Enhancing Weight Loss With Meal-Replacement Therapy in Teens With Severe Obesity
Phase: NA
Conditions: Obesity, Severe, Pediatric Obesity
Sponsor: University of Minnesota

 
 
Enhancing Weight Loss with Financial Incentives in Teens 
 
NCT03137433 
 
Study Protocol and Statistical Analysis Plan dated 2022Apr06 

 
University of Minnesota 
 
 
Enhancing Weight Loss with Financial Incentives in Teens 
 
 
Regulatory Sponsor: 
University of Minnesota 
Funding Sponsor: 
National Institutes of Health (NIH) 
National Institute of Diabetes and Digestive and Kidney 
Diseases (NIDDK) 
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. 
Robert Jeffery, Ph.D. 
Amy Gross, Ph.D., L.P. 
Brandon Nathan, M.D. 
Muna Sunni, M.D. 
Justin R. Ryder, Ph.D. 
Donald R. Dengel, Ph.D. 
M. Jennifer Abuzzahab, M.D. 
Seema Kumar, M.D. 
Betsy Schwartz, M.D. 
Megan Oberle, M.D. 
Version Date: 
Version 12, April 6, 2022 

 
 
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Protocol Change History: 
Version 1: March 2, 2017 
Version 2: April 11, 2017 blood volumes added, clarification to 
6.11.7 
Version 3: June 27, 2017 reduction in number of vascular 
endpoints, elimination of FitBit device, revision of meal replacement 
therapy (Seattle Sutton food provision) 
Version 4: November 1, 2017 reduction of physical exams & 
Tanner staging to baseline only, add Megan Oberle as Co-
Investigator 
Version 5: December 8, 2017 neuromuscular disorder exclusion, 
substance abuse exclusion 
Version 6: January 10, 2019  Seattle Sutton Healthy Meals 
business name change to: Healthy for Life Meals 
Version 7: Revised the consent process to include consent 
conducted virtually  
Version 8: Revised section 11.3 of the protocol to discuss the types 
of virtual consent that will be utilized and any encryption 
Version 9: Reduces the sample size to 120 participants.  Eliminates 
the Week 78 visit.  Revises the statistical plan.  Removes the food 
diary. 
Version 10: Clarifies the reporting period for adverse events and 
serious adverse events now that the protocol has been shortened 
to 52 weeks.  This version also clarifies questionnaires, how blood 
pressure is being measured, corrects a mention of Seattle Sutton’s 
Healthy Eating, updates the number of iDXA scans, the number of 
participants, clarifies the monthly phone calls and the total 
compensation.   
Version 11: Removes the metabolic rate/energy expenditure 
testing.  We were not allowed to resume this once we were allowed 
to re-start visits after COVID started.  The decision has been made 
to completely remove it from the protocol at this time. This version 
also increases enrollment to 130 as a recent batch of recruitment 
letters has yielded significant interest and we would like to enroll 
those who are deemed eligible. 
 
Version 12:  Makes changes to the statistical plan (section 7) of the 
protocol. 
 
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 CONTENTSSTUDY SUMMARY ...................................................................................................... 1 
1 INTRODUCTION/SUMMARY ................................................................................................................................ 2 
1.1 
BACKGROUND AND RATIONALE ................................................................................................................... 2 
1.2 
CLINICAL DATA TO DATE ............................................................................................................................ 4 
2 
STUDY OBJECTIVES ....................................................................................................................................... 8 
2.1 
PRIMARY OBJECTIVE .................................................................................................................................... 8 
2.2 
SECONDARY OBJECTIVES ............................................................................................................................. 8 
3 
STUDY DESIGN ................................................................................................................................................. 8 
3.1 
GENERAL DESIGN ........................................................................................................................................ 8 
3.2 
PRIMARY AND SECONDARY STUDY ENDPOINTS ........................................................................................... 8 
4 
SUBJECT SELECTION AND WITHDRAWAL ............................................................................................. 9 
4.1 
INCLUSION CRITERIA ................................................................................................................................... 9 
4.2 
EXCLUSION CRITERIA .................................................................................................................................. 9 
4.3 
EARLY WITHDRAWAL OF PARTICIPANTS ................................................................................................... 10 
4.3.1 
When and How to Withdraw Participants ....................................................................................... 10 
4.3.2 
Data Collection and Follow-up for Withdrawn Participants ......................................................... 10 
5 
TREATMENT .................................................................................................................................................... 10 
5.1 
TREATMENT REGIMEN ............................................................................................................................... 10 
5.2 
METHOD FOR ASSIGNING PARTICIPANTS TO TREATMENT GROUPS ........................................................... 10 
5.3 
PRIOR AND CONCOMITANT THERAPY ........................................................................................................ 10 
6 
STUDY PROCEDURES .................................................................................................................................. 10 
6.1 
SCREENING VISIT OR PHONE CALL ............................................................................................................ 11 
6.2 
BASELINE VISIT (SCREENING AND BASELINE VISIT MAY BE COMPLETED ON THE SAME DAY) .................... 11 
6.3 
8-WEEK VISIT (8 WEEKS ±7 DAYS FROM BASELINE VISIT) ......................................................................... 12 
6.4 
17-WEEK VISIT (17 WEEKS ±7 DAYS FROM BASELINE VISIT) ..................................................................... 12 
6.5 
26-WEEK VISIT (26 WEEKS ±7 DAYS FROM BASELINE VISIT) ..................................................................... 12 
6.6 
34-WEEK VISIT (34 WEEKS ±7 DAYS FROM BASELINE VISIT) ..................................................................... 13 
6.7 
43-WEEK VISIT (43 WEEKS ±7 DAYS FROM BASELINE VISIT) ..................................................................... 13 
6.8 
52-WEEK VISIT (52 WEEKS ±7 DAYS FROM BASELINE VISIT) ..................................................................... 13 
6.9 
MONTHLY PHONE CALL/EMAIL/TEXT MESSAGE (COMPLETED BETWEEN IN-PERSON STUDY VISITS) ......... 14 
6.10 
DETAILED STUDY PROCEDURES ................................................................................................................. 14 
6.10.1 Anthropometric Measurements and Assessment of Pubertal Status ........................................ 14 
6.10.2 Blood Pressure and Heart Rate ....................................................................................................... 15 
6.10.3 Blood Analyses ................................................................................................................................... 15 
6.10.4 Lifestyle/Behavioral Modification Counseling ................................................................................ 15 
6.10.5 Meal Replacement Therapy ............................................................................................................. 15 
6.10.6 Financial Incentives ........................................................................................................................... 15 
6.10.7 Assessment of Motivation, and Other Behavioral and Psychosocial Factors .......................... 16 
6.10.8 Vascular Measurements ................................................................................................................... 16 
Vascular testing will be performed in the morning in a quiet room of constant temperature (22º C – 
23º C).  Participants will be fasting and will be instructed to refrain from caffeine and medications 
prior to the study. .............................................................................................................................................. 16 
7 
STATISTICAL PLAN ....................................................................................................................................... 16 
7.1 
PARTICIPANT POPULATIONS FOR ANALYSIS .............................................................................................. 16 
7.2 
SAMPLE SIZE DETERMINATION .................................................................................................................. 17 
7.3 
STATISTICAL METHODS ............................................................................................................................. 17 
7.3.1 
Specific Aim #1 (Primary and Secondary Endpoints) .................................................................. 17 
7.3.2 
Specific Aim #2 ................................................................................................................................... 18 
7.3.3 
Safety Analyses .................................................................................................................................. 18 

 
 
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7.4      MISSING DATA ................................................................................................................................................ 19 
8 
SAFETY AND ADVERSE EVENTS .............................................................................................................. 19 
8.1 
POTENTIAL RISKS ....................................................................................................................................... 19 
8.1.1 
Dual-energy X-ray Absorptiometry (iDXA) Scan ........................................................................... 19 
8.1.2 
Blood Sampling .................................................................................................................................. 19 
8.1.3 
Questionnaires ................................................................................................................................... 19 
8.2 
DEFINITIONS ............................................................................................................................................... 19 
8.2.1 
Adverse Event .................................................................................................................................... 19 
8.2.2 
Serious Adverse Event ...................................................................................................................... 20 
8.2.3 
Adverse Event Reporting Period ..................................................................................................... 20 
8.2.4 
Preexisting Condition ........................................................................................................................ 20 
8.2.5 
General Physical Examination Findings ......................................................................................... 21 
8.2.6 
Abnormal Laboratory Values ............................................................................................................ 21 
8.2.7 
Hospitalization, Prolonged Hospitalization or Surgery ................................................................. 21 
8.3 
RECORDING OF ADVERSE EVENTS ............................................................................................................. 21 
8.4 
REPORTING OF SERIOUS ADVERSE EVENTS ............................................................................................... 22 
8.4.1 
IRB Notification by Investigator ........................................................................................................ 22 
8.5 
STOPPING RULES ........................................................................................................................................ 22 
8.6 
MEDICAL MONITORING .............................................................................................................................. 22 
8.7 
DATA AND SAFETY MONITORING BOARD ................................................................................................. 23 
9 
DATA HANDLING AND RECORD KEEPING ............................................................................................ 23 
9.1 
CONFIDENTIALITY ...................................................................................................................................... 23 
9.2 
SOURCE DOCUMENTS AND CASE REPORT FORMS ...................................................................................... 23 
9.3 
RECORDS RETENTION ................................................................................................................................ 23 
10 
STUDY MONITORING, AUDITING, AND INSPECTING .......................................................................... 23 
10.1 
STUDY MONITORING PLAN ........................................................................................................................ 23 
10.2 
AUDITING AND INSPECTING ....................................................................................................................... 24 
11   ETHICAL CONSIDERATIONS ........................................................................................................................ 24 
11.1 
HUMAN SUBJECTS INVOLVEMENT AND CHARACTERISTICS ....................................................................... 25 
11.2 
SOURCE OF RESEARCH MATERIALS ........................................................................................................... 25 
11.3 
RECRUITMENT AND INFORMED CONSENT .................................................................................................. 25 
11.4 
POTENTIAL RISKS TO PARTICIPANTS .......................................................................................................... 26 
11.5 
PROTECTIONS AGAINST RISK ..................................................................................................................... 26 
11.6 
POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO THE PARTICIPANTS AND OTHERS ........................ 27 
11.7 
IMPORTANCE OF THE KNOWLEDGE TO BE GAINED ..................................................................................... 27 
11.8 
DATA AND REGULATORY MONITORING PLAN ........................................................................................... 27 
12   STUDY FINANCES ........................................................................................................................................... 27 
12.1 
FUNDING SOURCE ...................................................................................................................................... 27 
12.2 
CONFLICT OF INTEREST .............................................................................................................................. 27 
12.3 
PARTICIPANT STIPENDS OR PAYMENTS ...................................................................................................... 28 
13 
PUBLICATION PLAN ..................................................................................................................................... 28 
 

 
 
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List of Abbreviations 
 
 
AE 
 
Adverse Event 
AEBQ  
Adult Eating Behavior Questionnaire 
BIPAP  
Bilevel Positive Airway Pressure 
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 
CRF 
 
Case Report Form 
CTSI  
Clinical Translational Science Institute 
DSMB  
Data safety and monitoring board 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders version 5 
ECG 
 
Electrocardiogram 
EDE-Q  
Eating Disorder Examination Questionnaire 
FDA 
 
Food and Drug Administration 
GCP 
 
Good Clinical Practice 
HDL 
 
High density lipoprotein 
HIPAA  
Health Insurance Portability & Accountability Act of 1996 
iDXA  
i Dual Energy X-ray Absorptiometry 
IWQOL-Kids Impact of Weight on Quality of Life  
IRB 
 
Institutional Review Board 
ITT  
 
Intent to Treat 
LDL 
 
Low density lipoprotein 
MN-POC 
Minnesota Pediatric Obesity Consortium 
QEWP  
Questionnaire of Eating and Weight Patterns-Adolescent 
PedsQL™  
Young Adult Quality of Life Inventory) Child and Parent 
PHI 
 
Personal Health Information 
REPA  
Report of External Professional Activities 
SCARED 
Screen for Child Anxiety Related Disorders 
SAE 
 
Serious Adverse Event 
TC 
 
Total Cholesterol 
TG 
 
Triglycerides 
UPIRTSO 
Unanticipated problems involving risk to subjects or others 

 
 
Page 1 
 
Study Summary 
Title 
Enhancing Weight Loss with Financial Incentives in Teens 
Phase 
N/A 
Methodology 
Randomized, controlled clinical trial 
Study Duration 
5 Years 
Study Center 
University of Minnesota Center for Pediatric Obesity Medicine in 
collaboration with the Minnesota Pediatric Obesity Consortium (MN-
POC) 
Objectives & 
Hypotheses 
Primary Objective: Evaluate the effect of meal replacement 
therapy plus financial incentives on weight loss, cardiometabolic 
risk factors, vascular health, and behavior change among 
adolescents with severe obesity.  We hypothesize that the use of 
meal replacement therapy with financial incentives (vs. no financial 
incentives) will lead to greater percent reduction in BMI (primary 
endpoint) as well as reduce body fat, blood pressure, triglycerides/HDL 
ratio, inflammation, oxidative stress, arterial stiffness, and improve 
heart rate variability at 26 and 52 weeks.   
 
Secondary Objectives: Identify weight loss thresholds associated 
with significant improvements in cardiometabolic risk factors and 
vascular health in adolescents with severe obesity.  We 
hypothesize that a minimum weight loss threshold exists, that when 
exceeded, will be associated with meaningful improvements in multiple 
cardiometabolic risk factors and parameters of vascular health. 
Number of 
Participants 
130 
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 13-17 years 
Study Intervention 
All participants will engage in 52 weeks of meal replacement therapy.  
Participants will be randomly assigned to receive financial incentives for 
weight loss or no financial incentives.  
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 (additional analyses will use the 26-week 
time-point as secondary) of follow-up between the financial incentives 
and no financial incentives groups, adjusted for BMI at randomization 
and insurance status (randomization stratification factor) 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.   
 

 
 
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1 Introduction/Summary 
 
Severe obesity, defined as a body mass index (BMI) ≥20% above the 95th percentile or BMI ≥35 
kg/m2, is the fastest growing category of pediatric obesity, with a reported prevalence near 6% 
in the United States.1-5  The number and magnitude of cardiometabolic risk factors and co-
morbidities, including vascular abnormalities, is much higher in severe obesity vs. overweight or 
obesity.2, 6  Severe obesity tracks strongly into adulthood6 and increases the risk of 
cardiovascular disease6 and type 2 diabetes.7  Initiating effective weight loss interventions prior 
to adulthood offers the best opportunity to alter the disease trajectory and meaningfully improve 
long-term health.8, 9  However, because conventional treatment approaches rarely result in 
sufficient weight loss in adolescents with severe obesity,10-13 highly-innovative and effective 
strategies are desperately needed. 
 
The financial incentive model has been used successfully in adult obesity trials to address 
suboptimal adherence to lifestyle modification therapy and improves weight loss outcomes.14-18  
Although yet to be investigated as a weight loss intervention among adolescents, financial 
incentives have been shown to improve many health-related behaviors in teenagers including 
compliance with wearing physical activity accelerometers,19 treatment adherence in type 1 
diabetes,20 school attendance in youth at risk for HIV infections,21 and smoking cessation.22, 23  
Owing to the refractory nature of pediatric severe obesity, financial incentives are more likely to 
be effective if used in concert with a structured dietary plan such as meal replacement therapy 
(pre-portioned, calorically defined meals), which has been shown to elicit superior weight 
reduction compared to conventional diets among adults.24  Although a relatively new treatment 
for pediatric obesity, meal replacement therapy has produced promising short-term weight loss 
(6% BMI reduction at 4 months) in adolescents with severe obesity.25  However, much of the 
initial weight lost by participants was regained after 4 months, owing to diminished adherence to 
the meal replacement regimen over time.25  Our concept is to capitalize on the potential synergy 
of meal replacement therapy and financial incentives to optimize weight loss and improve 
cardiometabolic risk factors and vascular health in teens with severe obesity.   
 
This study will afford a unique opportunity to address another key unanswered question related 
to the treatment of pediatric severe obesity: how much weight loss is necessary to elicit 
clinically-meaningful improvements in cardiometabolic risk factors and vascular health?  It will 
be critically important for pediatricians to have evidence-based weight loss targets for their 
patients with severe obesity since it will better inform the type and intensity of the treatments 
selected in clinical practice.  Although evidence-based benchmarks have been established for 
adults,26 no such thresholds have been identified for youth with severe obesity.  Therefore, we 
plan to conduct a 12-month randomized, controlled clinical trial to evaluate the effects of meal 
replacement therapy plus financial incentives on weight loss and cardiometabolic/vascular 
outcomes among 142 adolescents (ages 13-17 years old) with severe obesity and to identify 
thresholds of weight loss required to achieve clinically-meaningful cardiometabolic/vascular 
improvements in this patient population.  Importantly, we will be able to characterize the degree 
of normalization of risk factors and vascular outcomes according to amount of weight loss and 
compare post-intervention values to a database of youth with normal weight, overweight, and 
obesity in the same age-range tested in the same laboratory using identical methods. 
 
1.1 
Background and Rationale 
Severe obesity, defined as a BMI ≥20% above the 95th percentile or BMI ≥35 kg/m2, is the 
fastest growing pediatric obesity category, with a reported prevalence of nearly 6% in the United 

 
 
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States.1-5  The number and magnitude of cardiometabolic risk factors and co-morbidities, 
including vascular abnormalities, is much higher in severe obesity vs. overweight or obesity.2, 6  
Approximately 85% of children and adolescents with severe obesity have at least 1 
cardiovascular risk factor and 60% have 2 or more.6  Subclinical atherosclerosis and arterial 
stiffening in the carotid artery is present in youth with severe obesity at levels similar to those 
with type 2 diabetes.27  Compared to overweight and obese peers, youth with severe obesity 
have higher levels of inflammation and oxidative stress,28 more adverse adipokine profiles,29 
and greater arterial endothelial activation.30  Moreover, longitudinal data uniformly implicate 
obesity in childhood as a strong predictor of future risk factor clustering and sub-clinical 
atherosclerosis in adulthood.31-33  The risk of developing type 2 diabetes is also high in youth 
with severe obesity.7, 34-41  The prevalence of impaired glucose tolerance in children and 
adolescents with severe obesity is notable, with estimates ranging from 4.5%-25%.42-44  Perhaps 
most alarming is the poor prognosis for youth afflicted with severe obesity.  Approximately 90% 
will have a BMI ≥35 kg/m2 in adulthood;6 and severe obesity in adulthood reduces life 
expectancy by 7-14 years.45  In summary, if left untreated, severe obesity in childhood tracks 
strongly into adulthood6 and increases the risk of premature cardiovascular disease6 and the 
development of type 2 diabetes.7   
 
Initiating effective weight loss interventions during childhood offers the best opportunity to 
meaningfully alter the disease trajectory and improve long-term health.8, 9  Early intervention is 
especially relevant in light of evidence suggesting that duration of obesity is associated with the 
extent and severity of atherosclerosis.46  Unfortunately, the lowest-risk and ideal treatment 
approach, conventional lifestyle modification therapy (diet-, exercise-, behavioral counseling), is 
relatively ineffective when used alone in terms of BMI reduction and cardiometabolic risk factor 
improvement in adolescents with severe obesity.10-13  Indeed, one relatively large study 
demonstrated that only 2% of adolescents with severe obesity achieved a clinically-meaningful 
reduction in BMI after 3 years of comprehensive lifestyle modification therapy delivered in a 
specialty pediatric weight management clinic.12  The treatment-resistant nature of adolescent 
severe obesity, at least when conventional approaches are used, has been comprehensively 
reviewed in a recently-published scientific statement from the American Heart Association.2  
Orlistat is the only weight loss medication approved by the FDA for the treatment of obesity in 
adolescents but is rarely used owing to minimal effectiveness and notable side effects.47  
Weight loss surgery reduces BMI on the order of 30-40% in adolescents but is not widely 
available, is associated with greater risk than lifestyle modification therapy or pharmacotherapy, 
and is often reserved for only those with the most serious co-morbidities.48-50  Therefore, 
considering the serious nature of the disease, the poor efficacy of conventional lifestyle 
modification approaches, 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 in a meaningful way, highly innovative lifestyle modification strategies and unique 
combinations of treatments need to be tested in youth who have this difficult-to-treat chronic 
disease. 
 
The financial incentive model has been used successfully in adult obesity trials to address 
suboptimal adherence to lifestyle modification therapy and improve weight loss outcomes.14-18  
While probably inappropriate for young children, financial incentives may be an effective tool in 
teens to address ambivalence, inspire motivation, and improve compliance to obesity 
interventions, ultimately leading to meaningful behavior change and superior weight loss and 
risk factor improvement.  Indeed, adherence to behavioral targets is a strong predictor of long-
term weight loss success among youth.51  Although yet to be investigated as a weight loss 
intervention among adolescents, strong rationale supporting this approach can be drawn from 
evidence demonstrating that financial incentives significantly improved many health-related 

 
 
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behaviors in teens including compliance with wearing physical activity accelerometers,19 
treatment adherence in type 1 diabetes,20 school attendance in those at risk for HIV infections,21 
and smoking cessation.22, 23 
 
Owing to the refractory nature of pediatric severe obesity, financial incentives are more likely to 
be effective if used in concert with a structured dietary plan such as meal replacement therapy 
(pre-portioned, calorically defined meals), which has been shown to reduce body weight to a 
greater extent than the use of conventional dietary regimens among adults.24  The rationale for 
the use of meal replacements is that individuals with obesity, including adolescents,52 often 
under-estimate caloric intake, and that adherence to a strict, pre-determined meal regimen 
removes the “guess-work” from eating.   
 
Although a relatively new treatment for pediatric severe obesity, meal replacements elicited 
promising short-term weight loss (BMI reduction of 6% at 4 months) in a recent study of 
adolescents with severe obesity25 and in a separate ongoing trial being conducted by our group 
(unpublished; data shown in “Preliminary Studies” section).  However, in the published trial, 
much of the initial weight lost was regained by the participants between 4 and 12 months, owing 
to diminished adherence to the meal replacement regimen over time.25  Our unique concept is 
to capitalize on the potential synergy of meal replacement therapy and financial incentives (to 
optimize adherence), which we believe will lead to clinically-meaningful and sustained weight 
loss, superior risk factor modification, and vascular health improvement in this difficult-to-treat 
patient population.     
 
This study will afford a unique opportunity to address another key question related to the 
treatment of pediatric severe obesity: how much weight loss is necessary to elicit clinically-
meaningful improvements in cardiometabolic risk factors, co-morbidities, and vascular health 
among adolescents with severe obesity?  Acknowledging that most teens with severe obesity 
will opt for non-surgical interventions, it will be critically important for pediatricians to have 
evidence-based weight loss targets for their patients with severe obesity since it will better 
inform the type and intensity of the treatments used in clinical practice and may lead to the 
establishment of future guidelines.  Although evidence-based benchmarks have been 
established for adults,26 no such thresholds have been investigated in youth with severe obesity.   
 
Therefore, in the current study, we will conduct a clinical trial to determine whether meal 
replacement therapy plus financial incentives leads to superior weight loss and better health 
outcomes among adolescents with severe obesity and we will identify the various thresholds of 
weight loss necessary to achieve specific cardiometabolic risk factor, co-morbidity, and vascular 
improvements in this unique patient population.  Moreover, we will also be able to describe the 
degree of normalization of cardiometabolic risk factors and vascular outcomes according to 
varying amounts of weight reduction and compare (in a cross-sectional fashion) post-
intervention values to an existing database of youth with normal weight, overweight, and obesity 
tested in the same facilities/laboratory using the same protocol and methods.  Beyond body 
weight/BMI loss, we will also be able to identify thresholds of reduction in absolute and percent 
total body fat and absolute and percent visceral fat that are associated with improvements in 
cardiometabolic risk factors and vascular health. 
1.2 
Clinical Data to Date 
Significance and Preliminary Work 
The significance of, and rationale for, the proposed research are that 1) adolescent severe 
obesity is a prevalent and serious disease that is extremely difficult to successfully treat; 2) 
conventional lifestyle modification treatment approaches are rarely effective among adolescents 

 
 
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with severe obesity; and 3) although never before evaluated in youth, the combination of meal 
replacements and financial incentives represents a novel, promising, and relatively low-risk 
(compared to medications or surgery) treatment approach.  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.  Indeed, evidence 
suggests that early interventions targeting adiposity and chronic disease risk factors during 
childhood is more effective than when instituted in adulthood.8, 9  Moreover, early weight loss 
success is associated with better long-term effectiveness and weight loss sustainability.53  The 
significance of our study is underscored by the improved outcomes that we expect to deliver 
(clinically-meaningful and sustained weight loss and risk factor management as well as 
improved vascular health) in this population in need of safe, effective, and durable treatments.  
Weight regain has been, and continues to be, a major hurdle in the field of obesity medicine.  
The use of financial incentives holds strong promise as a tool to encourage long-term 
adherence to specific dietary and physical activity regimens.  Drawing from the adult literature, 
12-month control-subtracted body weight reductions with financial incentives have ranged from 
4-6%.17, 18, 54  We expect to observe even greater weight loss efficacy in our trial owing to the 
concurrent use of meal replacement therapy.  Therefore, the magnitude of weight loss and risk 
factor/vascular improvement with our novel intervention has the potential to exceed all other 
lifestyle modification treatment approaches studied to date.   
 
Our second study aim will address an equally significant and highly-relevant unanswered 
question regarding the treatment of pediatric patients with severe obesity.  We will describe for 
the first time, the thresholds of weight loss required to elicit clinically-meaningful improvements 
in specific cardiometabolic risk factors and measures of vascular health among youth with 
severe obesity.  Pediatricians need evidence regarding the amount of weight loss they should 
strive to achieve for their pediatric patients with severe obesity since it will inform the type and 
intensity of the treatment approach.  Although evidence-based benchmarks have been 
established for adults,26 no such thresholds have been identified in youth with severe obesity.  
Owing to the distinct physiological, psychosocial, and demographic features of pediatric severe 
obesity,2 it would be inappropriate to assume that the thresholds of weight loss shown to be 
important for adults also apply to this unique patient population. Therefore, the new knowledge 
generated from our study will serve as a meaningful advancement in the field of pediatric 
obesity medicine as it will inform the treatment approach for individual patients and provide an 
evidence base from which to begin to develop clinical practice guidelines. 
 
The following studies provide the background and rationale for our plans to move forward.  Our 
project is a logical extension of this foundational work, which has informed the basis of the trial 
detailed in this protocol. 
 
Weight Loss with Meal Replacements in Adolescents with Severe Obesity 
Meal replacement therapy is an effective 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 diet plans.24  The rationale for the use of meal replacements is that 
individuals with obesity, including adolescents,52 often under-estimate caloric intake and that 
adherence to a strict, pre-determined meal regimen removes the “guess-work” from eating.  A 
recent study by Berkowitz et al.25 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.  Despite the positive outcome, adherence to the meal replacement 
regimen was suboptimal even over the short-term (baseline to month 4) and worsened from 
months 4 to 12 with a parallel trajectory of weight regain.25  Therefore, meal replacement 
therapy appears to be a promising weight loss intervention for adolescents with severe obesity; 

 
 
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however, efforts to improve short- and long-term adherence using strategies like financial 
incentives would likely enhance outcomes. 
 
Figure 1. Weight Loss with Meal Replacement Therapy in Adolescents with Severe 
Obesity 
 
 
We are currently conducting a clinical trial 
that includes a 4-week meal replacement 
induction period (prior to randomization to 
topiramate or placebo) and have observed 
promising BMI reduction in adolescents 
with severe obesity (N=19).  Mean BMI 
reduction was 3.2% in only four weeks 
(Figure 1).  These data are consistent with 
the findings of Berkowitz and colleagues25 
and demonstrate the feasibility of meal 
replacement therapy in our hands.  
Anecdotally, our participants have had a 
very positive experience with the meal 
replacement program and reported high levels of satisfaction with the degree of weight 
reduction in such a short period of time and with the convenience of the treatment regimen.   
   
Effectiveness of Financial Incentives in Improving Weight Loss and Health Outcomes 
The use of financial incentives to improve health is gaining in popularity among users, 
employers, and health groups.14  In particular, the financial incentive model has proven to be an 
effective weight loss intervention for adults.  Adult trials, ranging in length from 4-8 months, have 
reported weight loss outcomes of between 4-6%.17, 18, 54  Although yet to be evaluated as a 
weight loss intervention, financial incentives have been shown to improve other health-related 
behaviors in adolescents.  Compared to a control condition with only 30% compliance with 
wearing a physical activity accelerometer, teens who received financial incentives had a 
compliance rate of nearly 55%, almost double that of the controls.19  In another trial, over 35% 
of adolescent smokers who received financial incentives were able to quit smoking vs. 0% with 
cognitive behavior therapy alone.23  Despite the promising findings demonstrating improvements 
in health behaviors in both adults and adolescents, the financial incentive model has never been 
evaluated as a weight loss intervention among adolescents.  It is reasonable to hypothesize that 
money is at least as strong a motivator for teens as for adults19-23 and could serve as a powerful 
intervention for addressing severe obesity and its co-morbidities.   
 
Weight Loss Thresholds and Cardiometabolic Risk Factor Improvements in Adolescents with 
Severe Obesity 
Using data from the 19 participants who have completed the 1-month meal replacement period 
(prior to randomization to drug or placebo) in our ongoing previously-mentioned clinical trial, we 
compared cardiometabolic risk factor outcomes between those achieving ≥4% (N=7) vs. <4% 
(N=12) BMI reduction (Figure 2).  Note: comparisons of thresholds of 1%, 2%, and 3% BMI 
reduction did not yield either statistically-significant or clinically-meaningful improvements in risk 
factors at these lower levels of weight loss.  Although a much larger sample size will be required 
to sufficiently identify important and relevant thresholds of BMI reduction, these preliminary data 
suggest that 4% BMI reduction elicits significant and clinically-meaningful improvements in 
multiple cardiometabolic risk factors among teens with severe obesity (>10% improvements in 
many of the risk factors).   

 
 
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CONFIDENTIAL 
This material is the property of the University of Minnesota.  Do not disclose or use except as authorized in writing by the study sponsor 
 
In the context of the much larger proposed study, we will have the flexibility to compare a wide 
range of BMI reduction thresholds and identify the cutoffs most closely associated with specific 
cardiometabolic risk factors improvements.  Our findings will have an immediate and sustained 
clinical impact by providing pediatric weight management specialists with critical information 
regarding weight loss goals for their patients with severe obesity.  Beyond body weight/BMI 
loss, we will also be able to identify thresholds of reduction in absolute and percent total body 
fat and absolute and percent visceral fat that are associated with improvements in 
cardiometabolic risk factors and vascular health.  Our group has done some of the pioneering 
work validating the innovative use of iDXA technology to quantify visceral fat in youth.55 
 
Figure 2. Cardiometabolic Risk Factor Changes by Degree of BMI Reduction (≥4% vs. 
<4%) 
 
 
 
Importantly, we will be able to not only identify weight loss cutoffs that are associated with 
improvements in various cardiometabolic risk factors and vascular variables, but will also be 
able to describe the degree of normalization of these factors by comparing outcomes after 
weight loss to an existing database of adolescents in the same age-range who underwent 
identical testing in the same laboratory.  Our database, which continues to grow, currently 
contains data from over 200 adolescents with BMI values ranging from normal weight to severe 
obesity.  In a cross-sectional fashion, we will be able to compare post-weight loss 
cardiometabolic and vascular outcomes (non-invasively measured arterial stiffness and heart 
rate variability) of the adolescents with severe obesity in the proposed trial to those in the 
normal weight, overweight, and obese groups in the database in order to characterize the level 
of improvement.  This analysis will offer a unique perspective, which will enhance our ability to 
meaningfully interpret the results of the proposed clinical trial and maximize the impact. 
 
 
TC
LDL-c
TG
Insulin
BMI reduction <4%
-5.9%
-5.4%
7.9%
16.4%
BMI reduction ≥4%
-14.6%
-17.1%
-11.8%
-26.5%
-40.0%
-30.0%
-20.0%
-10.0%
0.0%
10.0%
20.0%
30.0%
40.0%
Percent Change after 4-weeks 
of meal replacement therapy
p=0.052
p=0.063
p=0.18
p=0.029

 
 
Page 8 
CONFIDENTIAL 
This material is the property of the University of Minnesota.  Do not disclose or use except as authorized in writing by the study sponsor 
2 
Study Objectives 
2.1 
Primary Objective 
Evaluate the effect of meal replacement therapy plus financial incentives on weight loss, 
cardiometabolic risk factors, vascular health, and behavior change among adolescents with 
severe obesity.  We hypothesize that the use of meal replacement therapy with financial 
incentives (vs. no financial incentives) will lead to greater percent reduction in BMI (primary 
endpoint) as well as reduce body fat, blood pressure, triglycerides/HDL ratio, inflammation, 
oxidative stress, arterial stiffness, and improve heart rate variability at 26 and 52 weeks.   
2.2 
Secondary Objectives 
Identify weight loss thresholds associated with significant improvements in cardiometabolic risk 
factors and vascular health in adolescents with severe obesity.  We hypothesize that a minimum 
weight loss threshold exists, that when exceeded, will be associated with meaningful 
improvements in multiple cardiometabolic risk factors and parameters of vascular health. 
3 
Study Design 
3.1 
General Design 
This will be a 52-week randomized, controlled clinical trial evaluating the effects of meal 
replacement therapy plus financial incentives on weight loss, cardiometabolic/vascular 
outcomes, and behavior change among 130 adolescents (ages 13-17 years old) with severe 
obesity and to identify the various thresholds of weight loss required to achieve 
cardiometabolic/vascular improvements in this patient population.  Randomization will be 
stratified by health insurance status (public/Medicaid vs. private), which is a highly-quantifiable 
variable and is closely associated with family income and socioeconomic status.  Throughout 
the entire study, all participants (regardless of financial incentives status) will engage in meal 
replacement therapy designed to achieve sustained weight loss. 
 
In an effort to maximize the rigor of the study design, we will utilize deception.  Upon 
recruitment, participants will be informed that they will be participating in a trial evaluating the 
effect of meal replacement therapy on weight loss – we will not mention the financial incentives 
component.  Following randomization, participants allocated to the financial incentives group will 
be informed of the true nature of the study and asked to sign an addendum assent form 
(parents will sign the parental consent) detailing the financial incentives protocol.  Participants 
allocated to the control group will remain blinded throughout the trial and will be informed of the 
true nature of the study once the project is fully completed.   
3.2 
Primary and Secondary Study Endpoints 
The primary analysis will be conducted using the intent-to-treat population to compare the mean 
BMI percent change from randomization to 52 weeks (additional analyses will use the 26-week 
time-point as secondary) of follow-up between the financial incentives and no financial 
incentives groups, adjusted for BMI at randomization and insurance status (randomization 
stratification factor) 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. 
 
Secondary endpoints of body fat, blood pressure, triglycerides/HDL ratio, inflammation, 
oxidative stress, arterial stiffness, heart rate variability, and adherence to the meal replacement 
regimen will be characterized at 26 and 52 weeks.  The evaluation will be in a similar fashion as 

 
 
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CONFIDENTIAL 
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the primary outcome wherein analyses will be adjusted for baseline values and the 
randomization stratification factor. 
 
We will explore cut-offs of percent change in BMI from randomization that are associated with 
significant improvement in cardiometabolic risk factors and vascular health.  We anticipate a 
range of values for consideration as the cut-off across the two treatment groups.  We also 
anticipate the cut-off not necessarily being the same across different endpoints.  The analyses 
will be similar to those for continuous outcomes outlined above with adjustment for baseline 
values, but groups will be determined by candidate cut-offs rather than treatment assignment.  
This will also allow for quantifying the degree of normalization within each subgroup with point 
estimates and confidence intervals and also for comparing the post-intervention values against 
the distribution of values from the existing control database. 
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 
• 
13-17 years old 
4.2 
Exclusion Criteria 
• 
Type 1 or 2 diabetes mellitus 
• 
Previous (within 6 months) or current use of meal replacements 
• 
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 
• 
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 or planning to become pregnant 
• 
Tobacco use 
• 
Bulimia nervosa 
• 
Endorsement of vomiting, laxative use, and/or diuretic use for weight control (EDE-Q) 
• 
Binge eating disorder 
• 
Neuromuscular disorder 
• 
Hypothalamic obesity 
• 
Obesity associated with genetic disorder (monogenetic obesity) 
• 
Hyperthyroidism or uncontrolled hypothyroidism 
• 
History of cholelithiasis 
 

 
 
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CONFIDENTIAL 
This material is the property of the University of Minnesota.  Do not disclose or use except as authorized in writing by the study sponsor 
Participants 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, or IRB 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 protocol 
and/or who choose to stop the intervention altogether but do not withdraw consent will 
remain in the study for follow-up in order to preserve the ability to perform 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 
Treatment  
5.1 
Treatment Regimen 
All participants will engage in meal replacement therapy throughout the entire 52-week 
treatment period.  Participants will be randomized (1:1) to either financial incentives or no 
financial incentives.  
5.2 
Method for Assigning Participants to Treatment Groups 
Each participant will be randomly assigned (1:1) to financial incentives or no financial incentives 
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.    
5.3 
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.    
6 
Study Procedures 
Participants will be asked to withhold all medication(s), if applicable, for study visits.  Table 1 
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).  Phone calls will be made monthly to assess adverse events, 
compliance, and deliver lifestyle/behavioral modification counseling.  All participants, regardless 
of assignment, will receive modest reimbursement for completing study visit assessments 
(separate from the financial incentive payments described later). 

 
 
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Table 1.  Measured Variables by Visit 
 
 
Baseline 
Week 8 
Week 17 
Week 26 
Week 34 
Week 43 
Week 52 
Physical exam 
X 
 
 
 
 
 
 
Tanner staging 
X 
 
 
 
 
 
 
Safety labs 
X 
 
 
 
 
 
 
Fasting labs and blood biomarkers 
X 
 
 
X 
 
 
X 
BMI/anthropometrics 
X 
X 
X 
X 
X 
X 
X 
iDXA scan (total- and visceral fat) 
X 
 
 
X 
 
 
X 
Vascular assessment 
X 
 
 
X 
 
 
X 
Blood pressure 
X 
X 
X 
X 
X 
X 
X 
Questionnaires 
X 
 
 
X 
 
 
X 
AE assessment 
 
X 
X 
X 
X 
X 
X 
Lifestyle counseling 
X 
X 
X 
X 
X 
X 
X 
Financial incentive payment (if 
eligible) 
 
X 
X 
X 
X 
X 
X 
 
6.1 
Screening Visit or Phone Call 
• 
Informed consent/assent 
• 
Medical record review 
• 
Evaluation against inclusion and exclusion criteria 
• 
Reminder for participant to fast for 8 hours prior to baseline visit 
 
6.2 
Baseline Visit (screening and baseline visit may be completed on the same day) 
 
(Visit completed following an 8-hour fast and confirmation that all medications have been 
withheld on the morning of the study visit) 
 
• 
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, 
and body mass index)  
• 
iDXA scan 
• 
Physical exam with Tanner (pubertal) stage determination  
• 
Urine pregnancy test for all female subjects  
• 
Questionnaires: 
§ 
      PedsQL™ (Young Adult Quality of Life Inventory) Child and Parent 
§ 
Impact of Weight on Quality of Life: IWQOL-Kids 
§ 
Children’s Power of Food Scale 
§ 
Child’s Eating Behavior Questionnaire (CEBQ) 
§ 
Depression Scale for Children (CES-DC) 
§ 
Screen for Child Anxiety Related Disorders (SCARED) 
§ 
Eating Disorder Examination Questionnaire (EDE-Q) 
§ 
If applicable, additional questionnaires 
• 
Fasting blood draw: complete metabolic panel, lipid profile (total 
cholesterol, LDL cholesterol, HDL cholesterol, triglycerides), insulin, and 
hemoglobin A1c 
• 
Blood draw for frozen plasma and serum storage  
• 
Vascular assessment 
• 
Urine sample collection for frozen storage 

 
 
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• 
Meal replacement instructions (including food journaling to track 
compliance) 
• 
Lifestyle/behavioral modification counseling 
• 
Instruction on choosing, ordering, and receiving meals from Healthy for Life 
Meals  
 
6.3 
8-Week Visit (8 weeks ±7 days from baseline visit) 
 
• 
Anthropometric measurements (height, weight, hip/waist circumference, 
body mass index) 
• 
Interim medical history review 
• 
Vital signs (heart rate and blood pressure) 
• 
Adverse event assessment 
• 
Eating Disorder Examination Questionnaire (EDE-Q) 
• 
Lifestyle/behavioral modification counseling 
• 
Financial incentive payment (if applicable) 
• 
Review of ordering meals from Healthy for Life Meals 
 
6.4 
17-Week Visit (17 weeks ±7 days from baseline visit)   
 
• 
Anthropometric measurements (height, weight, hip/waist circumference, 
body mass index) 
• 
Interim medical history review 
• 
Vital signs (heart rate and blood pressure) 
• 
Adverse event assessment 
• 
Eating Disorder Examination Questionnaire (EDE-Q) 
• 
Lifestyle/behavioral modification counseling 
• 
Financial incentive payment (if applicable) 
• 
 Review of ordering meals from Healthy for Life Meals 
6.5 
26-Week Visit (26 weeks ±7 days from baseline visit) 
(Visit completed following an 8-hour fast and confirmation that all medications have been   
withheld on the morning of the study visit) 
 
• 
Interim medical history review 
• 
Vital signs (heart rate and blood pressure) 
• 
Concomitant medications  
• 
Anthropometric measurements (height, weight, hip/waist circumference, and 
body mass index)  
• 
iDXA scan 
• 
Urine pregnancy test for all female subjects  
• 
Questionnaires: 
§ 
PedsQL™ (Young Adult Quality of Life Inventory) Child and Parent 
Questionnaire 
§ 
Impact of Weight on Quality of Life: IWQOL-Kids 
§ 
Children’s Power of Food Scale 
§ 
Children’s Eating Behavior Questionnaire (CEBQ) 
§ 
Depression Scale for Children (CES-DC) 

 
 
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This material is the property of the University of Minnesota.  Do not disclose or use except as authorized in writing by the study sponsor 
§ 
Screen for Child Anxiety Related Disorders (SCARED) 
§ 
Eating Disorder Examination Questionnaire (EDE-Q) 
§ 
If applicable, additional questionnaires 
• 
Fasting blood draw: lipid profile (total cholesterol, LDL cholesterol, HDL 
cholesterol, triglycerides), glucose, insulin, and hemoglobin A1c 
• 
Blood draw for frozen plasma and serum storage  
• 
Vascular assessment 
• 
Urine sample collection for frozen storage 
• 
Adverse event assessment 
• 
Lifestyle/behavioral modification counseling 
• 
Financial incentive payment (if applicable) 
• 
 Review of ordering meals from Healthy for Life Meals 
6.6 
34-Week Visit (34 weeks ±7 days from baseline visit) 
 
• 
Anthropometric measurements (height, weight, hip/waist circumference, 
body mass index) 
• 
Interim medical history review 
• 
Vital signs (heart rate and blood pressure) 
• 
Adverse event assessment 
• 
Eating Disorder Examination Questionnaire (EDE-Q) 
• 
Lifestyle/behavioral modification counseling 
• 
Financial incentive payment (if applicable) 
• 
 Review of ordering meals from Healthy for Life Meals 
6.7 
43-Week Visit (43 weeks ±7 days from baseline visit) 
 
• 
Anthropometric measurements (height, weight, hip/waist circumference, body mass 
index) 
• 
Interim medical history review 
• 
Vital signs (heart rate and blood pressure) 
• 
Adverse event assessment 
• 
Eating Disorder Examination Questionnaire (EDE-Q) 
• 
Lifestyle/behavioral modification counseling 
• 
Financial incentive payment (if applicable) 
• 
 Review of ordering meals from Healthy for Life Meals 
6.8 
52-Week Visit (52 weeks ±7 days from baseline visit) 
(Visit completed following an 8-hour fast and confirmation that all medications have been   
withheld on the morning of the study visit) 
 
• 
Interim medical history review 
• 
Vital signs (heart rate and blood pressure) 
• 
Concomitant medications  
• 
Anthropometric measurements (height, weight, hip/waist circumference, and body mass 
index)  
• 
iDXA scan 
• 
Urine pregnancy test for all female subjects  

 
 
Page 14 
CONFIDENTIAL 
This material is the property of the University of Minnesota.  Do not disclose or use except as authorized in writing by the study sponsor 
• 
Questionnaires: 
• 
PedsQL™ (Young Adult Quality of Life Inventory) Child and Parent 
Questionnaire 
• 
Impact of Weight on Quality of Life: IWQOL-Kids 
• 
Children’s Power of Food Scale 
• 
Children’s Eating Behaviour Questionnaire (CEBQ) 
• 
Depression Scale for Children (CES-DC) 
• 
Screen for Child Anxiety Related Disorders (SCARED) 
• 
Eating Disorder Examination Questionnaire (EDE-Q) 
• 
If applicable, additional questionnaires 
• 
Fasting blood draw: lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides), glucose, insulin, and hemoglobin A1c 
• 
Blood draw for frozen plasma and serum storage  
• 
Vascular assessment 
• 
Urine sample collection for frozen storage 
• 
Adverse event assessment 
• 
Lifestyle/behavioral modification counseling 
• 
Financial incentive payment (if applicable) 
6.9 
Monthly Phone Call/Email/Text message (completed between in-person study 
visits)   
• 
Interim current health/medical history review including changes to 
concomitant medications 
• 
Adverse event assessment 
• 
Lifestyle/behavioral modification counseling 
 
6.10 Detailed Study Procedures 
 
6.10.1 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 
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.   

 
 
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CONFIDENTIAL 
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6.10.2 Blood Pressure and Heart Rate 
Blood pressure measurements will be obtained digitally on the same arm using the same 
cuff size and equipment.  Standardized procedures will be employed as described in 
previously published standards.56  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. 
 
6.10.3 Blood Analyses 
Fasting (≥8 hours) blood (approximately 2 tablespoons) will be collected for the 
measurement of lipids (total-, LDL-, HDL-cholesterol, and triglycerides), glucose, and 
insulin (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 will be 
processed and stored at -80 degrees C for a batched analysis in the University of 
Minnesota Cytokine Reference Laboratory (CLIA licensed).   
 
6.10.4 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 materials57 and utilized 
by our group in a previous58 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.58  The intensity of the lifestyle modification is designed to be practical 
and feasible in the clinic setting.   
 
6.10.5 Meal Replacement Therapy 
All participants, regardless of assignment to the financial incentives group or control 
group, will engage in meal replacement therapy throughout the entire 52-week trial.    
Participants will be asked to strictly follow the prescribed eating regimen, which will 
include provision (home delivery) of pre-packaged meals from Healthy for Life (1,200 
kcals per day).  Meals will be provided free of charge.  Guidance will be provided 
regarding the use of the meals at school, and participants will be encouraged to engage 
in family meal sessions despite eating different foods. 
 
6.10.6 Financial Incentives 
With the intent of utilizing a straight-forward process with clear goals for the participants, 
financial incentives will be tied to individual percent reduction in body weight (changes in 

 
 
Page 16 
CONFIDENTIAL 
This material is the property of the University of Minnesota.  Do not disclose or use except as authorized in writing by the study sponsor 
body weight and BMI can differ slightly based on growth but are highly correlated).  We 
believe the complexity of basing incentives on BMI reduction would create confusion and 
frustration for the participants owing to the interplay between changes in height and 
weight ultimately making it difficult to effectively communicate goals to the participants.  
Moreover, change in height is obviously beyond the domain of control for participants 
and offering higher payouts to individuals who experience greater increases in height will 
be viewed as unfair.  Using the baseline body weight as the reference for all subsequent 
study visits (to avoid offering incentives for weight cycling – gain and subsequent loss), 
participants will receive $20 (in the form of a gift card) for every 0.5% reduction in body 
weight from baseline.  To make goals clear for participants, individual tables will be 
created displaying the amount of weight loss (in pounds) corresponding to each half 
percentage-point reduction in body weight.  Financial incentive payments, if earned, will 
be made to participants in the financial incentives group at all study visits.  Even if 
unsuccessful in earning a payment at a preceding visit, participants will remain eligible 
for the incentives at all subsequent visits (i.e., if weight is gained or remains stable, 
participants will be have the opportunity to get back on track; again, in relation to the 
baseline body weight).  No payment will be made for partial goal attainment (i.e., full 
0.5% weight reduction increments must be achieved). 
 
6.10.7 Assessment of Motivation, and Other Behavioral and Psychosocial Factors 
Questionnaires to be utilized at the same time points will measure quality of life (PedsQL 
Child and Parent questionnaire; Impact of Weight on Quality of Life: IWQOL-Kids), 
anxiety (Screen for Child Anxiety Related Disorders: SCARED questionnaire) and 
depression (Depression Scale for Children: CES-DC questionnaire).  Weight reduction 
will be measured at all study visits. 
 
6.10.8 Vascular Measurements 
Vascular testing will be performed in the morning in a quiet room of constant 
temperature (22º C – 23º C).  Participants will be fasting and will be instructed to refrain 
from caffeine and medications prior to the study.   
 
Carotid-radial, carotid-femoral, and/or carotid-foot augmentation index and pulse wave 
velocity will be measured by the SphygmoCorâ MM3 system (AtCor Medical, Sydney, 
Australia).  Augmentation index is a measure of the relative magnitude of the reflected 
(or retrograde) pulse wave early in the cardiac cycle.  Higher values represent increased 
arterial stiffening.  Pulse wave velocity will be calculated as distance divided by transit 
time.  Higher values of pulse wave velocity represent increased arterial stiffness.  
Resting heart rate variability will be measured with the SphygmoCorâ MM3 system. 
7 
Statistical Plan 
7.1 
Participant Populations for Analysis 
The primary analysis will be on an intent-to-treat population where all randomized participants 
will be evaluated according to their treatment assignment (financial incentives vs. no financial 
incentives).  The analysis will be conducted with multiple imputation techniques, if necessary.  A 
secondary per protocol analysis will include participants who are without major protocol 
violations.  Safety assessments will include all participants who receive any treatment according 
to the treatment they receive.  Randomization will be stratified by health insurance status 

 
 
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This material is the property of the University of Minnesota.  Do not disclose or use except as authorized in writing by the study sponsor 
(public/Medicaid vs. private), which is highly-quantifiable, clinically-relevant, and closely 
associated with family income and socioeconomic status. 
• Intent-to-treat (ITT): All participants randomized according to the treatment assignment 
received. 
• Per-Protocol (PP): All participants randomized without major protocol violations and who 
were compliant (at least 80%) with the treatment assignment received.  Major protocol 
violations include: cessation of study meals.   
• Safety Population: All participants who receive any amount of treatment according to the 
treatment they receive. 
7.2 
Sample Size Determination 
Based on results of adult clinical trials of financial incentives for weight loss, we anticipate a 
control-subtracted treatment effect (BMI reduction, our primary endpoint) of 5% at 52 weeks.17, 
18, 54  We estimate having a dropout rate of no more than 20% (our previous clinical trial 
experience with this population has been 10-15%).58, 61  We do not expect to observe differential 
attrition by treatment arm based on results of adult financial incentives trials demonstrating 
nearly identical study completion rates among the control and treatment groups.17, 18, 54  Using 
BMI variability estimates from a previous trial using meal replacements over 12 months25 
suggesting a standard deviation of approximately 8.8 and using a conservative correlation 
between baseline and follow-up scores of 0.6, we present in Table 2 the power associated with 
a clinically-meaningful control-subtracted BMI reduction of 5% based on an overall sample size 
of 130 (60 in each treatment arm) and a range of degrees of attrition (including rows reflecting 
scenarios of higher than expected levels). 
 
Table 2. Conservative Estimates of Power for a Range of Potential Treatment Effects at 
52 Weeks 
 
 
Difference in BMI Percent Change 
5% 
Two-sided Unadjusted 
97.18% 
Two-sided with 10% attrition 
95.67% 
Two-sided with 15% attrition 
94.5% 
Two-sided with 20% attrition 
93.25% 
 
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. Safety analyses will use the Safety analysis population and 
will be primarily descriptive, reporting the number and percentage of adverse events.  
 
7.3.1 Specific Aim #1 (Primary and Secondary Endpoints) 
The primary analysis will be conducted using the intent-to-treat population to compare 
the mean BMI percent change from randomization to 52 weeks (additional analyses will 
use the 26-week time-point as secondary) of follow-up between the financial incentives 
and no financial incentives groups, adjusted for BMI at randomization and insurance 
status (randomization stratification factor) 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 per-protocol population will 

 
 
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also be conducted along with consideration of adjustment for residual imbalances 
between treatment groups after randomization (e.g., in sex).   
 
Secondary endpoints of body fat (total, visceral, and subcutaneous), blood pressure, 
triglycerides/HDL ratio, inflammation, oxidative stress, arterial stiffness, heart rate 
variability, and adherence to the meal replacement regimen will be characterized at 26 
and 52 weeks.  The evaluation will be in a similar fashion as the primary outcome 
wherein analyses will be adjusted for baseline values and the randomization stratification 
factor.  Longitudinal analyses will also be conducted, incorporating the variables that are 
measured at multiple time points (e.g., blood pressure, adherence). Supportive analyses 
using the PP population will also be conducted.  We also recognize there is always the 
possibility of subgroups with differential treatment effect.  We do not a priori have a 
particular subgroup of interest the study is designed to evaluate, though exploratory 
analyses would be able to investigate such. 
 
 
7.3.2 Specific Aim #2 
We will explore cut-offs of percent change in BMI from randomization that are associated 
with significant improvement in cardiometabolic risk factors and vascular health.  We 
anticipate a range of values for consideration as the cut-off across the two treatment 
groups.  We also anticipate the cut-off not necessarily being the same across different 
endpoints.  The analyses will be similar to those for continuous outcomes outlined above 
with adjustment for baseline values, but groups will be determined by candidate cut-offs 
rather than treatment assignment.  This will also allow for quantifying the degree of 
normalization within each subgroup with point estimates and confidence intervals and 
also for comparing the post-intervention values against the distribution of values from the 
existing control database (normal weight, overweight, and obese groups).   
 
Other scales will also be explored, e.g., absolute BMI, percent of the 95th BMI percentile, 
BMI z-score, total body fat, percent body fat, total visceral fat, and percent visceral fat at 
follow-up, in addition to percent change in BMI from randomization.  Results of these 
analyses will be considered exploratory, interpreted as suggestive, requiring 
confirmation.  It is also possible thresholds may differ for different types of participants, 
e.g., based on sex.  Such interactions will be explored to the extent there are sufficient 
numbers of individuals within subgroups and sufficient variability over which to explore 
thresholds.  In addition, these results will be used to aid in the interpretation of the 
clinical meaningfulness of the treatment effect from aim #1.  For example, if a cutoff of 
4% BMI reduction is associated with clinically meaningful improvements in at least some 
of the cardiometabolic risk factors, we will examine how many participants met this 
threshold in each group.  In an exploratory fashion, we will utilize the receiver operating 
characteristic (ROC) analysis to describe the sensitivity and specificity of various BMI 
reductions cut-points associated with remission of dichotomous co-morbidities at 
baseline such as dyslipidemia, pre-hypertension/hypertension, pre-diabetes, etc. (in the 
subset of participants with these conditions at baseline).     
 
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 

 
 
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intervention.  In addition, incidence of disordered eating behaviors will be evaluated 
between groups and monitored by the data and safety monitoring board (DSMB) 
throughout the trial.  
7.4      Missing Data  
Despite best efforts, it is possible that some data will be missing, which could limit the 
interpretation and generalizability of results. If the missing data is missing completely at random, 
the consequence will merely be lost precision.  Based upon attrition rates in our previous 
trials,58, 61 we anticipate that no more than 20% of the participants will be lost to follow-up.  
Taking this into account, the planned enrollment of 130 is inflated to account for potential drop 
out.  As such, in the ‘worst case’ situation of observing missing data as high as 20%, we will still 
have >85% and >95% power to detect a 4% and 5%, respectively, control-subtracted percent 
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.  Imputation 
techniques will be considered for missing data issues (e.g., multiple imputation).  Secondary 
endpoints will be handled similarly.  We do not expect to observe differential attrition by 
treatment arm based on results of adult financial incentives trials demonstrating nearly identical 
study completion rates among the control and treatment groups.17, 18, 54  But, it is possible we 
may observe differential attrition.  Sensitivity analyses will include differential imputed values to 
examine the degree of robustness of the results.  We will also collect data on why participants 
decide to discontinue, enabling us to examine differences between study arms and in participant 
characteristics between completers and dropouts. 
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, participants will undergo a total of three iDXA scans.     
 
8.1.2 Blood Sampling  
There is minimal risk of bruising and infection associated with the blood draw.  
 
8.1.3 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 
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: 

 
 
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• 
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 
Adverse events will be followed from the initiation of any study procedures until the 
Week 52 visit.  Serious adverse events will be followed from the initiation of any study 
procedures until resolution. 
 
All serious adverse events will be followed from the initiation of any study procedures 
until the events are resolved, the participant is lost to follow-up, or the serious adverse 
event is otherwise explained.  At the final visit, if there is an ongoing serious adverse 
event, the participant and the parent/guardian will be instructed to report any subsequent 
event(s) that they, or their personal physician, believe might be reasonably related to 
participation in this study. 
 
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. 

 
 
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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 
that meet the definition of an adverse event will be recorded and documented as an 
adverse event.  
 
8.2.6 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. 
 
8.2.7 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 an 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 
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.   

 
 
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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. 
8.5 
Stopping Rules  
In the event that a participant has a serious adverse event that is deemed study-related by the 
lead-investigator for medical safety, the participant will be required to immediately withdraw from 
the study.  The overall study may be stopped at any time at the request of the DSMB, principal 
investigator, and/or lead-investigator for medical safety.  The main adverse effect that we expect 
to observe is excessive weight loss during the meal replacement period.  In the context of this 
trial, we will define excessive weight loss as 2 consecutive weeks during which ≥5 pounds are 
lost per week for those with a BMI <40 kg/m2 and ≥7 pounds are lost per week for those with a 
BMI ≥40 kg/m2.  Individuals endorsing vomiting, laxative use, and/or diuretic use for weight 
control at the baseline visit will be excluded.  We will also monitor for the incidence of 
disordered eating behaviors using the EDE-Q questionnaire, which will be administered at all in-
person study visits.  Any participant endorsing vomiting, laxative use, and/or diuretic use for 
weight control (via the EDE-Q) at any time during the trial will be interviewed using the Eating 
Disorders Module of the Structured Clinical Interview for DSM-5.  If disordered eating is present 
upon clinical interview, the participant will be removed from the trial and referred to an eating 
behavior specialist for clinical follow-up.  If no eating disorder is present, the participant may 
continue in the trial.  The DSMB will be given the authority to stop the trial if the occurrence of 
excessive weight loss and/or incidence of disordered eating are deemed to be at an 
unacceptably high level.  Participants will be instructed that they may withdraw from the study at 
any time and for any reason.   
8.6 
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 of the study intervention and 
provided with phone numbers to reach the principal investigator/study coordinator in case of 
emergencies. 

 
 
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8.7 
Data and Safety Monitoring Board 
A DSMB will be established, which will include a pediatrician with obesity expertise, a pediatric 
psychologist or psychiatrist with eating disorders expertise, and a 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 participant 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. 
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. diagnostic laboratory, CTSI, 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 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.  The risk lies mainly in the use of a low calorie diet 
in the form of meal replacements (shakes and entrees of known caloric content) to elicit weight 
loss among adolescents (ages 13-17 years old) with severe obesity.   
 
Claudia Fox, M.D., M.P.H. (lead-study investigator for medical safety), a pediatric obesity 
medicine specialist with experience conducting pediatric obesity clinical trials, will be 
responsible for the medical safety aspects of this trial.  Dr. Fox is board-certified in Obesity 
Medicine by the American Board of Obesity Medicine.  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 participants; b) the relation of 
the anticipated benefit to the risk is at least as favorable to the participants as that presented by 
available alternate approaches; and c) adequate provisions are made for soliciting the assent of 
the adolescents and permission of their parents or guardians.   

 
 
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11.1 Human Subjects Involvement and Characteristics   
One-hundred, twenty (130) adolescents (ages 13-17 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 
Masonic Children’s Hospital, Pediatric Weight Management Clinic and Minnesota Pediatric 
Obesity Consortium (MN-POC) sites and by recruitment letters through various health systems.  
Adolescents are typically referred to these clinics to address issues related to excess body 
weight and adverse cardiometabolic risk factors.  Participants in this study will undergo a series 
of clinical measurements, 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 participant 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  
Participants will be recruited from the University of Minnesota Masonic Children’s Hospital, 
Pediatric Weight Management Clinic and MN-POC sites and through various health systems.  
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). 
 
In an effort to minimize participant face-to-face time due to COVID-19 concerns, the consent 
discussion and process may be done virtually.  This will be offered to be conducted via Zoom for 
families with a computer and an internet connection and the Zoom connection will be encrypted 
so that it will be private.  For families where this is not an option, we would ask that the parent 
and the participant discuss the project over the phone.  The study coordinator will mail two 
copies of the parental consent, assent and HIPAA forms and will review the study, review the 
documents and address any concerns that the parent or participant may have.  If the participant 
and parent agree to enroll in the study, they will be asked to sign both copies of each of the 
forms and return one set of originals via mail to the study coordinator for placement in the 
participant file.  We anticipate that there will be a date discrepancy between when the 
participant and parent sign the forms and the date the form is returned to the study coordinator 
and a notation will be made about the discrepancy. 

 
 
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11.4 Potential Risks to Participants   
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. 
 
Meal Replacements and Monitoring for Excessive Weight Loss and Disordered Eating 
Behaviors 
Adverse events will be comprehensively documented at all study visits and during each monthly 
phone call.  Participants will be instructed to contact study staff immediately if any adverse 
event is experienced.  All participants will receive counseling regarding avoidance of unhealthy 
weight loss behaviors such as use of diuretics, diet pills, purging, or excessive exercise.  
However, this message will be delivered conscientiously so as not to provide participants with 
ideas they may not already have.  We will serially assess multiple domains of unhealthy weight 
loss behaviors using the EDE-Q.  The EDE-Q identifies disordered eating behaviors and 
unhealthy attitudes about weight such as purging, unhealthy obsession with dieting and/or body 
weight, prolonged fasting/starvation, use of laxatives to control weight, and excessive exercise.  
The EDE-Q has been validated and used extensively in the adolescent population and 
normative values and cut-points have been established for this age group.  Participants will be 
asked to weigh themselves regularly, and monthly phone calls will be performed.  We will use 
the in person visits to monitor for excessive weight loss defined as ≥5 pounds per week for 
those with a BMI <40 kg/m2 and ≥7 pounds per week for those with a BMI ≥40 kg/m2.  
Participants reporting excessive weight loss will be given supplemental counseling regarding 
unhealthy weight loss behaviors and removed from the trial if excessive weight loss is noted for 
2 consecutive visits. 
11.5 Protections Against Risk   
Claudia Fox, M.D., M.P.H. (lead-study investigator for medical safety) will be responsible for the 
medical safety aspects of this trial.  Dr. Fox is board-certified in Obesity Medicine by the 
American Board of Obesity Medicine and has experience conducting pediatric obesity clinical 
trials in collaboration with Dr. Kelly.  Participants will be evaluated at each visit for potential 
adverse effects.  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 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. 
 
Females will undergo pregnancy tests at each study visit requiring a DXA scan.  Absolute 
confidentiality will be maintained.  All data will be stored in locked offices and will not be 
released without consent of participants.  Blood samples sent to other laboratories will be 

 
 
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identified only by study identification number, never by name.  Data to be used in scientific 
presentations or publications will not contain participant identifiers. 
11.6 Potential Benefits of the Proposed Research to the Participants and Others   
The investigators believe the potential benefits to the participants outweigh the risks in this 
study.  Since data from clinical trials in adults and one relatively large study in adolescents have 
demonstrated reduction in weight and improvements in co-morbidities and cardiometabolic risk 
factors with the use of meal replacements, it is reasonable to expect similar results in this trial of 
adolescents with severe obesity.  The alternative treatment approach is standard-of-care 
lifestyle modification therapy.   
11.7 Importance of the Knowledge to be Gained 
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 standard 
approaches to lifestyle modification and may benefit from adjunctive treatment strategies to 
reduce weight and improve the cardiometabolic risk factor profile.  Novel approaches such as 
meal replacements plus financial incentives should be explored.  Data obtained from this study 
will determine whether combining these approaches is a promising weight loss strategy for 
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 participants will be provided with information 
about the risks of the study intervention and provided with phone numbers to reach the principal 
investigator/study coordinator in case of emergencies. 
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. 
 
    

 
 
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12.3 Participant Stipends or Payments 
Participants will receive $100 (in the form of a gift card) for completing each study visit – in total, 
participants may receive $700 if they complete all study visits (7 visits total).  In addition, if 
applicable, hotel, 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 
 
 
(1)  Flegal KM, Wei R, Ogden CL, Freedman DS, Johnson CL, Curtin LR. Characterizing 
extreme values of body mass index-for-age by using the 2000 Centers for Disease 
Control and Prevention growth charts. Am J Clin Nutr 2009 November;90(5):1314-20. 
 
(2)  Kelly AS, Barlow SE, Rao G et al. Severe obesity in children and adolescents: 
identification, associated health risks, and treatment approaches: a scientific statement 
from the American Heart Association. Circulation 2013 October 8;128(15):1689-712. 
 
(3)  Koebnick C, Smith N, Coleman KJ et al. Prevalence of extreme obesity in a multiethnic 
cohort of children and adolescents. J Pediatr 2010 July;157(1):26-31. 
 
(4)  Madsen KA, Weedn AE, Crawford PB. Disparities in peaks, plateaus, and declines in 
prevalence of high BMI among adolescents. Pediatrics 2010 September;126(3):434-42. 
 
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