
for home delivery)  

 
 
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6.3 4-Week, 6-Week (optional), and 8-Week Meal Replacement Phase Visits 
(note: 6- and 8-week visits may be unnecessary if 5% BMI reduction is achieved at   
previous visit) 
6 week (optional), and 8 weeks ± 3 days from baseline visit 
 
• 
Anthropometric measurements (height, weight, hip/waist circumference, 
body mass index) 
• 
Adverse event assessment 
• 
Meal replacement compliance assessment 
• 
Lifestyle/behavioral modification counseling 
• 
Dispensation of meal replacement shakes and entrees (or order placement 
for home delivery) 
• 
PHQ-2 
6.4 Randomization Visit – Study Medication Phase  
(note: the randomization visit will occur in place of the 4-week, 6-week, or 8-week 
visit, shown above, if 5% BMI reduction is achieved at that time-point)   
(Visit completed following a 8-hour fast and confirmation that all medications have been 
withheld on the morning of the study visit) 
Refer to visit windows at 4-, 6-, and 8-weeks above 
 
• 
Interim medical history review 
• 
Vital signs (heart rate and blood pressure) 
• 
Review concomitant medications  
• 
Anthropometric measurements (height, weight, hip/waist circumference, 
body mass index, iDXA) 
• 
Tanner stage determination 
• 
Urine pregnancy test for all female subjects  
• 
PHQ-2 
• 
Questionnaires: 
• 
PedsQL™ (Young Adult Quality of Life Inventory) Child and Parent 
Questionnaire 
• 
PedsQL™ Gastrointestinal Symptoms Scale 
• 
Impact of Weight on Quality of Life: IWQOL-Kids 
• 
Children’s Power of Food Scale 
• 
Adult Eating Behavior Questionnaire (AEBQ) 
• 
Dutch Eating Behavior Questionnaire  
• 
Questionnaire of Eating and Weight Patterns-Adolescent (QEWP) 
• 
Depression Scale for Children (CES-DC) 
• 
Screen for Child Anxiety Related Disorders (SCARED) 
• 
Physical activity patterns questionnaire 
• 
If applicable, additional questionnaires examining dietary habits, 
quality of life, and physical activity patterns 
• 
Fasting blood draw: complete metabolic panel, lipid profile (total 
cholesterol, LDL cholesterol, HDL cholesterol, triglycerides), insulin, 
hemoglobin A1c, calcitonin, amylase, lipase, prolactin, TSH, FSH, LH, 

 
 
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testosterone, estradiol, dehydroepiandrosterone sulfate (DHEAS), and 
carcinoembryonic antigen (CEA) 
• 
ECG 
• 
Blood draw for frozen plasma and serum storage  
• 
Resting metabolic rate assessment 
• 
Meal test 
• 
Urine sample collection for frozen storage 
• 
Lifestyle/behavioral modification counseling 
• 
For all female subjects, contraceptive counseling and confirmation of use of 
2 acceptable forms of contraception when engaging in sexual activity 
throughout the study (acceptable methods are described in the counseling 
tool document, which will be given to subjects and discussed at each visit 
and phone call) 
• 
Randomization to study medication or placebo 
• 
Study medication/placebo administration and dose escalation training 
• 
Dispensation of study medication/placebo 
 
6.5 
4-Week Follow-up Visit 
4 weeks ± 3 days from randomization visit 
 
• 
Interim current health/medical history review 
• 
Review concomitant medications 
• 
Blood draw for safety labs: complete metabolic panel, and calcitonin 
• 
Adverse event assessment  
• 
Assessment of injection site reactions (incidence and severity) 
• 
Study drug/placebo compliance/accountability 
• 
Anthropometrics (height, weight, hip/waist circumference,  body mass index) 
• 
Vital signs (heart rate and blood pressure)  
• 
Lifestyle/behavioral modification counseling 
• 
Urine pregnancy test for all female subjects; for all female subjects,  
contraceptive counseling, confirmation of use of 2 acceptable forms of 
contraception when engaging in sexual activity, and dispensation of home 
pregnancy tests (all female patients will be instructed to perform test monthly 
and contact study staff immediately if positive) 
• 
Dispensation of study medication/placebo 
• 
PHQ-2 
6.6 
12-Week Follow-up Visit 
12 weeks ± 7 days from randomization visit 
 
• 
Interim current health/medical history review 
• 
Review concomitant medications 
• 
Blood draw for safety labs: complete metabolic panel, and calcitonin 
• 
Adverse event assessment  
• 
Assessment of injection site reactions (incidence and severity) 
• 
Study drug/placebo compliance/accountability 
• 
Anthropometrics (height, weight, hip/waist circumference,  body mass index) 
• 
Vital signs (heart rate and blood pressure)  

 
 
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• 
Lifestyle/behavioral modification counseling 
• 
Urine pregnancy test for all female subjects; for all female subjects,  
contraceptive counseling, confirmation of use of 2 acceptable forms of 
contraception when engaging in sexual activity, and dispensation of home 
pregnancy tests (all female patients will be instructed to perform test monthly 
and contact study staff immediately if positive) 
• 
Dispensation of study medication/placebo 
• 
PHQ-2 
6.7 
26-Week Follow-up Visit 
(Visit completed following a 8-hour fast and confirmation that all medications, except 
study medication/placebo, have been withheld on the morning of the study visit) 
26 weeks ± 7 days from randomization visit 
 
• 
Interim medical history review 
• 
Vital signs (heart rate and blood pressure) 
• 
Review concomitant medications  
• 
Adverse event assessment 
• 
Assessment of injection site reactions (incidence and severity) 
• 
Study drug/placebo compliance/accountability 
• 
Anthropometric measurements (height, weight, hip/waist circumference, 
body mass index, iDXA) 
• 
Tanner stage determination 
• 
Urine pregnancy test for all female subjects 
• 
PHQ-2  
• 
Questionnaires: 
• 
PedsQL™ (Young Adult Quality of Life Inventory) Child and Parent 
Questionnaire 
• 
PedsQL™ Gastrointestinal Symptoms Scale 
• 
Impact of Weight on Quality of Life: IWQOL-Kids 
• 
Children’s Power of Food Scale 
• 
Adult Eating Behavior Questionnaire (AEBQ) 
• 
Dutch Eating Behavior Questionnaire  
• 
Questionnaire of Eating and Weight Patterns-Adolescent (QEWP) 
• 
Depression Scale for Children (CES-DC) 
• 
Screen for Child Anxiety Related Disorders (SCARED) 
• 
Physical activity patterns questionnaire 
• 
If applicable, additional questionnaires examining dietary habits, 
quality of life, and physical activity patterns 
• 
Fasting blood draw: complete metabolic panel, lipid profile (total 
cholesterol, LDL cholesterol, HDL cholesterol, triglycerides), insulin, 
hemoglobin A1c, calcitonin, amylase, lipase, prolactin, TSH, FSH, LH, 
testosterone, estradiol, dehydroepiandrosterone sulfate (DHEAS), and 
carcinoembryonic antigen (CEA) 
• 
ECG 
• 
Blood draw for frozen plasma and serum storage  
• 
Resting metabolic rate assessment 
• 
Meal test 
• 
Urine sample collection for frozen storage 

 
 
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• 
Lifestyle/behavioral modification counseling 
• 
For all female subjects, contraceptive counseling and confirmation of use of 
2 acceptable forms of contraception when engaging in sexual activity 
throughout the study (acceptable methods are described in the counseling 
tool document, which will be given to subjects and discussed at each visit 
and phone call)  
• 
Dispensation of study medication/placebo 
6.8 
39-Week Follow-up Visit 
39 weeks ± 7 days from randomization visit 
 
• 
Interim current health/medical history review 
• 
Review concomitant medications 
• 
Blood draw for safety labs: complete metabolic panel, and calcitonin 
• 
Adverse event assessment  
• 
Assessment of injection site reactions (incidence and severity) 
• 
Study drug/placebo compliance/accountability 
• 
Anthropometrics (height, weight, hip/waist circumference,  body mass index) 
• 
Vital signs (heart rate and blood pressure)  
• 
Lifestyle/behavioral modification counseling 
• 
PHQ-2 
• 
Urine pregnancy test for all female subjects; for all female subjects,  
contraceptive counseling, confirmation of use of 2 acceptable forms of 
contraception when engaging in sexual activity, and dispensation of home 
pregnancy tests (all female patients will be instructed to perform test monthly 
and contact study staff immediately if positive) 
• 
Dispensation of study medication/placebo 
6.9 
52-Week Follow-up Visit 
(Visit completed following a 8-hour fast and confirmation that all medications, except 
study medication/placebo, have been withheld on the morning of the study visit) 
52 weeks ± 7 days from randomization visit 
 
• 
Interim medical history review 
• 
Vital signs (heart rate and blood pressure) 
• 
Review concomitant medications  
• 
Adverse event assessment 
• 
Assessment of injection site reactions (incidence and severity) 
• 
Study drug/placebo compliance/accountability 
• 
Anthropometric measurements (height, weight, hip/waist circumference, 
body mass index, iDXA) 
• 
Tanner stage determination 
• 
Urine pregnancy test for all female subjects 
• 
PHQ-2  
• 
Questionnaires: 
• 
PedsQL™ (Young Adult Quality of Life Inventory) Child and Parent 
Questionnaire 
• 
PedsQL™ Gastrointestinal Symptoms Scale 
• 
Impact of Weight on Quality of Life: IWQOL-Kids 

 
 
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• 
Children’s Power of Food Scale 
• 
Adult Eating Behavior Questionnaire (AEBQ) 
• 
Dutch Eating Behavior Questionnaire  
• 
Questionnaire of Eating and Weight Patterns-Adolescent (QEWP) 
• 
Depression Scale for Children (CES-DC) 
• 
Screen for Child Anxiety Related Disorders (SCARED) 
• 
Physical activity patterns questionnaire 
• 
If applicable, additional questionnaires examining dietary habits, 
quality of life, and physical activity patterns 
• 
Fasting blood draw: complete metabolic panel, lipid profile (total 
cholesterol, LDL cholesterol, HDL cholesterol, triglycerides), insulin, 
hemoglobin A1c, calcitonin, amylase, lipase, prolactin, TSH, FSH, LH, 
testosterone, estradiol, dehydroepiandrosterone sulfate (DHEAS), and 
carcinoembryonic antigen (CEA) 
• 
ECG 
• 
Bone age x-ray 
• 
Blood draw for frozen plasma and serum storage  
• 
Resting metabolic rate assessment 
• 
Meal test 
• 
Urine sample collection for frozen storage 
• 
For all female subjects, contraceptive counseling and confirmation of use of 
2 acceptable forms of contraception when engaging in sexual activity 
throughout the study (acceptable methods are described in the counseling 
tool document, which will be given to subjects and discussed at each visit 
and phone call) 
6.10 Phone Call/Email/Text message – Weeks 8, 16, 20, 30, 34, 43, and 47   
 
± 7 days from randomization  
• 
Interim current health/medical history review including changes to 
concomitant medications 
• 
Adverse event assessment 
• 
Study drug/placebo compliance/accountability 
• 
For all female subjects, contraceptive counseling and confirmation of use of 
2 acceptable forms of contraception when engaging in sexual activity 
• 
Lifestyle/behavioral modification counseling 
 
6.11 Detailed Study Procedures 
 
6.11.1 Anthropometric Measurements and Assessment of Pubertal Status 
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.  Two 

 
 
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consecutive waist and hip measurements will be averaged.  If the first two values for 
either measure differ by more than 0.3 cm, a third measurement will be obtained and the 
average of three measurements will be calculated.  Total percent body fat, visceral fat 
(novel feature of the iDXA), and lean muscle mass will be determined by dual energy x-
ray absorptiometry (iDXA, GE Healthcare).  The scanning table accommodates body 
sizes of up to 204 kg.  Tanner stage will be determined by a trained pediatrician or a 
trained nurse.   
 
6.11.2 Blood Pressure and Heart Rate 
Blood pressure measurements will be obtained manually on the same arm using the 
same cuff size and equipment.  Standardized procedures will be employed as described 
in previously published standards.63  Individual cuff size will be determined by measuring 
the arm circumference midway between the acromial process and the bony olecranon.  
Sitting blood pressure and heart rate will be measured after the participant has been 
resting quietly without legs crossed for 10 minutes.  Measurements will be made three 
consecutive times (3-minute intervals).  The final two of three independent 
measurements will be averaged. 
 
6.11.3 Blood Analyses 
Fasting (≥8 hours) blood will be collected for the measurement of lipids (total-, LDL-, 
HDL-cholesterol, and triglycerides), glucose, insulin, and hemoglobin A1c (to be assayed 
in Fairview Diagnostics Laboratories, Fairview-University Medical Center, Minneapolis, 
MN - a Center for Disease Control and Prevention certified laboratory).  Fasting samples 
for C-reactive protein and oxidized LDL cholesterol, along with the biomarkers obtained 
from the standardized meal tests, will be processed and stored at -80 degrees C for a 
batched analysis in the University of Minnesota Cytokine Reference Laboratory (CLIA 
licensed).   
 
 
6.11.4 Lifestyle/Behavioral Modification Counseling 
All participants, regardless of group assignment, will receive the same 
lifestyle/behavioral modification counseling monthly throughout the entire study: 
delivered at each in-person study visit and on the phone for months when there is no 
study visit.  The lifestyle/behavioral modification curriculum has been adapted from the 
NIDDK-sponsored TODAY study lifestyle modification program materials64 and utilized 
by our group in a previous54 and ongoing trial.  Trained study coordinators will deliver the 
lifestyle/behavioral modification counseling, which will focus on small, successive 
changes in dietary (after meal replacement induction period) and physical activity 
behaviors through the use of evidence-based behavior change strategies such as self-
monitoring, goal setting, reinforcement for goal achievement, stimulus control, social 
support, problem solving, and motivational techniques.  The educational materials will be 
given to subjects and parents at the first study visit and selected sections will be 
reviewed and discussed at each face-to-face and phone-based lifestyle modification 
counseling session.  We have previously demonstrated the effectiveness of this lifestyle 
modification protocol in a randomized, placebo-controlled trial among adolescents with 
severe obesity.54  The intensity of the lifestyle modification is designed to be practical 
and feasible in the clinic setting.   

 
 
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6.11.5 Meal Replacement Induction Period 
All participants will engage in a meal replacement induction period (that will range from 4 
to 8 weeks) with a goal of reducing individual BMI by at least 5%.  The meal replacement 
plan has been used successfully in adolescents with severe obesity.55  Participants will 
be asked to strictly follow the prescribed eating regimen, which will include three Slim-
Fast® shakes (one for breakfast and two for lunch or vice-versa), two pre-packaged 
frozen entrée meals for dinner (Weight Watchers, Smart Ones®), two servings of fruit, 
and three servings of vegetables per day (Note: shakes contain 190 kcals each (570 
total) + meals contain 250 kcals each (500 total) + fruits and vegetables will provide 
approximately 300 total kcals = 1370 total kcals per day).  Shakes/meals will be provided 
free of charge – fruits/vegetables will be purchased by the participants.  Guidance will be 
provided regarding the use of the meal replacement shakes at school, and participants 
will be encouraged to engage in family meal sessions despite eating different foods.  
Meal replacement compliance will be assessed by requiring participants to maintain a 
dietary log throughout the trial.  The percentage of days for which the protocol was 
strictly followed (no additional calories consumed) will serve as the primary metric of 
compliance.  Study coordinators will perform weekly reminder phone calls during which 
the importance of maintaining the dietary log will be emphasized.   
 
6.11.6 Questionnaires 
Self-report appetite and satiety will be measured using the AEBQ.  Additional relevant 
eating behavior domains addressed in the AEBQ include emotional overeating and 
enjoyment of food (hedonic eating).  Additional questionnaires will address disordered 
eating patterns, anxiety, depression, etc.  These questionnaires, and others that might 
be added, will allow us to examine the impact of other eating behaviors and external 
factors in relation to weight loss.  However, results will be considered hypothesis-
generating. 
 
An individual who receives a score of 3 or greater on the PHQ-2 will be referred to the 
study psychometrist, Amy Gross, for a follow-up clinical interview.  Dr. Gross and Dr. 
Fox will then make a determination about whether or not the participant can remain in 
the trial or should be withdrawn.   
 
6.11.7 Standardized Meal Test 
The standardized meal test will serve many purposes in this study and will be performed 
at baseline, randomization, 26- and 52 weeks.  After having fasted for ≥8 hours, 
participants will consume (within five minutes) a fixed-size, single-item breakfast meal of 
chilled Optifast (474 mL, 320 kcals, 50% carbohydrate, 35% protein, 15% fat; Novartis).  
Fasting (-10 minutes and 0 minutes) and serial postprandial (15-, 30-, 45-, 60-, and 90-, 
and 120-minutes: 8 total blood sampling time-points) plasma concentrations of glucose, 
insulin, C-peptide and a panel of hormones either directly or indirectly associated with 
appetite, satiety, and/or energy intake including leptin, ghrelin, peptide YY (PYY), GLP-1, 
glucose-dependent insulinotropic polypeptide (GIP), amylin, pancreatic polypeptide, and 
cholecystokinin will be measured (will require insertion of a polyethylene catheter in an 
antecubital vein), along with ratings on 15-cm  visual analog scales from “not at all” to 
“extremely” for appetite, satiety, desire to eat, and nausea.  This method has been 
validated for use in appetite research69 and was recently utilized by Sysko et al.70 in a 
study of adolescents with severe obesity.  We will calculate the area-under-the-curve 
(AUC) for all the biomarkers and visual analog scale results for the entire standardize 
meal test.  As recently reported,71 the standardized meal test can be utilized to evaluate 

 
 
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insulin sensitivity and beta cell function.  Gastric emptying rate will be measured during 
the meal test by obtaining serial samples (same time points as hormone measurements) 
of blood paracetamol (acetaminophen) levels (1,000 mg administered with the meal test, 
as previously described).72 
 
6.11.8 Measurement of Energy Expenditure 
Resting energy expenditure will be measured by indirect calorimetry after participants 
have been fasting for ≥8 hours.  Metabolic data will be collected using a ventilated hood 
(Parvo Medics; Sandy UT).  Previous investigations have shown the ventilated hood 
method to be more accurate and reliable when compared to the other techniques.73, 74  
This method has been shown to be more comfortable in tests that last more than five to 
ten minutes.74  Participants will be instructed to not engage in exercise on the day prior 
to testing.  Participants will be positioned comfortably in a semi-recumbent fashion for 60 
minutes.  Resting gas exchange measurements will be collected using a Parvo Medics 
TrueOne 2400 Metabolic Cart, (Sandy, UT).  The cart will be calibrated for gas analyses 
and volume at least twice prior to each test session.  Room air (25°C) will be drawn 
through the hood at a rate of 40 L/min.  Resting metabolic rates will be collected over the 
initial 30-minute reclining period with the last 10-minutes averaged into an estimate of 
resting metabolic rate. 
 
 
7 
Statistical Plan 
7.1 
Participant Populations for Analysis 
• Intent-to-treat (ITT): All participants randomized according to the treatment assignment 
received. 
• Per-Protocol (PP): All participants randomized without protocol violations and who were 
compliant (at least 80% of planned doses) with the treatment assignment received.  
Protocol violations include: change in status of weight loss/altering medication(s).   
• Safety Population: All participants who receive any amount of treatment according to the 
treatment they receive. 
7.2 
Sample Size Determination 
Based on our preliminary data, results of the Berkowitz et al. trial,55 and results of the Wadden 
et al. trial (in which 90% achieved 5% weight loss during the low calorie diet induction period),34 
we conservatively anticipate that at least 60% will achieve the 5% BMI reduction goal during the 
meal replacement induction period and would therefore be randomized.  Considering a 
conservative dropout rate as high as 20% (our previous clinical trial experience with this 
population has been 10-15%),50, 54 we will enroll 100 participants to have complete follow-up 
data at 52 weeks on at least 48 individuals.  Table 4 presents the power associated with a 
placebo-subtracted BMI reduction ranging from 5-7% based on an overall sample size of 60 (30 
in each treatment arm), variability estimates from the pilot trials50, 54 suggesting a conservative 
standard deviation of approximately 6, and a conservative correlation between baseline and 
follow-up scores of 0.5.   
 
 
 

 
 
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Table 4. Power for Values of BMI Percent Change Treatment Effects at 52 weeks   
 
 
 
 
 
Difference in BMI Percent 
Change 
5% 
6% 
7% 
Two-sided (N=60) 
96.1% 99.4% 99.9% 
Two-sided with 20% attrition 
(N=48) 
91.5% 97.9% 99.7% 
 
7.3 
Statistical Methods 
Descriptive analyses of baseline characteristics and outcomes will include means and standard 
deviations for continuous variables and frequencies for categorical variables.  Treatment 
compliance will also be evaluated.  
 
 
7.3.1 Primary Endpoint 
The primary analysis will be conducted using the ITT population to compare the mean 
BMI percent change from randomization to 52 weeks of follow-up between GLP-1RA 
and placebo groups, adjusted for values of 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 if there is a 
concerning imbalance between treatment arms). These results will be complemented 
with analyses summarizing the difference between treatment groups in the proportion of 
subjects able to maintain ≥5% reduction from baseline.  Analyses will be summarized by 
an odds ratio through use of a logit link function and adjusted for BMI at randomization 
with robust variance estimates for confidence intervals and P-values. 
 
 
7.3.2 Secondary Endpoints 
Secondary endpoints of body fat (total body-, visceral-, and subcutaneous fat), 
triglycerides/HDL ratio, blood pressure, inflammation, oxidative stress, postprandial 
glucose and insulin response, insulin resistance, and beta cell dysfunction will be 
characterized 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 and robust variance estimation will be used for 
confidence intervals and P-values.  Longitudinal analyses will also be conducted, 
incorporating the multiple time points at which these features are measured. Supportive 
analyses using the PP population will also be conducted. 
 
Mechanism of action metrics of appetite and satiety at 52 weeks follow-up will each be 
evaluated in a similar fashion as other secondary endpoints wherein analyses will be 
adjusted for values at randomization and confidence intervals and P-values will use 
robust variance estimation. 
 

 
 
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7.3.3 Safety Analyses   
The safety profile will be evaluated using the Safety analysis population and evaluated 
using data collected throughout follow-up.  Analyses will be primarily descriptive 
reporting the number and percentage of adverse events along with categorizations of 
seriousness, severity, frequency (within a subject), and perceived relatedness to the 
intervention.  In addition, safety labs of calcitonin, ALT, AST, amylase, lipase, prolactin, 
TSH, FSH, LH, testosterone, estradiol, dehydroepiandrosterone sulfate (DHEAS), 
carcinoembryonic antigen (CEA), and creatinine, along with change in sexual 
maturation, bone mineral content from iDXA scans, bone age, QTc interval from ECG, 
injection site reactions, and gastrointestinal side effects will be evaluated between 
groups and monitored by the data and safety monitoring board (DSMB) throughout the 
trial. 
 
 
7.3.4 Exploratory Analyses  
Exploratory analyses will include investigating potential treatment effect modifiers of 
appetite at randomization (high vs. low, based on AEBQ cutoff and alternatively area-
under-the-curve from the visual analog scale and meal test hormones) and sex.  These 
will each be evaluated separately for estimates of treatment effect within each subgroup 
along with a test of interaction analyzed in a similar fashion as the primary endpoint, with 
adjustment for BMI values at randomization. Complementary analyses using the PP 
population will also be conducted.   
7.4      Missing Data  
Despite best efforts to avoid missing data, it is possible that some data will be missing, which 
could limit the interpretation and generalizability of results. If the missing data is missing 
completely at random, the consequence will merely be lost precision.  Based upon attrition rates 
in our previous trials,50, 54 we conservatively anticipate that no more than 20% of the subjects will 
be lost to follow-up.  Taking this into account, the planned enrollment of 100 is inflated to 
account for potential drop out.  As such, in the ‘worst case’ situation of randomizing only 60 
participants and observing missing data as high as 20%, we will still have >90% power to detect 
a 5% placebo-subtracted change in BMI from randomization to 52 weeks (primary endpoint).  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 through sensitivity analyses.   
 
Imputation techniques will be considered for missing data issues, e.g., multiple imputation.  In 
particular, in the event there is missing data for the primary analysis, we will use a last 
observation carried forward approach.  Sensitivity analyses will also be conducted, using 
multiple imputation. Variables to be included in the imputation analysis model include sex, and 
age along with baseline and interim visit values.  In this fashion, observations obtained during 
interim visits will be used to facilitate these analyses. Analyses will be based on 100 imputed 
values using Markov chain Monte Carlo simulation.  Secondary endpoints will be handled 
similarly. 

 
 
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8 
Safety and Adverse Events 
8.1 
Potential Risks 
As with any research study, there may be unforeseen risks.  A trained interdisciplinary research 
staff comprised of physicians, scientists, nurses, and coordinators carefully guard against all 
potential risks.   
 
8.1.1 Dual-energy X-ray Absorptiometry (iDXA) Scan 
The iDXA is painless and involves exposure to a very low dose of radiation.  As part of 
this study, subjects will undergo a total of four iDXA scans.     
 
8.1.2 Blood Sampling  
There is minimal risk of bruising and infection associated with the blood draw. 
 
8.1.3 Medication 
All participants will be directed to immediately contact study staff if any symptoms of an 
adverse event are experienced regardless if the participant believes it may or may not 
be related to study medication. 
 
Adverse events will be reviewed and documented at each study visit and phone call 
(monitored monthly throughout the study).  Participants will be instructed to contact 
study staff immediately if any adverse event is experienced.  Overall, the safety profile of 
exenatide is favorable, with nausea as the most commonly- reported side effect.  The 
metabolic effects of exenatide are glucose-dependent; therefore, the risk of 
hypoglycemia is extremely low when used as a mono-therapy, as will be the case in the 
proposed study.75  Mild injection site reactions (bruising, injection site pain, etc.) have 
ranged from 2-8% in studies with exenatide extended-release.59-62  Evidence is mixed 
regarding whether acute pancreatitis and other potential pancreatic issues are 
associated with the use of GLP-1RAs among adult patients with T2DM.  Although 
multiple studies have reported no association between GLP-1RA use and pancreatitis,76-
79 others have suggested a link.80, 81  It is important to note that in the studies showing an 
association,80, 81 the absolute increase in risk of pancreatitis was extremely low.  In the 
proposed study, we will minimize any potential risk of pancreatitis by excluding patients 
with T2DM, a disease known to be associated with an increased risk of pancreatitis.77  
Furthermore, we will carefully monitor for reports of abdominal pain at each visit, and will 
measure lipase levels (pancreatic enzyme).  Of note, the FDA and European Medicines 
Agency released communications in the summer of 2013 stating that available data do 
not confirm recent concerns over an increased risk for pancreatic side effects with GLP-
1 based therapies.   
 
8.1.4 Questionnaires 
There are no risks associated with the questionnaires to be used in the study.  
Participants may refuse to answer any questions or stop participating at any time. 
8.2 
Definitions 
             8.2.1 Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or 

 
 
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worsens in severity during the course of the study.  Inter-current illnesses or injuries 
should be regarded as adverse events.  Abnormal results of diagnostic procedures are 
considered to be adverse events if the abnormality: 
• 
results in study withdrawal 
• 
is associated with a serious adverse event 
• 
is associated with clinical signs or symptoms 
• 
leads to additional treatment or to further diagnostic tests 
• 
is considered by the investigator to be of clinical significance 
 
 Adverse events relationship to the study will be based on the following scale: 
• 
Unrelated: Clearly not related to study 
• 
Unlikely: Unlikely to be related to study 
• 
Possible: May be related to study 
• 
Probable: Likely to be related to study 
• 
Definite: Clearly related to study 
 
8.2.2 Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is 
any AE that is:  
• 
fatal 
• 
life-threatening 
• 
requires or prolongs hospital stay 
• 
results in persistent or significant disability or incapacity 
• 
a congenital anomaly or birth defect 
• 
an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are 
clearly of major clinical significance.  They may jeopardize the participant, and may 
require intervention to prevent one of the other serious outcomes noted above. 
 
All adverse events that do not meet any of the criteria for serious should be regarded as 
non-serious adverse events.  
 
8.2.3 Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as 
the period from the initiation of any study procedures to the end of the study treatment 
follow-up.  For this study, the study treatment follow-up is defined as 30 days following 
the last administration of study treatment at which time a final phone call visit will be 
completed.   
 
8.2.4 Preexisting Condition 
 A preexisting condition is one that is present at the start of the study.  A preexisting 
 condition will only be recorded as an adverse event if the frequency, intensity, or the 
 character of the condition worsens during the study period. 
 
8.2.5 General Physical Examination Findings 
At screening, any clinically significant abnormality will be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities 

 
 
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that meet the definition of an adverse event will be recorded and documented as an 
adverse event.  
 
8.2.6 Post-study Adverse Event 
All unresolved adverse events will be followed until the events are resolved, the 
participant is lost to follow-up, or the adverse event is otherwise explained.  At the final 
visit, the participant and the parent/guardian will be instructed to report any subsequent 
event(s) that they, or their personal physician, believe might reasonably related to 
participation in this study.   
 
8.2.7 Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one 
of the following conditions is met:  
• 
The laboratory abnormality is not otherwise refuted by a repeat test to 
confirm the abnormality 
• 
The abnormality suggests a disease and/or organ toxicity 
• 
The abnormality is of a degree that requires active management; e.g., 
change of dose, discontinuation of the drug, more frequent follow-up 
assessments, further diagnostic investigation, etc. 
 
8.2.8 Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization will be 
documented and reported as a serious adverse event unless specifically instructed 
otherwise in this protocol.  Any condition responsible for surgery will be documented as 
an adverse event if the condition meets the criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported 
as an adverse event in the following circumstances: 
 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  Surgery should not be reported as an 
outcome of an adverse event if the purpose of the surgery was elective or 
diagnostic and the outcome was uneventful. 
• 
Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
• 
Hospitalization or prolonged hospitalization for therapy of the target disease 
of the study, unless it is a worsening or increase in frequency of hospital 
admissions as judged by the clinical investigator. 
8.3 
Recording of Adverse Events 
At each contact with the participant and their parent/guardian adverse events will be assessed 
by specific questioning and, as appropriate, by examination.  Information on all adverse events 
will be recorded immediately in the source document, and also in the appropriate adverse event 
form.   All clearly related signs, symptoms, and abnormal diagnostic procedures results will be 
recorded in the source document, although they should be grouped under one diagnosis. 
 
All adverse events occurring during the study period will be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause.  Serious adverse events that are still 

 
 
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ongoing at the end of the study period must be followed up to determine the final outcome.  Any 
serious adverse event that occurs after the study period and is considered to be possibly related 
to the study treatment or study participation will be recorded and reported immediately.   
8.4 
Reporting of Serious Adverse Events 
 
8.4.1 IRB Notification by Investigator 
Reports of all serious adverse events (including follow-up information) will be submitted 
to the IRB within 10 working days if it falls under the UPIRTSO guidelines.  Copies of 
each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s binder. 
 
8.4.2 FDA Notification by Sponsor 
The study sponsor shall notify the FDA by telephone or by facsimile transmission of any 
unexpected fatal or life-threatening experience associated with the use of the drug as 
soon as possible but no later than 7 calendar days from the sponsor’s original receipt of 
the information. 
 
If a previous adverse event that was not initially deemed reportable is later found to fit 
the criteria for reporting, the study sponsor will submit the adverse event in a written 
report to the FDA as soon as possible, but no later than 15 calendar days from the time 
the determination is made  
8.5 
Un-blinding Procedures 
When necessary, and at the discretion of the medical officer in consultation with the principal 
investigator, un-blinding on an individual-participant basis (e.g., adverse event related) will be 
performed by the University of Minnesota IDS Pharmacy. 
8.6 
Stopping Rules  
In the event that a participant has a serious adverse event that is deemed study-related by the 
medical officer, the participant will be required to immediately discontinue the study drug.  The 
overall study may be stopped at any time at the request of the DSMB, principal investigator, 
and/or medical officer.  The main adverse effect that we expect to observe with GLP-1 treatment 
is gastrointestinal discomfort.  In particular, nausea is a common side effect associated with 
treatment, especially within the first few weeks of initiation.  Because this is an expected side 
effect and in many cases can be tolerated, participants who experience this adverse effect will 
not automatically be removed from the study.  Participants will be removed from the study if 
gastrointestinal distress is deemed severe by the medical officer or if the participant is 
hospitalized for gastrointestinal-related symptoms.  If more than five participants are 
hospitalized for gastrointestinal-related symptoms, the trial will be stopped.  Participants will be 
instructed that they may withdraw from the study at any time and for any reason.   
8.7 
Medical Monitoring 
Safety monitoring will include individual participant comprehensive assessment and appropriate 
reporting of adverse events as they occur.  Adverse events will be monitored closely and 
participants will be provided with information about the risks/side effects of the study medication 
and provided with phone numbers to reach the principal investigator/study coordinator in case of 
emergencies. 
 

 
 
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8.8 
Data and Safety Monitoring Board 
A DSMB will be established, which will include at least one adult endocrinologist, one pediatric 
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) 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 principal investigator 
and co-investigators advising on the continuation of the study.  
9 
Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study participants will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
• 
What protected health information (PHI) will be collected from participants 
in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research participant to revoke their authorization for use of 
their PHI.  
 
In the event that a participant revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For participants that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) 
at the end of their scheduled study period. 
9.2 
Source Documents and Case Report Forms 
All data will be collected and transcribed onto source documents. These source documents will 
act as the CRF. The source documents will have a unique identification number assigned by the 
study staff and will not include any personal identifiers. 
9.3 
Records Retention 
The investigator will retain study essential documents for at least 6 years after the conclusion of 
the study.     
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
The study will undergo regular monitoring (annually during the enrollment and follow up period) 
of the facility, staff, and study documents by clinical research associates in the University of 
Minnesota Clinical Trials Monitoring Service, which specializes in regulatory compliance for 
clinical trials associated with the Food and Drug Administration.  This service provides regular 
monitoring of all research-related activities and is offered free of charge through the University 
of Minnesota CTSI.  Monitoring staff will present a summary report to the PI after each site visit.  

 
 
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If necessary, corrective action plans will be devised and implemented by the PI to address 
deficiencies. 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, government regulatory bodies, and University compliance and quality assurance 
groups of all study related documents (e.g. source documents, regulatory documents, data 
collection instruments, study data etc.).  The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
11   Ethical Considerations 
This study will be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal approval 
of the study conduct.  The decision of the IRB concerning the conduct of the study will be made 
in writing to the investigator and a copy of this decision will be provided to the sponsor before 
commencement of this study.  The investigator should provide a list of IRB members and their 
affiliate to the sponsor. 
 
All participants and parents/guardians for this study will be provided an assent and consent 
form, respectively, describing this study and providing sufficient information for 
participants/families to make an informed decision about participation in this study.  The consent 
form will be submitted with the protocol for review and approval by the IRB for the study.  The 
formal assent of a participant and consent of the parent/guardian, using the IRB-approved 
assent and consent forms, must be obtained before that subject is submitted to any study 
procedure.  This consent form will be signed by the participant or legally acceptable surrogate, 
and the investigator-designated research professional obtaining the consent.  
 
Based upon guidance provided in 45 CFR 46, subpart D sections 401-409 regarding research in 
children, we believe that the proposed study poses greater than minimal risk but provides the 
prospect of direct benefit to the participants (half of the participants will be treated with GLP-1RA, 
which may provide benefit).  The risk lies mainly in the administration of a medication approved 
for use in adults with type 2 diabetes in an “off label” population (adolescents ages 12-17) for an 
“off label” purpose (reduction of BMI and improvement of cardiometabolic risk factors and 
comorbidities).  An Investigational New Drug (IND) exemption inquiry will be submitted (or a full 
IND application, if necessary) prior to commencement of the study (note: we received IND 
exemptions for our previous clinical trials with exenatide in the same patient population).  We will 
utilize the expertise of staff in the IND Assistance Program, within the University of Minnesota 
Clinical and Translational Science Institute, to draft the IND exemption request/IND application.   
 
Claudia Fox, M.D., M.P.H., a pediatrician who is board-certified in obesity medicine, will serve 
as the medical officer for the trial.  The study will undergo regular monitoring by clinical research 
associates employed by the University of Minnesota Clinical Trials Monitoring Service, which 
specializes in regulatory issues related to studies monitored by the Food and Drug 
Administration.  The following sections detail how each subpart D criterion will be satisfied: a) 
the risk is justified by the anticipated benefits to subjects; b) the relation of the anticipated 
benefit to the risk is at least as favorable to the subjects as that presented by available alternate 

 
 
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approaches; and c) adequate provisions are made for soliciting the assent of the adolescents 
and permission of their parents or guardians.   
11.1 Human Subjects Involvement and Characteristics   
One-hundred (100) adolescents (ages 12-17 years old) with severe obesity (BMI ≥ 1.2 times the 
95th percentile or BMI ≥35 kg/m2) will be recruited from the University of Minnesota Children’s 
Hospital, Pediatric Weight Management Clinic and member sites of the MN-POC: Mayo Clinic, 
Children’s Hospitals and Clinics of Minnesota, and Park Nicollet.  Adolescents are typically 
referred to these clinics to address issues related to excess body weight, comorbid conditions, 
and adverse cardiometabolic risk factors.  Participants in this study will undergo a series of 
measurements of BMI, body composition, meal testing, and cardiometabolic risk factors, which 
will require blood draws.  All costs of testing will be covered by the research study and subjects 
will be reimbursed for study participation. 
11.2 Source of Research Materials  
The following types of research material will be obtained from the participants: blood specimens, 
anthropometric data, blood pressure data, and other clinical variables.  This material will be 
used exclusively for research.  Pre-existing chart information will be used.  Data obtained will be 
stored in a confidential database without direct subject identifiers.  The principal investigator and 
designated study staff will have access to the subject linkages, which will be stored in a 
separate, secured location.  Hard copies of data, including source documents with patient 
identifiers, will be kept in locked file cabinets in a locked office until the completion and 
publication of the study, at which point any patient identifiers will be removed and data will be 
stored at a secure storage facility for 6 years.  Access to the locked file cabinet will be given to 
the study coordinators and principal investigator only.  Any study files that will be shared with 
the University of Minnesota will remove patient identifying information.   
11.3 Recruitment and Informed Consent  
Subjects will be recruited from the University of Minnesota Masonic Children’s Hospital, 
Pediatric Weight Management Clinic and member sites of the MN-POC.  Appropriate designees 
will discuss study participation with interested participants and their parents at which time the 
initial consent and assent discussion will be conducted.  Assent and consent will be obtained by 
the study coordinator after explaining the entire study in detail, asking the participant and the 
parent(s)/guardian(s) to explain the purpose, risk and benefits, and other details of the study, 
and giving the participant and parent(s)/guardian(s) an opportunity to ask questions.  A copy of 
the assent and consent form will be given to the participants and parent(s)/guardian(s). 
11.4 Potential Risks to Subjects   
As with any research study, there may be unforeseen risks.  A trained interdisciplinary research 
staff comprised of physicians, scientists, nurses, and study coordinators carefully guard against 
all potential risks.   
 
Blood Sampling (fasting and during meal test) 
There is minimal risk of bruising and infection associated with the blood draw and IV placement. 
 
Medication 
Expected Adverse Events – Exenatide Extended-Release 
The long-acting, extended-release formulation of exenatide will be utilized for this trial.  Despite 
a much lower incidence of nausea and vomiting, the magnitude of weight reduction with 
exenatide extended-release has been shown to be very similar to the twice per day formulation 

 
 
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in multiple trials.  Exenatide extended-release is administered one time per week by 
subcutaneous injection in the upper arm, abdomen, or thigh.  Exenatide will be initiated and 
maintained at a dose of 2.0 mg per week.  The 2.0 mg dose was previously shown to achieve 
plasma exenatide concentrations similar to the maximum concentration achieved with a single 
injection of 10 mcg exenatide and was demonstrated to be the most efficacious dose for weight 
loss – a dose of 0.8 mg elicited no weight loss at 15 weeks in adults with T2DM.  Exenatide 
extended-release and matching placebo pens will be provided by Astra Zeneca 
Pharmaceuticals.  Placebo and active exenatide devices will be indistinguishable.   
 
Study drug and placebo will be housed, dispensed, and tracked in the University of Minnesota 
Investigational Drug Service Pharmacy.  Subjects will be given identical administration 
instructions regardless of group assignment.  Instructive education will include reviewing 
procedures with a trained study coordinator and/or physician.  Subjects will be instructed to 
administer the medication under the supervision of a parent/guardian.  Subjects will be required 
to complete a study medication log. 
 
Adverse events will be carefully and comprehensively reviewed and documented at each study 
visit and during each phone call (adverse events will be monitored monthly throughout the 
study).  Subjects will be instructed to contact study staff immediately if any adverse event is 
experienced.  Overall, the safety profile of exenatide is favorable, with nausea as the most 
commonly reported side effect.  The metabolic effects of exenatide are triggered by the 
presence of food in the gut (i.e., glucose-dependent); therefore, the risk of hypoglycemia is 
extremely low when used as a mono-therapy, as will be the case in the proposed study.  Mild 
injection site reactions (bruising, injection site pain, etc.) have ranged from 2-8% in studies with 
exenatide extended-release.   
 
Evidence is mixed regarding whether acute pancreatitis and other potential pancreatic issues 
are associated with the use of GLP-1 receptor agonists among adult patients with T2DM.  In the 
proposed study, we will minimize any potential risk of pancreatitis by excluding patients with 
T2DM, a disease known to be associated with an increased risk of pancreatitis.  Furthermore, 
we will carefully monitor for reports of abdominal pain at each visit, and will measure lipase 
(pancreatic enzyme).  Regarding potential associations of GLP-1 receptor agonists and 
pancreatic issues, the FDA and European Medicines Agency released communications in the 
summer of 2013 stating that available data do not confirm recent concerns over an increased 
risk for pancreatic side effects with GLP-1 based therapies. 
11.5 Protections Against Risk   
Claudia Fox, M.D., M.P.H., a pediatrician who is board-certified in obesity medicine, will be 
responsible for the medical safety aspects of this trial.  Participants will be evaluated at each 
visit for potential side effects.  Participants will be contacted by phone between visits to monitor 
and assess possible side effects and to encourage adherence to the medication regimen.  At 
each contact with the participant and their parent/guardian, adverse events will be assessed by 
specific questioning and, as appropriate, by examination.  Information on all adverse events will 
be recorded immediately in the source document, and also in the appropriate adverse event 
form.   All clearly related signs, symptoms, and abnormal diagnostic procedures results will be 
recorded in the source document and will be grouped under one diagnosis.  All adverse events 
occurring during the study period will be recorded.  The clinical course of each event should be 
followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the 
study period must be followed up to determine the final outcome.  Any serious adverse event 

 
 
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that occurs after the study period and is considered to be possibly related to the study treatment 
or study participation will be recorded and reported immediately.  
 
Calcitonin, amylase, lipase, prolactin, TSH, FSH, LH, testosterone, estradiol, 
dehydroepiandrosterone sulfate (DHEAS), and carcinoembryonic antigen (CEA) will be 
measured throughout the study.  Participants who at any time have a level of calcitonin 
exceeding 50 ng/L will be immediately withdrawn from the study.  Sexual maturation and stature 
will be tracked throughout the study.  Bone mineral content will be measured by iDXA and bone 
age via x-ray.  Of note, we do not expect to observe an interaction between exenatide treatment 
and bone maturation but believe it is an important variable to measure in a pediatric drug trial.  
Duration of the QTc interval will be measured by ECG.  Gastrointestinal side effects (mainly 
nausea) and other adverse events will be monitored monthly via regular phone calls by the 
study coordinator.  Quantitative grading of the incidence and severity of gastrointestinal side 
effects will be conducted with the PedsQL Gastrointestinal Symptoms Scale at each study visit.  
A comprehensive metabolic panel will be performed at baseline and all post-randomization 
study visits. 
11.6 Potential Benefits of the Proposed Research to the Subjects and Others   
We believe the potential benefits (the prospect of benefit exists in that half of the participants will 
receive exenatide, which may reduce BMI and improve risk factors) to the participants outweigh 
the risks in this study.  Since data from clinical trials in adults and evidence from our own 
research in adolescents with severe obesity have demonstrated reduction in BMI and 
improvements in cardiometabolic risk factors with exenatide, it is reasonable to expect similar 
results in the proposed clinical trial.  The side effect profile of exenatide is favorable and the 
proposed tests are not more than minimal risk.  The alternative treatment approach is standard-
of-care lifestyle/behavioral modification therapy and/or treatment with orlistat or “off-label” 
weight loss medications.  All participants in this study will receive lifestyle/behavioral 
modification therapy.  Based upon data in adults and our preliminary evidence in adolescents, it 
is possible that the benefits of exenatide will be additive to the lifestyle/behavioral modification 
therapy.   
11.7 Importance of the Knowledge to be Gained 
Early development of cardiovascular disease and type 2 diabetes may be preventable if 
targeted interventions can be instituted early in life in adolescents who are at the greatest risk.  
Lifestyle modification, focusing on weight loss and increased physical activity, should be the 
foundational approach to treating severe obesity in adolescents.  However, most adolescents 
with severe obesity are unable to reduce their weight to an acceptable level with lifestyle 
modification alone and may benefit from adjunctive pharmacotherapy to reduce adiposity and 
the risk of developing cardiovascular disease and type 2 diabetes.  Few weight loss medications 
have been evaluated in obese adolescents and novel approaches should be explored.  Data 
obtained from this study will determine whether exenatide is a safe and effective treatment for 
weight loss maintenance and sustained improvements in cardiometabolic risk factors among 
adolescents with severe obesity.   
11.8 Data and Regulatory Monitoring Plan 
Medical Monitoring 
Safety monitoring will include careful assessment and appropriate reporting of adverse events.  
Adverse events will be monitored closely and subjects will be provided with information about 
the risks/side effects of the study medication and provided with phone numbers to reach the 
principal investigator/study coordinator in case of emergencies. 

 
 
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Study Monitoring 
The study will undergo regular monitoring (annually during the enrollment and follow up period) 
of the facility, staff, and study documents by clinical research associates in the University of 
Minnesota Clinical Trials Monitoring Service, which specializes in regulatory compliance for 
clinical trials associated with the Food and Drug Administration.  This service provides regular 
monitoring of all research-related activities and is offered free of charge through the University 
of Minnesota CTSI.  Monitoring staff will present a summary report to the PI after each site visit.  
If necessary, corrective action plans will be devised and implemented by the PI to address 
deficiencies. 
12   Study Finances 
12.1 Funding Source 
The study is funded by the National Institutes of Health (NIH) through the National Institute of 
Diabetes and Digestive and Kidney Diseases (NIDDK).   
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must refer to the 
Regents Policies on Individual Conflict of Interest Policy or Institutional Conflict of Interest 
Policy. These policies require University Faculty and staff to report external professional 
activities and business and significant financial interests related to his or her University activities 
by submitting a REPA (Report of External Professional Activities) at least once per year. Faculty 
and staff should also file a REPA when substantial changes in business or financial interests 
occur, when an activity that presents a potential conflict of interest is anticipated, or when 
submitting an application for research support or technology transfer, submitting research 
protocols to the IRB, or receiving financial contributions. All University of Minnesota 
investigators will follow the University conflict of interest policy. 
 
Dr. Kelly serves as a consultant for Novo Nordisk pharmaceuticals and Takeda pharmaceuticals 
but does not accept personal or professional payment for his services.  None of the other 
investigators have relevant conflicts to report.    
12.3 Subject Stipends or Payments 
Participants will receive a total of $1,400 in the form of gift cards if they complete all study visits 
(10 visits total).  In addition, if applicable, parking and/or meal vouchers will be provided at each 
visit.   Participants who are withdrawn early from study participation will be paid for the visits 
completed to that point. 
13 Publication Plan 
Data from this trial may be published.  Dr. Aaron Kelly holds the primary responsibility for the 
publication of these data.   
 
 

 
 
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14   Reference List 
Reference List 
 
 
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 (10)  Freedman DS, Mei Z, Srinivasan SR, Berenson GS, Dietz WH. Cardiovascular risk 
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 (20)  Morrison JA, Friedman LA, Wang P, Glueck CJ. Metabolic syndrome in childhood 
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