Activity, Adiposity, and Appetite in Adolescents 2 Intervention
Phase: NA
Conditions: Obesity, Energy Balance, Appetite, Metabolism, Insulin Sensitivity
Sponsor: Children's Mercy Hospital Kansas City

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PROTOCOL TITLE: 
Activity, Adiposity, and Appetite in Adolescents 2 Exercise 
PRINCIPAL INVESTIGATOR: 
Robin Shook 
Center for Children’s Health Lifestyles and Nutrition 
816-234-9443 
rpshook@cmh.edu 
 
VERSION NUMBER/DATE: 
04.26.2023 
 
REVISION HISTORY 
 
Revision 
# 
Version Date 
Summary of Changes 
Consent 
Change? 
 
9.22.2022 
Adding option of exercise at home 
Y 
 
11.28.2022 
Changes to insulin sensitivity visit infusion 
protocol, removal of resistance intervention 
group 
Y 
 
03.09.2023 
Update insulin sensitivity protocol 
Y 
 
04.26.2023 
Adding KUMC as a site 
N 
 
05.15.2023 
Update Inclusion Criteria 
N 
 
 
 

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Table of Contents  
1.0 
Study Summary ........................................................................................................ 3 
2.0 
Objectives ................................................................................................................ 3 
3.0 
Background .............................................................................................................. 3 
4.0 
Study Endpoints ....................................................................................................... 7 
5.0 
Study Intervention/Investigational Agent ................................................................ 8 
6.0 
Procedures Involved................................................................................................. 9 
7.0 
Data and Specimen Banking ................................................................................ 117 
8.0 
Genetic Analysis Information ................................................................................ 17 
9.0 
Sharing of Results with Subjects ........................................................................... 17 
10.0 Study Timelines ................................................................................................... 118 
11.0 Inclusion and Exclusion Criteria .......................................................................... 118 
12.0 Vulnerable Populations ........................................................................................ 119 
13.0 Local Number of Subjects ..................................................................................... 20 
14.0 Screening and Recruitment Methods ..................................................................... 21 
15.0 Reimbursement, Payment and Tangible Property provided to subjects ................ 22 
16.0 Withdrawal of Subjects .......................................................................................... 22 
17.0 Risks to Subjects .................................................................................................... 24 
18.0 Potential Benefits to Subjects ................................................................................ 24 
19.0 Investigator Assessment of Risk/Benefits Ratio. ................................................... 24 
20.0 Data Management and Confidentiality .................................................................. 26 
21.0 Provisions to Monitor the Data to Ensure the Safety of Subjects .......................... 27 
22.0 Provisions to Protect the Privacy Interests of Subjects .......................................... 27 
23.0 Compensation for Research-Related Injury ........................................................... 27 
24.0 Economic Burden to Subjects ................................................................................ 28 
25.0 Permission/Assent/Consent Process ...................................................................... 29 
26.0 Process to Document Permission/Assent/Consent................................................. 29 
27.0 Setting .................................................................................................................... 30 
28.0 Resources Available............................................................................................... 30 
29.0 Multi-Site Research ............................................................................................... 30 
30.0 International Research ........................................................................................... 32 
 
 
 
 
 

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1.0 
Study Summary 
 
Study Title 
Activity, Adiposity, and Appetite in Adolescents 2 
Exercise (AAAA2 Exercise) 
Study Design 
Randomized Intervention 
Primary Objective 
To examine structured aerobic exercise on appetite control in 
adolescents, with metabolic function serving as a mediator. 
Secondary 
Objective(s) 
n/a 
Research 
Intervention(s)/ 
Investigational 
Agent(s)  
Exercise program 
IND/IDE #  
n/a 
Study Population 
Adolescents age 14-17 (Tanner Stage III-V) 
Sample Size 
Approximately 44 completing the protocol  
Study Duration for 
Individual 
Participants 
~190 days (this can be extended to accommodate 
participant’s schedules) 
Study Specific 
Abbreviations/ 
Definitions  
RD – registered dietitian, MS – measurement session, EE – 
energy expenditure, EI – energy intake, DXA – dual energy 
X-ray absorptiometer, EGC – Hyperinsulinemic-Euglycemic 
Clamp, CRF – Cardiorespiratory fitness, RMR – resting 
metabolic rate, TEF – thermal effect of feeding, CEQ – 
control of eating questionnaire, VAS – visual analogue scale, 
FM – fat mass, FFM – free fat mass, CCHLN – Center for 
Children’s Healthy Lifestyles and Nutrition,  CRF – 
cardiorespitory fitness 
 
 
2.0 
Objectives 
2.1 
 To test if increased physical activity through an aerobic exercise 
intervention influences metabolic function and appetite control. 
2.2 
Hypothesis 1: Sedentary adolescents exposed to the exercise training 
intervention will have improvements in appetite which will be mediated by 
improvements in metabolic function (defined as insulin sensitivity measured by 
hyperinsulinemic euglycemic clamp) compared to adolescents in the control 
intervention. 
2.3 
 
3.0 
Background 
3.1 This project is considered an ancillary project to IRB STUDY00001808: Activity, 
Adiposity, and Appetite in Adolescents 2 (AAAA2), and the second project in Dr. 

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Shook’s NIH K01 award (1K01DK119545). AAAA2 is a cross-sectional 
assessment of appetite regulation and insulin sensitivity in adolescents; AAAA2 
Exercise consists of the same assessments as AAAA2 and adds a two-arm 
randomized intervention in addition to post-intervention testing.  
3.2 AAAA2 Exercise will enroll sedentary adolescents and randomize them to 12-wk 
intervention consisting of aerobic training or newsletter control.  
3.3 Sedentary participants from AAAA2 will be invited to participate in AAAA2 
Exercise; we will ‘carry forward’ their AAAA2 baseline data to minimize burden. 
We anticipate 22 participants from AAAA2 will be eligible for AAAA2 Exercise.     
3.4 Overall Scientific Premise- Weight gain is determined by energy balance status. 
Data from the National Health and Nutrition Examination Survey (NHANES) 
indicate that 16.9% of US children and adolescents are classified as obese (BMI > 
95th percentile) and 31.8% of youth are either overweight or obese (BMI > 85th 
percentile) (Ogden, Carroll et al. 2012, Ogden, Carroll et al. 2014). This is driven, 
in part, by declines in physical activity that begin around age 15 years for boys and 
age 10-13 years for girls (Barreira, Schuna et al. 2015), with only 27% of 12-17 
year olds obtaining 60 minutes of moderate to vigorous physical activity (Centers 
for Disease Control and Prevention 2014). Healthy eating follows a similar same 
age-related decline, but at an even lower level with only 10% eating five servings of 
fruits/vegetables per day (Shook, Halpin et al. 2018). At the most basic level, 
obesity is the result of a mismatch between the amount of calories consumed and 
the amount of calories expended over an extended period of time. In reality a 
variety of known and unknown systems involving complex relationships between 
biological, physiological, psychosocial, and environmental factors (Foresight 2007, 
Shook 2016) influence the components of energy balance (Hill, Wyatt et al. 2012, 
Shook, Hand et al. 2014). Clearly, if effective prevention and treatment strategies 
currently existed based on a complete understanding of energy balance, worldwide 
levels of obesity would not have reached 
pandemic proportions (Shook, Blair et al. 
2014).  
Physical Activity is Associated with Appetite 
Control.  The concept of dysregulation of 
appetite at low levels of physical activity is not 
new, with Mayer and others (Passmore, 
Thomson et al. 1952, Edholm, Fletcher et al. 
1955) exploring the topic in a series of studies 
in the 1950s. It was observed in mice, rats, and 
humans (Mayer 1953, Mayer, Marshall et al. 
1954, Mayer, Roy et al. 1956) that energy 
intake only increased proportionally with 
energy expenditure within a certain range of physical activity, described by Mentor 
Dr. John Blundell (2011) as the ‘zone of regulation’ (Figure 2). In contrast, when 
activity levels are low (inactivity), the relationship between intake and expenditure 
is uncoupled and in the “non-regulated zone”, resulting in energy imbalance.  
3.5 Recent work has confirmed the links between elevated energy intake and appetite 
dysregulation at low levels of physical activity.  We (Shook and Blundell, among 

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others) recently completed an analysis of energy balance among adults (N=421, 
mean age=28 years) over a 12-month period which included grouping participants 
by quintiles according to their level of objectively measured physical activity 
(Shook, Hand et al. 2015). First, we observed increasing levels of physical activity 
in quintiles 2-5 corresponded with 
increases in energy intake, indicating 
energy balance. However, individuals 
in 
the lowest quintile of physical 
activity had a higher energy intake 
than 
groups 2 and 3, despite expending 
less 
energy (Figure 1). Second, 
individuals in this lowest quintile of 
physical activity had higher levels of 
disinhibition and preference for 
savory foods compared to their more 
active peers. Third, individuals with 
low 
levels of physical activity experienced the largest gains in fat mass, resulting in 3.8 
higher risk of gaining clinically significant (>3%) amounts of fat mass over 1-year. 
Our findings have since been replicated by others (Beaulieu, Hopkins et al. 2016, 
Beaulieu, Hopkins et al. 2017, Church and Martin 2018). Taken together, our 
results support the hypothesis proposed by Mayer et al. (1956) and others that a low 
level of physical activity is a risk factor for weight gain via a link to not only 
reduced energy expenditure but also dysregulated appetite control which leads to 
gains in fat mass. However, these findings raise important unanswered questions. 
What are the biological mechanisms by which physical activity influences appetite? 
What is the temporal relationship between physical activity and appetite control? 
Are the links observed in adults also present in adolescents?  
Evidence that Metabolic Function may be a Mediator. As noted by Blundell 
(Hopkins, Jeukendrup et al. 2011) and by others (Lam and Ravussin 2017), several 
clues point to metabolic function as a mediator in the relationship between activity 
status and appetite control. First, resting substrate metabolism has been shown to 
partially explain post-exercise eating behavior (Alméras, Lavallée et al. 1995, 
Barwell, Malkova et al. 2009) and be predictive of long-term weight gain (Zurlo, 
Lillioja et al. 1990, Seidell, Muller et al. 1992, Ellis, Hyatt et al. 2010). We have 
previously shown that high utilization of stored carbohydrates and low utilization of 
stored fat 
(elevated 
respiratory 
quotient (RQ)) 
predicts weight 
gain 1 year later 
in healthy adults 
(Figure 4) 
(Shook, Hand et 
al. 2015), and 
partially explains 
Figure 5. LPGC1a+/- mice have A) reduced hepatic mitochondrial complete 
FAO and B) ADP-couple respiration of palmitoyl-carnitine which is associated with C) 
increased weight gain following 3-day western diet 
Figure 6. LPGC1a+/- mice fed high fat diet for 3-days have A) increased food intake 
compared to low fat diet. 3-days of WD in LPGC1a+/- mice results in altered feeding 
patterns: B) food intake per event, C) number of feeding events.  
Figure 4. High RQ (low fat oxidation) is associated 
with increases in fat mass after 1 year. 

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unexpected weight gain among those who increased their  MVPA over 1 year 
(Shook, Hand et al. 2017). Second, blunted hepatic and skeletal muscle metabolism 
has been linked to increased energy intake and subsequent weight gain. Dr. John 
Thyfault recently observed greater food intake and short-term weight gain 
following a 3-day western diet in rodents with chronically reduced hepatic fatty 
acid oxidation (via low aerobic capacity) and mitochondrial respiratory function 
(Morris, Jackman et al. 2014). His group has recapitulated these findings in mice 
with liver-specific reductions in mitochondrial FAO due to PGC-1α heterozygozity 
(Morris et al., in review) (Figures 5 & 6). Third, there is evidence that manipulating 
substrate metabolism has causal effects on energy balance. For example, 
stimulating liver specific glucose or fat utilization can prevent weight gain 
(Orellana‐Gavaldà, Herrero et al. 2011, Visinoni, Khalid et al. 2012), while 
inhibiting glucose or fat oxidation and subsequent declines in hepatic ATP increases 
food intake via vagal afferent signaling to the central nervous system  (Rawson, 
Blum et al. 1994, Friedman 1995, Friedman, Harris et al. 1999, Langhans 2008). 
We believe that sedentary behavior induces negative changes in substrate 
metabolism that results in the metabolic phenotype described in this section, but it 
is unknown if this is associated with appetite dysregulation and subsequent weight 
gain. Conversely, it is well known that increasing physical activity obtained through 
structured exercise will improve systemic metabolic function (Jones, Basilio et al. 
2009, Lee, Bacha et al. 2012, Lee, Deldin et al. 2013), but it is not clear if this will 
also improve appetite regulation.  
Appetite Control in Adolescents is Unknown. Despite a growing body of evidence 
in adults that physical activity plays a role in mediating appetite control, little work 
has been performed in adolescents. Most studies in adolescents consists of appetite 
measures performed as secondary outcomes in studies with possible confounding 
factors (e.g. underlying disease risk) (Alderete, Gyllenhammer et al. 2012, Lee, 
Kim et al. 2012, Lee, Deldin et al. 2013). Observational data suggests higher levels 
of obesity are associated with dysregulated appetite as defined by satiety and 
responses to food cues (Carnell and Wardle 2008) and higher energy intake despite 
lower levels of physical activity (Berkey, Rockett et al. 2000). A smaller number of 
clinical trials have found that exercise trials in adolescents improves biomarkers of 
appetite control (Kim, Lee et al. 2008). Of particular note is an eight-month aerobic 
intervention among OW/OB adolescents, with the effects of exercise isolated since 
there were no changes in body weight (but improvements in body composition) 
during the study (Jones, Basilio et al. 2009). Hormones peptide YY and resistin 
decreased following completion of the intervention, suggesting improved regulation 
of appetite with higher levels of physical activity. However, assessments in each of 
these studies were limited to fasted measurements, not as part of a more 
methodologically rigorous and informative meal challenge. Taken together, a small 
number of studies in adolescents support the scientific premise that physical activity 
and appetite are associated. What is not clear is strength of the association between 
the activity and appetite, the role of metabolism in this relationship, nor the effects 
of a structured exercise regimen in this association.    
We know from multiple meta-analyses and systematic reviews that regular exercise is 
positively associated with metabolic health in children and adolescents (for all youth: 

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Hedges’ D effect size of 0.48 for fasting insulin, 0.31 for insulin resistance (Fedewa, Gist et 
al. 2014); for overweight or obese youth: −3.37 μU/mL, p=0.003 for fasting insulin and 
HOMA −0.61, p=0.040) (Marson, Delevatti et al. 2016). What is less clear is the most 
beneficial mode (I.e., type of exercise). A meta-analysis and systematic review by Marson 
et al. indicates that aerobic exercise (i.e., walking, cycling) may be more effective than 
resistance training (i.e. muscle strengthening) at improving insulin sensitivity in 
adolescents (fasting insulin -4.52 μU/mL, p=0.002 for aerobic exercise vs. -2.98 μU/ml, 
p=0.10 for resistance training) (Marson, Delevatti et al. 2016). However, since there is a 
relatively small amount of available research to evaluate (only four resistance studies met 
inclusion criteria in Marson et al.) there remains considerable variability in findings. 
Challenges to Existing Paradigms. The status quo as it pertains to appetite control 
emphasizes the role of peripherally derived signals mediating energy intake in the 
CNS [Figure 7 - e.g. insulin and ghrelin mediate appetite through pathways 
centered in the hypothalamus (Morton and Schwartz 2001, Schwartz 2001, Keesey 
and Powley 2008)]. This concept is supported by a strong body of evidence, dating 
from as far back as 50 years, including the discovery of leptin in 1994. However, it 
has been argued that this paradigm primarily accounts for the inhibition of eating as 
opposed to the drive of eating. An alternative approach, centered on the concept of 
energy balance, postulates that daily energy expenditure regulates appetite (Figure 
7). It has been put forth by Mentor Blundell, and adopted by others (Lam and 
Ravussin 2017, Church and Martin 2018), that overall appetite is regulated through 
three components: 1) a tonic (i.e. constant) drive for food driven by energy 
demands; 2) tonic inhibition from signals of energy storage (e.g. leptin); 3) episodic 
(i.e. response-initiated) signals from the periphery in response to food. This new 
approach emphasizes the contribution of physical activity and energy expenditure 
on both the tonic excitatory drive to eat and episodic regulation of fasting hormones 
(ghrelin) and satiety hormones (GLP-1 and PYY) (Blundell, Stubbs et al. 2003, 
Blundell, Caudwell et al. 2012, Beaulieu, Hopkins et al. 2017). Importantly, this 
new formulation recognizes the role of resting metabolic rate (Blundell, Caudwell 
et al. 2011) and fat free mass on appetite control. We extend this theory to include 
metabolic function, as there is evidence that it is also associated with eating 
behavior (see section A.2.), pointing to a specific biological mechanism by which 
appetite regulation may occur. 
3.6 New Approaches. The proposed research is innovative because it shifts beyond the 
tonic inhibition approach, to include the regulation of appetite via energy 
expenditure and metabolic function. Our preliminary studies (see sections 2.1-2.5) 
indicate that energy intake and disinhibition become dysregulated at low levels of 
physical activity, resulting in 3.8 fold greater fat mass 1 year later (Shook, Hand et 
al. 2015). We will extend previous findings in adults to adolescents, a previously 
unexamined population in regard to this concept. Additionally, we have expanded 
upon previous studies in the proposed project by exploring plausible metabolic 
mechanisms that underlie appetite dysregulation at low levels of activity (markers 
of skeletal muscle function and metabolism).Through this work, it is our 
expectation that we will have described the independent effects of physical activity 
(amount and type) and obesity on appetite and energy metabolism in adolescents. 
4.0 
Study Endpoints 

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4.1 
The primary study endpoint is the testing completion of 44 participants 
4.2 
There are no safety endpoints for this study.  
5.0 
Study Intervention/Investigational Agent 
This project will enroll sedentary adolescents and randomize them to a two-arm 12-wk 
intervention consisting of aerobic training or newsletter control. 
Aerobic training. Adolescents randomized to the aerobic training intervention will participate in 
supervised exercise consisting of treadmill walking or cycling on stationary bike) on 3 days 
equivalent to approximately 180 min/week of moderate-intensity exercise. To control for 
variations in body weight, exercise intensity, and exercise frequency, the actual prescribed dose in 
kilocalories will be 15.0 kcal/kg/week. American College of Sports Medicine equations (American 
College of Sports Medicine Guidelines for Exercise Testing and Prescription 11th Edition) will be 
used to estimate caloric expenditure during each session. All exercise will occur at a moderate 
intensity (40-60% of heart rate reserve, as assessed by heart rate monitor worn on the chest). All 
exercise will be supervised by trained staff with heart rate, treadmill speed and grade, or cycle 
ergometer wattage monitored by an exercise specialist every five minutes. This training will occur 
at the Center for Children’s Healthy Lifestyles and Nutrition or other CMH exercise facilities such 
as Village West under the supervision of trained staff. Participants will have the option to complete 
exercise at home one day per week after initial acclimation to the aerobic exercise protocol under 
supervision at Don Chisholm. Participants will be sent home with a chest strap heart rate monitor 
as well as a watch that can receive this heart rate information between in person sessions if at-
home exercise is to take place. Examples of at-home exercise include but are not limited to walking 
outside, walking on a treadmill, or biking on a stationary bike.  
The rationale for the dose of structured aerobic exercise is based on national and international 
physical activity recommendations for youth of 60 minutes.(Department of Health and Human 
Services 2008, Jones, Basilio et al. 2009, Lee, Bacha et al. 2012, Lee, Deldin et al. 2013, 2017)  
Compliance will be defined as completion of ≥90% of the prescribed exercise dose, will be 
monitored on a weekly basis, and participants will be excluded if they fail to meet this requirement. 
The exercise intervention will be offered to all control group participants in an effort to be equitable 
to all participants that are interested in participating in the exercise program. No data will be 
collected on these participants during their post-control group exercise program participation. 
 
CHLN Don Chisholm Building Location: A 2400 ft2 exercise area, with adjacent private male 
and female locker rooms and shower facilities, provides convenient space for controlled exercise 
studies. Exercise equipment includes five treadmills, two cycle ergometers, and two elliptical 
trainers (Paramount, St. Louis, MO, USA). A stretching/yoga studio is also connected to the 
exercise area by a movable wall. All exercise areas are exclusively reserved for research use. 
Televisions, iPads, and stereo equipment are available for use by participants while exercising. 
 
Newsletter control. Families randomized to the newsletter intervention will receive a bi-monthly 
newsletter with “parenting tips, sample praise statements, and child-appropriate activities and 
recipes” identical to what has been used in the work of leaders in the field of pediatric 
obesity.(Epstein, Roemmich et al. 2008) Previous research suggests that newsletter/mail 
interventions are well received by participants(Kipping, Jago et al. 2012) and are frequently 

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included in federally funded health intervention studies. Participants assigned to the newsletter 
condition will be given the option to participate in the exercise intervention following study 
completion; no data will be completed during this period if they choose this option. The aerobic 
exercise group will also receive the bi-monthly newsletter in addition to the exercise program.  
 
Randomization. We will use a balanced randomization plan 1:1 for the two intervention arms.  
Randomization will occur using a computerized program developed by the study statistician, 
stratified by sex and body weight status. 
 
6.0 
Procedures Involved 
 
6.1 
NOTE: As described earlier, these procedures are identical to CM IRB 
STUDY00001808: Activity, Adiposity, and Appetite in Adolescents 2 (AAAA2), and the 
second project in Dr. Shook’s NIH K01 award (1K01DK119545). AAAA2 is a cross-
sectional assessment of appetite regulation and insulin sensitivity in adolescents; AAAA2 
Exercise consists of the same assessments as AAAA2 and adds a structured exercise 
intervention in addition to post-intervention testing.  
Randomization 
7 days 

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6.2 
AAAA2 Exercise will enroll sedentary adolescents and randomize them to 12-wk 
aerobic training or newsletter control.  
6.3 
Sedentary participants from AAAA2 will be invited to participate in AAAA2 
Exercise; we will ‘carry forward’ their AAAA2 data to minimize burden. We anticipate 
22 participants from AAAA2 will be eligible for AAAA2 Exercise.     
 
Orientation Session: 1 hour. The orientation session will serve as a visit to explain the details 
of the study, with example images of what tests will be completed.  P/A/C documentation will 
also be completed at this visit if they decide to participate. If a participant and parent opt for in-
person orientation, after consent, their height, weight and blood pressure will be collected to 
classify each participant into an arm of the study. If a virtual orientation is chosen, height and 
weight will be reported from them, according to their most recent measures. Following P/A/C for 
both in-person and virtual orientation, the Contact Information Questionnaire will be 
completed. After completion of the orientation session, the parent and subject will be instructed 
to complete the Medical History and Demographics Questionnaire prior to the first 
measurement session visit. This questionnaire will be sent through a RedCap link.  
Measurement Session 1: 5.0-6.0 hours. This study visit will take place at the Don Chisholm 
Center in the morning (<9:00am) following an overnight dietary fast. This study visit will be 
conducted to assess appetite control and relevant variables under laboratory conditions. The 
measures conducted in this visit are provided below 
• Surveys 
• TFEQ 
• CEQ 
• VAS Pre-Meal 
• VAS Post-Hedonic 
• VAS 
• Anthropometry and Body Composition via DXA. 
• Fat mass (FM) and fat-free mass (FFM) will be measured using a 
whole-body dual energy X-ray absorptiometer (DXA, Lunar DPX 
system, version 3.6). 
• Waist and Hip Measurements. Waist measured in centimeters, two 
inches above the umbilicus at skin level, at the end of a normal breath 
expiration, with arms relaxed at sides. Hip measured in centimeters at the 
maximum circumference of the buttocks, with arms relaxed at the sides. 
• Fixed/Ad libitum Meals.  Appetite (see below) will be assessed following 
a fixed standard breakfast (40% of RMR, composed of 55% carbohydrate, 
15% protein, 30% fat). Food intake (total kcals) will also be assessed 
using an ad libitum meal served three hours after the fixed meal. 
Participants will be instructed to eat until comfortably full and informed 
that they can request more of the meal at any point.  
• Each plate of food will be weighed before and after serving, without the 
subjects’ knowledge. 
• Appetite and Eating Behavior Subjective assessment of hunger and 
palatability will be completed using self-rated visual analogue scales 

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(VAS) (Rogers and Blundell 1993), with each scale consisting of a 10-cm 
long line separating statements such as “not at all hungry” and “extremely 
hungry”. [VAS tools are widely used to assess health conditions and show 
good test-retest reliability (Flint, Raben et al. 2000), especially in within-
subject repeated measures study designs (Stubbs, Hughes et al. 2000).] 
Perceptions of dietary restraint, disinhibition, and hunger will be measured 
during each measurement session using the Three Factor Eating 
Questionnaire (TFEQ) (Stunkard and Messick 1985). The Control of 
Eating Questionnaire (CEQ) will be used to assess hunger, fullness, 
cravings, the desire to eat certain types of foods, and the ability to resist 
urges to eat (Greenway, Fujioka et al. 2010). Objective assessment of 
appetite will be completed using blood samples taken from an indwelling 
catheter, and analyzed for episodic regulation of the following fasting and 
satiety hormones: glucose, insulin, leptin, ghrelin, glucagon-like peptide 1 
(GLP-1), and peptide YY (PYY). All samples will be mixed with  
standard preservatives (400 µL of 10,000 KIU aprotinin, dipeptidyl 
peptidase at a ratio of 10 µL/mL of blood, pefabloc at a ratio of 50 µL/mL 
of blood), centrifuged, the plasma divided and stored in -80°C freezer until 
later analysis.  
• Resting Metabolic Rate.  Resting metabolic rate (RMR) will be measured 
via indirect calorimetry using a ventilated hood and open-circuit system 
metabolic cart (ParvoMedics, Salt Lake City, Utah) following a standard 
protocol (Shook, Hand et al. 2014).  
 
Continuous, Free-living Home Assessments of Energy intake/expenditure: 7 days 
between Measurement Session 1 and Measurement Session 2.   
• The free-living assessment period is defined as the 7 days between 
Measurement Session 1 and Measurement Session 2. During these 7 
days, subjects will be completing two energy intake/ expenditure 
assessments while going about everyday life activities at home. These 
assessments are explained in proceeding bullets.  
• Energy intake will be assessed during the free-living 7-day assessment 
period via standardized 24-hour dietary recalls. Energy intake will be 
assessed using three dietary recalls occurring on randomly selected non-
consecutive days over each 7-day free-living assessment period 
(including at least one weekend day) to minimize preparation that could 
bias recall, by a team of experienced staff employing a multi-pass 
approach, which utilizes prompts to reduce food omissions and 
standardizes the interview methodology.  
• Physical activity and energy expenditure will be estimated using two 
physical activity monitors (Actigraph GT9X Link, Actigraph Inc., and 
ActivPAL, PAL Technologies), which assesses movement using tri-axial 
accelerometry. The monitors themselves are not being studied as a part of 
this protocol, and while they do not have 501(k) documents, the devices 
used in this study are not considered to be more than minimal risk. 

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Measurement Session 2: 2-3.0 hours. This study visit will take place at the Don 
Chisholm Center. This visit will include a DXA scan, mitochondrial function testing via 
NIRS, and cardiorespiratory fitness testing (CRF): 
• Body Composition via DXA: 
 Fat mass (FM) and fat-free mass (FFM) will be measured using a whole-
body dual energy X-ray absorptiometer (iDXA, Lunar DPX system) with 
the participant dressed in surgical scrubs and in bare feet.  
• Grip Strength Testing:  
 Grip strength will be assessed using a handheld dynamometer. The 
participant will hold the device in one hand in line with the forearm at the 
level of the thigh, away from the body. 
 The participant squeezes the handgrip dynamometer as hard as possible 
without holding their breath. Neither the hand nor the dynamometer should 
touch the body. The test is repeated twice in each hand and scored as the 
sum of the highest measurement from each hand.  
• Mitochondrial Function via Near-Infrared Spectroscopy 
 Assessment of skeletal muscle oxidative capacity using near-infrared 
spectroscopy (NIRS) will be performed. The specific protocol used to 
measure skeletal muscle oxidative capacity was initially described by Ryan 
et al (2014). An ISS Medical (Champaign IL, USA) Dual-Channel 
OxiplesTS advanced NIRS device that uses Frequency Domain technology 
to provide an absolute determination of oxy[heme] and deoxy[heme] in 
various tissues will be used. This device uses 8 near infrared lasers emitting 
690nm to 830nm wavelengths which penetrate the skin without damage and 
are reflected to a Hamanatsu R928 detector. The instrument is controlled 
through a laptop computer and specialized software package (both provided 
by ISS Medical). 
 The NIRS muscle probe will be positioned on the skin longitudinally above 
the belly of the vastus lateralis muscle of the right leg, halfway between the 
patella and the hip. The probe will be secured using double-sided adhesive 
tape and Velcro straps around the thigh. After device calibration and a 30-
minute warm-up period, blood pressure cuff designed for the thigh (specific 
size will be dependent on the patient) will be placed proximal to the NIRS 
probe as high as anatomically possible. The inflation of the cuff will be 
controlled with a rapid-inflation system set to a pressure between 
>200mmHg, powered with a 15-gallon air compressor. 
 Participants will perform short duration (10-15 second) voluntary isometric 
contractions of the quadriceps to increase muscle oxygen consumption. 
Following voluntary contraction, recovery kinetics of the muscle will be 
measured using a series 10 transient arterial occlusions with timing of 5 
seconds on – 5 seconds off; followed by a series of another 10 transient 
arterial occlusions with timing of 10 seconds on – 10 seconds off. Post each 
occlusion, the rate of change (slope) in the decline in deoxy[heme] will be 

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calculated. The resting procedure will be performed twice with results 
averaged. 
• Skinfold Measurement 
 Skin and adipose tissue thickness will be measured at the site of the NIRS 
probe using skinfold calipers. The technician will ‘pinch’ the skin and 
adipose tissue with their thumb and fore finger and measure the tissue 
thickness with a set of calipers.  
• Cardiorespiratory Fitness Testing: 
 Submaximal oxygen consumption (fitness test) and maximal oxygen 
consumption will be assessed using an indirect calorimetry system with 
mouthpiece via standard protocols using a treadmill. Prior to the start of the 
test, resting blood pressure, heart rate, and oxygen saturation will be 
assessed using an automated vital signs monitor.  
 The submaximal exercise test will consist of walking at two speeds for five 
minutes each estimated as ‘light’ and ‘moderate’ intensity by the research 
technician. Following a five-minute break, the maximal test will be 
performed using the Bruce protocol. The Bruce protocol is the most widely 
used fitness testing protocol used in the US and consists of a series of three-
minute stages that gradually increase the speed and grade of the treadmill. 
The majority of individuals reach volitional fatigue 9-12 minutes into the 
test. During both the submaximal and maximal tests, heart rate will be 
measured via monitor (Polar) and gas exchanged will be measured using 
indirect calorimetry (TrueOne, ParvoMedics, Parvo, UT, USA). Following 
completion of the test, blood pressure, heart rate, and oxygen saturation will 
be assessed using an automated vital signs monitor to ensure an appropriate 
post-exercise response. 
• Muscular Strength Testing: 
 Muscular strength will be assessed with a one-repetition maximum (1-RM) 
test for the chest press and seated leg press using weight stack equipment 
(Paramount, St. Louis, MO, USA) following the protocol used by Co-I 
White [Jurca, Lee et al 2004]. Resistance will be progressively increased by 
2.5-20 kg until a maximal lift is achieved with a full range of motion within 
four attempts (3–5 min rest between trials). Muscular strength will be 
calculated as the sum of the 1-RM scores for the bench and leg press per kg 
of body weight. 
 
Insulin Sensitivity Visit: 5 hours. This study visit will take place at University of 
Kansas Medical Center Clinical and Translational Science Unit (KUMC CTSU) 
located on the Fairway campus. This visit will involve baseline blood samples and 
blood samples taken throughout the insulin sensitivity test.  
• Hyperinsulinemic euglycemic clamp.  
o The hyperinsulinemic-euglycemic clamp is the gold standard for 
assessing insulin sensitivity as stated by the World Health 

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Organization. It allows the insulin levels to be ‘clamped’ at a 
constant state so that insulin stimulated by physiological measures 
can be assessed. Insulin sensitivity can be determined by the 
amount of glucose that is infused to maintain euglycemia. The 
higher the amount of glucose that needs to be infused while insulin 
is clamped, the more insulin sensitive the subject is. 
o The hyperinsulinemic euglycemic clamp will be performed at the 
University of Kansas Medical Center Clinical and Translational 
Science Unit (KUMC CTSU), located at 4330 Shawnee Mission 
Parkway, Suite 3220 Fairway, Kansas. The CTSU contains 17 
clinic rooms, 2 cognitive testing rooms, and open workspaces for 
up to 5 visiting study coordinators. The CTSU’s infusion center 
has 11 infusion bays supported by two nursing stations and activity 
in the center has steadily grown. The center also supports research 
infusions and intensive and complex metabolic research 
assessments such as hyperinsulinemic-euglycemic clamps (see 
Morris et al. 2016). There is a CTSU medical monitor available for 
Adverse Events. The CTSU medical monitor is contacted when 
there is an urgent, medical concern / AE with the participant; The 
medical monitors are MD’s or NP’s / APRN’s (aka Advanced 
Practice Registered Nurse). NOTE: This is in addition to the study- 
specific DSMB.   
o Participants will arrive fasted (12-hours overnight), and one 
catheter will be inserted into an antecubital vein of one arm to 
infuse insulin and 20% dextrose, and another catheter will be 
inserted into a contralateral vein in the hand/arm for blood 
sampling. Three baseline blood samples will be collected to 
establish baseline glucose levels. If baseline values are <60 mg/dL 
the procedure will not continue. Once baseline assessments have 
been completed, a primed continuous infusion of regular human 
insulin plus albumin will be administered at a rate of 40 
mU·m2 body surface area−1·min−1 along with a variable infusion of 
20% dextrose to maintain euglycemia to match baseline levels 
(expected 90-100 mg/dL). Blood glucose measurements will be 
completed every 5 minutes for determination of glucose infusion 
rate using a Nova Statstrip handheld glucometer and YSI analyzer 
as needed.  
o After approximately 90 minutes of acclimatization, a 30-minute 
data collection period will occur. Insulin sensitivity will be 
determined as average glucose concentration and glucose infusion 
rate during this 30-minute period of euglycemia (defined as 
glucose concentration and glucose infusion rate coefficient of 
variation <10%). 
o After this 30-min period, a 60-minute recovery period begins. 
Insulin infusion is stopped and glucose infusion continues at the 
last rate for 30-min to prevent hypoglycemia. Glucose infusion is 

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stopped 30-minutes into recovery if blood glucose levels remain at 
acceptable levels.  
o Participants will be provided a full lunch meal (e.g. sandwich, 
potato chips, drink) following the cessation of insulin infusion to 
minimize the chances of hypoglycemia. Participants will also be 
provided with a 20 mEq potassium pill after/with food. In rare 
instances hypokalemia can occur resulting from hyperinsulinemia 
and increased glucose disposal. Potassium supplementation helps 
prevent this from occurring. 
o Following the cessation of glucose, all participants will remain 
under observation at the CTSU for the final 30 minutes of recovery 
to monitor for hypoglycemia. 
o  Participants can be released if participant is asymptomatic and 
blood glucose levels are acceptable at the end of the observation 
period. 
o Blood is drawn from an hand/arm vein covered with a heating pad 
and this technique is called arterialization, as it makes the blood in 
the vein have similar characteristics to that flowing in the artery by 
dilating the vessels in the arm. This is a well-accepted technique 
that allows us to avoid performing an arterial IV placement. The 
hand/arm will be placed under the heating pad for the entire testing 
procedure.  
o Insulin Mixing Procedures: 
The CTSU Investigational Pharmacy (located onsite) will store the 
insulin and albumin. The unused insulin will be returned to the 
pharmacy after each study. CTSU nurses will mix the insulin, 
albumin, and saline. For the mixing procedures, 2mL of human 
albumin is injected into a bag of 250 mL sterile saline and gently 
inverted to mix the solution. Using an insulin syringe, 1.25 ml of 
insulin is added to the albumin/saline mixture and gently inverted 
to mix the solution. The mixing of insulin with albumin is essential 
to minimize the binding of insulin to the saline bag, as well as the 
catheter tubing. This procedure for mixing the infusate was 
described in the initial report of the hyperinsulinemic-euglycemic 
technique (DeFronzo et al, 1979) using blood rather than albumin 
and is still utilized by labs that perform the hyperinsulinemic-
euglycemic clamp. We are using albumin in this study to prevent 
the possibility of clotting associated with the use of blood. 
After completion of the initial insulin sensitivity visit, the 
participant will be randomly assigned to the newsletter or aerobic 
exercise intervention group (as describe in section 5.0).  

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They will remain in this arm of the study for 3 months and then 
complete another round of assessments described as above (except 
for the orientation session).  
6.4 
Data collected during the study includes self-report survey data (see myIRB 
local documents) as well as DXA, RMR, VO2, TEF, NIRS, and blood test 
results. Anthropometric measurements such as height and weight will also 
be collected. Dietary recall data and activity monitor data will be collected 
during the free-living assessment period (sample output available on local 
documents). Finally, insulin sensitivity will be determined through the 
Hyperinsulinemic-Euglycemic Clamp procedure.  
6.5 
There are no plans for long-term follow-up beyond study completion. 
6.6 
Standards and Safety of Participants 
• 
All devices used in the study are FDA approved (DXA, RMR hood 
machine, NIRS, ActiGraph, ActivPAL, etc.). 
• 
This study involves DXA scans –Female participants of child-bearing 
age are required to complete a pregnancy test before DXA scan.  
• 
A nurse will perform any blood draws and all study staff assigned to 
perform lab procedures or RQ will be specifically trained to work with 
that equipment. This is training that is above and beyond the regular 
research CMH or standard research education. 
• 
Appetite assessments: Blood will be collected via an IV catheter over 
8 time points) over a period of 3 hours. Approximately 36mL (two 
samples at time 0, one sample at all other time points, 9 samples x 4 
mL= 36 mL= 1.22 oz) of blood will be collected. 
• 
Euglycemic clamp: Three baseline blood samples will be collected at 
the onset of the session to determine baseline glucose levels. The total 
amount of blood collected will be approximately 9  mL (3 samples x 3 
mL/sample= 9 mL). Blood will be sampled every five minutes during 
the clamp procedure to monitor glucose levels. The total amount of 
blood collected to monitor glucose will be approximately 36 mL (36 
samples 1 mL/sample = 36 mL). Every 15 min we will also collect 
blood samples to store for assessment of insulin at study completion. 
The total amount of blood to assess for insulin will be approximately 
24 mL (12 samples X 2 mL/sample = 24 mL). During recovery, blood 
glucose is assessed every 10 minutes and insulin once. The total 
amount of blood collected during recovery is 8 mL (6 glucose samples 
x 1 mL = 6 mL; 1 insulin sample x 2 mL = 2 mL).  
• 
Total amount of blood collected during the entire clamp procedure is 
approximately 77 mL (9 mL + 36 mL + 24 mL + 8 mL) or 15.6 
teaspoons/2.6 ounces. 
• 
The amount of blood is within the allowable amounts to be collected 
for research purposes.   
• 
No subjects will be less than 16.5 kg 

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7.0 
Data and Specimen Banking 
7.1 
Samples will be stored in the CCHLN biochemistry lab. Samples collected 
at KUMC CTSU will be stored there temporarily, then moved to CCHLN 
Biochemistry lab every three months. 
7.2 
Samples will be stored with study ID, birth year, visit date only 
7.3 
CM research only, for the purposes of this study only 
7.4 
N/A – samples not retained for long-term research. Samples will be stored 
for up to 7 years and then destroyed.  
7.5 
Will this study involve handling, transporting, or shipping any potentially 
hazardous biological material at/from a Children’s Mercy location (e.g., 
blood, stool, saliva, tissue)? 
• ☒ Yes 
• ☐ No 
Will this study involve processing any potentially hazardous biological material at 
a Children’s Mercy location (e.g., blood, stool, saliva, tissue)? 
• ☒ Yes 
• ☐ No 
If processing potentially hazardous biological materials, where will this work be 
conducted? 
• ☐ Pediatric Clinical Research Unit (PCRU) 
• ☐ Children's Mercy Research Institute Biorepository (CRIB) 
• ☐ Children’s Mercy Research Institute labs (mySafety 
ID#:__________) 
• ☒ Other location 
If “Other location,” identify the location and mySafety ID# of the corresponding 
IBC protocol: 
• Location: CHLN Research Biochemistry Laboratory  
• mySafety ID#: IBC00033  
 
8.0 
Genetic Analysis Information 
N/A – no genetic analysis 
 
9.0 
Sharing of Results with Subjects 

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9.1 
At the conclusion of the study, a report with the participant’s study results 
will be shared with each participant. Results will include:  
• Height and weight 
• Blood pressure values 
• Fitness percentile 
• Resting metabolic rate 
• Activity monitor data such as steps per day 
• Two body composition scans with bone mineral density 
• Grip strength 
 
10.0 Study Timelines 
10.1 Describe: 
• 
Individual participation in the study will last approximately 190 days. 
• 
Recruitment and data collection will last approximately 18 months. 
 
11.0 Inclusion and Exclusion Criteria 
11.1 
 
Inclusion Criteria 
• Males (~50%) and females (~50%) 
• Age 14-17 (Tanner Stage III-V, as determined via self-assessment) 
• Non-smoking 
• Not currently involved in any other research study 
• No meds that may alter metabolism 
• Sedentary (<60 min/day exercise) 
• Willing to participate in an exercise program 
• Willing to give informed consent to participate 
 
Exclusion Criteria 
• BMI <5th percentile or >99th percentile for age and sex 
• Weight not stable 
• Age <14 or >17 at time of enrollment  
• Restrained eater (>13 on the restraint section of the three-factor eating 
questionnaire; Current/past diagnosis of an eating disorder. 
• Self-reported medical conditions (including, but not limited to, diabetes, Crohn’s 
disease, etc.) that may affect adherence to the protocol, exercising safely, or alter 
metabolism 
• Taking medications know to affect metabolism (e.g. thyroid medication, β-
blockers, or stimulants). 
• Gave birth in the past 12 months or <6 months post-lactation. 
• Active (>60 min/day exercise) 

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• Not willing to participate in an exercise program 
• Not willing to provide permission/assent 
 
Individuals who are not yet adults (infants, children, teenagers) will be included in this 
study (teenagers age 14-17). 
 
12.0 Vulnerable Populations 

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☐ Children/Minors (under 7 years of age) 
☒ Children/Minors (7-17 years of age) 
☐ Neonates (infants less than 30 days old) 
☐ Neonates of Uncertain Viability (infants less than 30 days old) 
☐ Non-Viable Neonates (infants less than 30 days old) 
☐ Wards of the State 
☐ Fetuses 
☐ Pregnant Women  
☐ Adults with impaired decision-making capacity 
☐ CM Employees 
☐ CM Students/Residents/ Fellows 
☐ Economically or Educationally Disadvantaged Persons 
☐ Prisoners 
 
• This study involves children who are not yet adults. The study will be 
explained to them at the study visit as well as during the informed consent 
discussion.  
• The research involves no more than minimal risk to the subjects. 
• HRP-416 - CHECKLIST - Children has been reviewed. 
 
Local Number of Subjects 
12.1 Our goal is to complete a total of 44 study participants. We 
anticipate the need to enroll about 60 total participants to account for 
screen fails and dropouts. 
12.2 We expect to send our study letter to 2,000 potential participants, 
screen about 900, and enroll around 60, to get our final enrollment 
goal of 44. This is based off our previous AAAA and BATE 
submissions with similar inclusion/exclusion criteria. 
12.3 N/A – no chart review beyond what is required for screening. 
13.0 Screening and Recruitment Methods 
13.1 
As described earlier, sedentary participants from AAAA2 will be invited 
to participate in AAAA2 Exercise; we will ‘carry forward’ their AAAA2 baseline 
data to minimize burden. We anticipate 22 participants from AAAA2 will be 
eligible for AAAA2 Exercise.     
13.2 Remaining participants will be recruited from previous Energy 
Balance research studies, from weight management programs at the 
Center for Children’s Healthy Lifestyles & Nutrition (CCHLN), 

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from a recruitment list generated by CMH MIT, a recruitment list 
generated from KUMC pioneers/frontiers, and any other applicable 
lists at the CCHLN. Recruitment letters will be mailed to the parents 
of potential participants from the above recruitment methods. 
Additional recruitment methods include social media resources, the 
CCHLN website, and dissemination of the study screener to partner 
departments and institutions, and the use of recruitment article 
posting on the CM Daily E-News.  
13.3 Participants will be recruited from CMH, KUMC, and the 
community. 
13.4 When available, study staff will use previous contact with Energy 
Balance research participants (or potential participants that stated 
they were interested in other opportunities), CMH MIT generated 
data or KUMC generated data to pre-screen (or identify) potential 
participants. When not available, study staff will use a Redcap 
screener to verify eligibility. 
13.5 
Study staff will record, and request (from resources such as CMH MIT) 
only the minimum necessary identifiable data for the purposes of contacting 
participants prior to ICF and pre-screening.  We are requesting a Waiver of 
HIPAA Authorization for recruitment and screening purposes only. Minimum 
necessary PHI on non-participants will only be kept until completion of 
enrollment. 
13.6 We may disseminate the study screener to other departments for the 
purposes of recruitment (Teen clinic, weight management clinic, 
etc). 
13.7 Individuals will be contacted a maximum of 3 times (including 
voicemails), when following up after mailing a study letter. 
14.0 Reimbursement, Payment and Tangible Property provided to 
subjects 
 
14.1 Participants will be paid via pre-paid debit card. Participants will be paid 
$175 when activity monitors are returned at the DXA/CRF visit, and another 
$125 at the insulin sensitivity visit. After the 3 month newsletter/exercise 
period, participants will be paid $175 again when activity monitors are 
returned at the DXA/CRF visit, and another $125 at the insulin sensitivity 
visit. 
 
14.2 Participants will be paid $5 for each of the 6 visits they attend as travel 
compensation (with the exception of the orientation visit, for a max possible 
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newsletter/exercise period). Max possible travel compensation of $30 to be 
paid at the completion of the study.  
 
14.3 Participants assigned to the aerobic training intervention group will be paid 
an additional $25 at the midpoint of the intervention and $75 at the end of 
the intervention. In addition, participants assigned to the aerobic 
intervention group will be paid $5 in travel compensation per visit to be paid 
at the end of each intervention month.  The total travel compensation will 
vary depending on how many exercise sessions the participant attends over 
the course of the month, this number will be between 8-16 sessions per 
month. Participants assigned to the newsletter group will be paid as lined out 
in 14.1-14.2. 
Payments will be administered as follows: 
 
 
For participants that were recruited from the AAAA2 study, because they 
already completed and were paid for the first three testing visits 
(measurement session #1, measurement session #2, and insulin sensitivity 
visit), they will only be eligible to receive compensation for the second 3 
visits that take place after the newsletter/exercise period.  
 
 
14.4 Participants assigned to the aerobic intervention group will be given a t-
shirt, sweat towel, water bottle, and phone pop-socket valued at less than 
$15 in total.  
 
15.0 Withdrawal of Subjects 
15.1 Non-compliance with the protocol. 
 
Pre-Intervention or AAAA2 study 
 
Post 
Total 
 
Measurement 
Session 1 
Measurement 
Session 2 
Insulin 
Sensitivity 
Visit 
Interventions 
or Newsletter 
Measurement 
Session 1 
Measurement 
Session 2 
Insulin 
Sensitivity 
Visit 
Total Max 
Payment 
Newsletter 
group 
- 
$125 if 
monitors 
returned 
 
$10 travel 
reimbursement 
$175 
 
$5 travel 
reimbursement 
- 
- 
$125 if 
monitors 
returned 
 
$10 travel 
reimbursement 
$175 
 
$5 travel 
reimbursement 
$630 
Aerobic 
exercise 
group 
 
$125 if 
monitors 
returned 
 
$10 travel 
reimbursement 
$175 
 
$5 travel 
reimbursement 
$100 
 
$5 travel 
reimbursement 
per visit (total 
amount will 
vary)  
- 
$125 if 
monitors 
returned 
 
$10 travel 
reimbursement 
$175 
 
$5 travel 
reimbursement 
$730 + 
intervention 
travel 
reimbursement 

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15.2 The study team will attempt to contact the participant for the 
purposes of determining a reason for withdrawal, attempting to 
reschedule, etc. 
15.3 If a participant decides to withdraw, all data up to the point of their 
withdrawal will be kept. 
16.0 Risks to Subjects 
16.1 
 
• Drawing blood from the participant’s arm and hand include discomfort 
and/or bruising. There is a very low risk of infection, bleeding, clotting, or 
fainting.  
• Wearing activity monitors poses no known risks.  However, the participant 
may feel some discomfort while initially getting used to wearing the 
monitors.  In addition, a small percent of participants have developed a 
rash associated with the adhesive from the leg activity monitor. If any 
participant experiences any irritation, itching or redness while wearing 
either monitor, they will be instructed to stop wearing the monitor 
immediately and inform the study staff.   
• While the radiation used for the body scan (DXA scan) has no observable 
radiological or biological effect, there is always a risk associated with 
radiation exposure. 
• During the fitness test the participant will experience an increase in heart 
rate and blood pressure. Additionally, sweating will occur, and they may 
become fatigued, all of which are to be expected with exercise. It is also 
possible that abnormal responses may occur such as dizziness, unusually 
high increases in heart rate and blood pressure, and in rare instances, 
fainting. Trained personnel will be on hand during the fitness test. 
Emergency equipment is kept in the exercise testing room and all staff 
have been trained in its use. Following the fitness test, they may 
experience muscle soreness for a few days.  
• During the study the participant will be asked to eat three meals (breakfast 
and lunch during the appetite assessment, lunch following the clamp 
procedure). The study team will inquire about any food allergies the 
participant may have. 
• During and immediately after the clamp procedure there is a risk of 
hypoglycemia. We will monitor blood glucose every five minutes during 
the technique and for 1 hour following the technique.  
• There is also a slight risk of loss of confidentiality, meaning that someone 
could know the child participated in this study if they study team’s 
research records are hacked. The participant’s confidentiality will be 
protected to the greatest extent possible.  
• Possible physical discomfort from the pressure from the NIRS 
muscle cuff 

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16.2 Overall, the risks involved in this study are minimal. At this time we 
do not see any unforeseeable risks, but as information comes available 
we plan to report it to participants. 
16.3 We will screen for pregnancy prior to completing DXA scans on 
women of child bearing age (all women enrolling in the study), but 
there are risks associated with radiation exposure. 
16.4 Loss of confidentiality could affect parents/family of participants as 
well as participants. 
17.0 Potential Benefits to Subjects 
17.1 N/A – no benefit. 
17.2 Participants may experience no direct benefit. 
18.0 Investigator Assessment of Risk/Benefits Ratio: (IRB makes the 
final determination) Based upon your response in Sections 17.0 and 18.0, 
please provide your assessment of risk and benefits in below table. 
 
Select as applicable: 
Pediatric Risk Category: 
x 
Category 1  Research not involving greater than minimal risk  
(45 CFR §46.404 and 21 CFR §50.51)   
 
Category 2 
Research involving greater than minimal risk but 
presenting the prospect of direct benefit to the 
individual 
subjects. (45 CFR §46.405 and 21 CFR §50.52) 
 
Category 3 
Research involving greater than minimal risk and no 
prospect of direct benefit to individual subjects, but 
likely to yield generalizable knowledge about the 
subject's disorder or condition.  
(45 CFR §46.406 and 21 CFR §50.53) 
 
Category 4 
Research not otherwise approvable which presents 
an opportunity to understand, prevent, or alleviate a 
serious problem affecting the health or welfare of 
children. (45 CFR §46.407 and 21 CFR §50.54) 
Select if applicable: 
Adult Risk Category: 
x 
Not Greater than Minimal Risk 
 
Greater than Minimal Risk 
 
19.0 Data Management and Confidentiality 
19.1 Statistical Analysis Plan. General analysis plan- Demographic 
characteristics will be summarized by mean and standard deviation 
(SD), or median and inter-quartile range for skewed, for continuous 
variables and by frequency and percentage for categorical variables. 
A one-way ANOVA and Fisher exact test will be performed to 
examine group differences at baseline. We will calculate area under 
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(VAS ratings of hunger, fullness) and subjective (ghrelin, GLP-1, 
PYY, etc.). 
19.2 To test if increased MVPA through an aerobic exercise intervention 
influences metabolic function and appetite control, we will conduct 
pairwise comparisons of changes in appetite AUC and iAUC pre- 
and post-intervention using a general linear regression model with 
insulin sensitivity as a covariate. Additional covariates will include 
sex, puberty status, and body composition. The effect of treatment 
was evaluated by intent-to-treat analysis including all randomized 
participants. We will also conduct per-protocol analysis given the 
feasibility of the intervention in this population is not well 
understood.  
19.3 Prior to the K01 application we conducted a pilot study with 
sedentary and active periods to test the feasibility of our protocols. 
We estimated an 11% decrease in hunger from baseline following 
the intervention, which at 90% power results in a sample size 
calculation of n=17 with an effect size of 0.5 (moderate effect). 
Assuming a drop-out rate of ~25% our final sample size is set at 
n=22 per group (total N=44) to detect differences between the 
newsletter control and intervention groups 
19.4 All study staff will complete research training, save study documents 
on drives that require authorization of access, password protection, 
or encryption. Paper study documents will be protected using 
physical controls (such as being kept in secured locked offices in 
locked file cabinets). Study staff will keep identifiers separate from 
study IDs and data [master list]) during storage, use, and 
transmission.   
19.5 A Certificate of Confidentiality has been issued for this study.  
Certificates are automatically issued for NIH funded research per 
NIH policy.   
19.6 Study surveys will use a study ID for an identifier, study staff will 
lock documents in secure office locations and keep data collection 
surveys and instruments with them at all times when in use. 
19.7 Describe how data or specimens will be handled study-wide: 
• 
Study ID and visit date will be included on source 
documentation 
• 
Study documents will be stored in secure offices in secure file 
cabinets, Redcap, the W drive, OneDrive, or BOX (the study 
team has previous approval to use). 

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• 
Study source documentation and other data will be kept at least 
3 years after submission of the Final Progress Report to the 
NIH. 
• 
The CMH study team, other approved staff members from 
approved organizations (KUMC, etc), the sponsor (NIH), the 
IRB. 
• 
The study lab coordinator, the PI. 
• 
No data will need to be transported, but blood samples will be 
transported to the analyzing lab through standard biohazard 
shipping protocols. All data obtained off of CM premises will 
be accessed by study staff electronically via approved secure 
sharing platforms such as OneDrive.  
20.0 Provisions to Monitor the Data to Ensure the Safety of Subjects 
20.1 
Per NIH requirements: 
Plan for safety monitoring and review 
There will be a chair of the Data Safety Monitoring Board to make decisions 
on safety of the participants, as well as two other members to serve in 
monitoring study progress and unanticipated/adverse events. Data will be 
reviewed twice a year by the Board Chair. If problems occur during the 
euglycemic clamp procedure, staff nurses will stop the procedure and notify 
the CTSU medical monitor, the Board Chair, and Dr. Shook of any issues. 
The Board Chair will then make a decision on whether the participant 
should continue with the remaining parts of the study. The PI and other key 
personnel will be examining research data on a subject to subject basis to 
ensure it is accurate and to address any potential problems that may arise 
with the protocols. In addition, Dr. Shook will examine data with KU team 
at least once per month through in person meetings or by phone to ensure 
that data collection is occurring in a consistent manner at both locations 
(KUMC and CMH). 
 
Plan for adverse event reporting 
Monitoring and reporting adverse events, whether anticipated or 
unanticipated, is the responsibility of the PI. The reporting requirements of 
the CMH and KUMC IRB’s and for serious and unexpected adverse events 
will be followed. All adverse events will be shared with Dr. Shook 
immediately and shared with the Board Chair and the DSMB within 48 hours 
of PI notification. 
 
Frequency of monitoring 
In addition to monitoring by the PIs, study coordinators, and safety officer, 
the IRB monitors all aspects of the project on an annual basis. The DSMB 
will review study progress (e.g., recruitment, retention, protocol adherence) 
and every six months at the semi-annual closed-door session, per the DSMB 

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charter. At the semi-annual DSMB session, the PI will provide a report 
detailing:  
a. List and summary of adverse events 
b. Whether adverse event rates are consistent with pre-study 
assumptions 
c. Summary of recruitment and retention and reason for dropouts 
d. Whether the study is on track to be completed and accomplish the 
stated aims. 
Section 4.1.6. ClinicalTrials.gov Requirements 
In accordance with Public Law 110-85, this clinical trial will be registered in 
ClinicalTrials.gov.  
 
21.0 Provisions to Protect the Privacy Interests of Subjects 
21.1 Study participants will be given a study ID number and all the information 
they will out for the study will only have that ID number on it. The 
participant will only be linked to the study with their permission/assent form 
and a master linking list that connects their ID and name.  
21.2 Participants will be given ample time to think about participation including 
taking the permission/assent form home to think about it before signing up if 
they prefer. They will also be told about the study over the phone before 
coming in for the orientation visit. 
21.3 The study team will be given access to a linking list of participants so they 
may identify participants in this way to call and remind them of visits, etc. 
The study team will not leave detailed messages, will not post on social 
media, and will not share the name or any other PHI with anyone who is not 
a member of the study team. 
21.4 Identifiers recorded for this project: Name, Date of Service, Date of birth, 
medical record number, hospital account number, Street address, Telephone 
number, Email address, Social Security number (for payment purposes 
only). 
21.5 The research team will be obtaining HIPAA Authorization from 
subjects/parents to access and/or record PHI for this research study.   
• the HIPAA Authorization will be wrapped in with the 
permission/assent/consent form(s) 
22.0 Compensation for Research-Related Injury 
22.1 N/A – not more than minimal risk 
22.2 N/A – will use standard NIH contract language 
23.0 Economic Burden to Subjects 

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23.1 For those that are randomized to receive the exercise intervention, 
they will need to take the time and gas to drive to all of the exercise 
appointments.  
24.0 Permission/Assent/Consent Process 
24.1 Indicate whether you will you be obtaining 
permission/assent/consent, and if so describe: 
• 
P/A/C will be obtained electronically via eConsent over the 
phone or in person at the Don Chisholm building via eConsent.  
• 
Participants will be invited to ask questions and if they are 
uncomfortable enrolling at the time of the PAC conversation 
they will be told they can take the form home to think about it. 
• 
As procedures are happening through the study they will be 
explained to the participant (and their parent/guardian). 
• 
We will be following CM research policies on informed 
permission/assent/consent.   
Subjects who are not yet adults (infants, children, teenagers) 
• 
Individuals <18 years 
• 
Parental permission will be obtained from a singular parent. 
• Permission may be obtained from individuals other than 
parents. These people will be determined to be Legally 
Authorized Representatives via court documentation either 
provided to the study team or already in the CMH HER.  
• 
Assent will be obtained from all children (our inclusion criteria 
includes only children of the age of assent). 
• 
When assent of children is obtained describe how it will be 
documented – children will sign and date the Permission 
Assent document. 
Consent at 18 years of age, when minor subjects become adults 
• We will re-consent any participants that turn 18 during the 
study with an adult addendum. 
Non-English Speaking Subjects 
• 
We plan to enroll only English speaking participants, due to the 
limitations of coordinating study visits with the assistance of an 
in-person interpreter.  

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• We will utilize translation services or Cyracom to obtain 
permission/assent for any Spanish speaking parents of 
participants. We would request ORI to provide translations 
of our uploaded surveys and P/A forms. 
 
25.0 Process to Document Permission/Assent/Consent 
25.1 
The study team will obtain permission/assent/consent via 
eConsent Lite over the phone or in-person at the Don 
Chisholm building at CM 
• The p/a/c process will take place via telephone or in-person at 
the Don Chisholm building on CM campus 
• The potential participant will have a chance to ask questions 
and decide if they’d like to participate. 
• The only ongoing P/A/C process will include an adult 
addendum, if necessary for a participant that turns 18 during the 
duration of their study participation 
• The Study team will be following CM research policies on 
informed permission/assent/consent. 
• The study team may obtain permission/assent/consent via 
telephone, and will follow CM research policy (10.05 
Telephone Process). 
• The study staff listed on the IRB, as well as the study 
coordinator, and PI’s, may complete consent 
• Participants and their families will be given plenty of time to 
consider participation (they can decline to participate during the 
consent appointment and request follow up) as well as ask any 
questions they have. 
• Study staff will explain each main section of the p/a/c form as 
well as provide a summary. Checking for understanding while 
going through the form. 
• The study team will follow CM research policy for phone 
consent, if necessary (not in-person). This policy as well as 
other helpful guidance on the use of alternative communication 
methods to obtain permission/assent/consent are available in 
10.05 Telephone Process. 
Subjects who are not yet adults (infants, children, teenagers) 

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• 
The study team will consider participants in the sample age 14 
- 17 not yet adults. 
• 
One parent will provide permission, even if the other parent is 
alive, known, competent, reasonably available, and shares legal 
responsibility for the care and custody of the child. 
• 
Permission may be obtained from individuals other than 
parents. These people will be determined to be Legally 
Authorized Representatives via court documentation either 
provided to the study team or already in the CMH records. 
 
26.0 Setting 
26.1 Describe the sites or locations where your research team will 
conduct the research. 
• 
Participants will be identified and recruited from CMH, 
KUMC, and the community. 
• 
Research procedures will be performed at CMH and KUMC. 
• 
We will not be conducting research at any institutions outside 
the organization that have site-specific regulations or customs 
affecting the research or local scientific and ethical review 
structures outside the organization. 
27.0 Resources Available 
27.1 Describe the resources available to conduct the research: For 
example, as appropriate: 
• See the Power Analysis for more information about the sample size 
determination. All Study Personnel will complete research training 
required by their institution. 
• The following resources are available for the Energy Balance lab at 
Don Chisholm: DXA, laboratory equipped with freezer and hood, 
blood draw capabilities, exam rooms, fitness test equipment 
(treadmill, mask, monitors), thermic effect of feeding equipment. 
Study staff and graduate student support to complete the study 
measures as well as a kitchen on site to prepare the fixed/ad lib 
meals is also available.  
• There is an established partnership with KUMC and Dr. Shook. Dr. 
Shook is a volunteer faculty in the KUMC Department of Pediatrics. 
 
28.0 Multi-Site Research 
 

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Choose ALL relationship types that apply:  
☐    Multi-Site Research: Multiple sites will be engaged in this human research 
project. Sites will use the same protocol to conduct the same human research 
activities (except for minor variations due to local context considerations).   
☒    Collaborative Research: Multiple sites will be engaged in this human 
research project. Sites will not be performing the same research activities. The 
Site submission will specify the specific research activities each site will perform.  
REQUIRED: Enter summary of site-specific activities that differ from the 
overall protocol: The insulin clamp procedures will be happening at the 
KUMC CTSU. Also, we will have KUMC study personnel assisting with 
study procedures, data analysis, and manuscript preparation.    
☐    Student(s):  Student(s) will help with this project and will be engaging their 
home institution.  
☐    Visiting Resident(s) / Visiting Fellow(s):  Visiting Resident(s) / Visiting 
Fellow(s) will help with this project and will be engaging their home institution.  
 
Is Children’s Mercy (CM) acting as the single IRB of Record (sIRB)? 
☐    No, each site is getting their own IRB approval.  
☒    Yes, some or all sites will rely on the CM as the sIRB.  
• Reliance is required for non-Exempt NIH or other Federally 
Funded research where: 
o The institution's employees or agents intervene or 
interact with human subjects for research purposes;     
o The institution's employees or agents obtain 
individually identifiable private information or 
identifiable biospecimens about human subjects for 
research purposes; or     
o The institution receives a direct HHS award to conduct 
human subjects research, even where all activities 
involving human subjects are carried out by a 
subcontractor or collaborator.  
If CM is sIRB for another site, complete the chart for that site(s) (Add a new row 
for each site relying on the CM IRB, delete chart if not acting as sIRB): 
Site Name 
Enrollment Goal for 
Site(s) 
Relying on CM IRB?  

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Choose One 
University of 
Kansas Medical 
Center 
☐  Site Enrollment 
Goal: Insert # 
 
☒  Site will not 
enroll  
☒  External Site will rely on the CM IRB as 
the IRB of Record using a reliance 
agreement. () 
☐  Not Applicable. Site will not interact or 
intervene with human participants or their 
identifiable data / identifiable biospecimens. 
Site is also not a primary NIH or federal 
grant recipient.   
 
 
29.0 International Research 
29.1.  
N/A 
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