Lisdexamfetamine for the Treatment of Severe Obesity in Children Aged 6 to 12 Years
Phase: EARLY_PHASE1
Conditions: Obesity, Childhood
Sponsor: University of Minnesota

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Lisdexamfetamine for the Treatment of Severe Obesity in Children Aged 
6 to 12 Years 
 
VERSION DATE: 19Sep2025 
 
Page 1 of 50 
 
 
ANCILLARY REVIEWS 
DO NOT DELETE.  Submit the completed checklist below with your protocol. 
Which ancillary reviews do I need and when do I need them? 
Refer to HRP-309 for more information about these ancillary reviews. 
Select yes or 
no 
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If yes… 
Impact on 
IRB Review 
☐ Yes 
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Include Gillette resources, staff 
or locations 
Gillette Scientific review and Gillette 
Research Administration approval is 
required.  Contact: 
research@gillettechildrens.com   
Required 
prior to IRB 
submission 
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☐ No 
 
Involve Epic, or Fairview 
patients, staff, locations, or 
resources? 
The Fairview ancillary review will be 
assigned to your study by IRB staff 
Contact: ancillaryreview@Fairview.org 
Approval 
must be 
received 
prior to IRB 
committee/ 
designated 
review.   
 
Consider 
seeking 
approval 
prior to IRB 
submission. 
☒ Yes 
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Include evaluation of drugs, 
devices, biologics, tobacco, or 
dietary supplements or data 
subject to FDA inspection? 
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assigned to your study by IRB staff 
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See: 
https://policy.umn.edu/research/indide  
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Investigator Manual (HRP-
103). 
 
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MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Lisdexamfetamine for the Treatment of Severe Obesity in Children Aged 
6 to 12 Years 
 
VERSION DATE: 19Sep2025 
 
Page 2 of 50 
 
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Include the use of 
recombinant or synthetic 
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eprotocol.umn.edu 
 
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MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Lisdexamfetamine for the Treatment of Severe Obesity in Children Aged 
6 to 12 Years 
 
VERSION DATE: 19Sep2025 
 
Page 3 of 50 
 
PROTOCOL COVER PAGE 
 
 
Protocol Title 
Lisdexamfetamine for the Treatment of Severe Obesity in Children 
Aged 6 to 12 Years 
Principal 
Investigator/Faculty 
Advisor 
Name: Claudia Fox, MD, MPH 
Department: Pediatrics 
Telephone Number: (612) 626-6616 
Email Address: lusc0001@umn.edu 
Student Investigator 
Name: not applicable 
Current Academic Status (Student, Fellow, Resident): 
  
Department: 
Telephone Number: 
Institutional Email Address: 
Scientific Assessment 
I believe Scientific Assessment is not required. 
IND/IDE # (if 
applicable) 
162424 
IND/IDE Holder 
Claudia Fox, MD 
Investigational Drug 
Services # (if 
applicable) 
6151 
Version 
Number/Date: 
Version 10.0, dated 19Sep2025 
 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Lisdexamfetamine for the Treatment of Severe Obesity in Children Aged 
6 to 12 Years 
 
VERSION DATE: 19Sep2025 
 
Page 4 of 50 
 
 
REVISION HISTORY 
 
Revision # 
Version Date 
Summary of Changes 
Consent Change? 
1 
29Mar2023 
Revises the number of participants, 
revises the drug titration schedule, 
revises the statistical analysis section, 
adds in safety labs at the screening 
visit, adds in urine pregnancy testing 
at all in-person visits and adds in 
depression/suicide screening at all in-
person visits.  Restructures the dietary 
recalls that will be conducted during 
the study. 
Yes 
2 
28Jun2023 
Notes the tests within the basic 
metabolic panel to the footnote of 
the schedule of events. 
Yes 
3 
12Sep2023 
Revises the visit windows for the 
study, adds a sleep log and a dose log 
for the parent, provides trinket 
incentives for the parent to give the 
child for wearing the ActiGraph 
(stickers, pens, markers, etc.), adds a 
lifestyle visit at the Week 24 visit, 
updates the questionnaires, changes 
the footnote in the schedule of events 
for the NDSR, notes that parents may 
be offered a portion plate and 
updates the resting metabolic rate 
collection methods. 
Yes 
4 
01Dec2023 
Notes that the screening visit may be 
broken into two visits, allowing for 
participants who have difficulty with 
the pill swallow test to try a second 
time.   
Yes 
 
 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Lisdexamfetamine for the Treatment of Severe Obesity in Children Aged 
6 to 12 Years 
 
VERSION DATE: 19Sep2025 
 
Page 5 of 50 
 
5 
02Feb2024 
Makes clarifications to the study 
inclusion and exclusion criteria.  
Revises protocol section 12.1 to 
expand the risks for elevated blood 
pressure, elevated heart rate and 
change in mental health status.  
Corrects references which had 
become corrupted during previous 
versions. 
No 
6 
16Jul2024 
Clarifies that pregnancy tests are to 
be done on all female participants, 
regarding of menstrual status, during 
the course of the study. 
Yes 
7 
18Oct2024 
Removes the EKG at Week 12.  
Removes the urine toxicology testing 
at screening,  Adds in that medical 
history to be done at screening 
includes asking about a history of 
chemical dependency. 
Yes 
8 
24Jun2025 
Corrects an omission from protocol 
version 8, section 7.3.  The urine 
collection at the Screening visit will 
NOT include a toxicology test 
No 
9 
19Sep2025 
We are adjusting the number of 
participants we will need to consent 
in order to randomize 44 participants.  
No 
 
 
 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Lisdexamfetamine for the Treatment of Severe Obesity in Children Aged 
6 to 12 Years 
 
VERSION DATE: 19Sep2025 
 
Page 6 of 50 
 
Table of Contents 
 
1.0 
Objectives ........................................................................................................................... 8 
2.0 
Background ........................................................................................................................ 8 
3.0 
Study Endpoints/Events/Outcomes ................................................................................. 14 
4.0 
Study Intervention(s)/Investigational Agent(s) ............................................................... 15 
5.0 
Procedures Involved ........................................................................................................ 16 
6.0 
Data and Specimen Banking ............................................................................................ 22 
7.0 
Sharing of Results with Participants ................................................................................ 22 
8.0 
Study Population .............................................................................................................. 23 
9.0 
Vulnerable Populations .................................................................................................... 28 
10.0 
Local Number of Participants ........................................................................................... 29 
11.0 
Local Recruitment Methods ............................................................................................. 29 
12.0 
Withdrawal of Participants .............................................................................................. 30 
13.0 
Risks to Participants ......................................................................................................... 31 
14.0 
Potential Benefits to Participants .................................................................................... 32 
15.0 
Statistical Considerations ................................................................................................. 32 
16.0 
Health Information and Privacy Compliance ................................................................... 35 
17.0 
Confidentiality .................................................................................................................. 39 
18.0 
Provisions to Monitor the Data to Ensure the Safety of Participants ............................. 39 
19.0 
Provisions to Protect the Privacy Interests of Participants ............................................. 42 
20.0 
Compensation for Research-Related Injury ..................................................................... 43 
21.0 
Consent Process ............................................................................................................... 43 
22.0 
Setting .............................................................................................................................. 44 
23.0 
Multi-Site Research .......................................................................................................... 44 
24.0 
Coordinating Center Research ......................................................................................... 44 
25.0 
Resources Available ......................................................................................................... 44 
26.0 
References ........................................................................................................................ 45 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Lisdexamfetamine for the Treatment of Severe Obesity in Children Aged 
6 to 12 Years 
 
VERSION DATE: 19Sep2025 
 
Page 7 of 50 
 
ABBREVIATIONS/DEFINITIONS 
 
ADHD 
Attention deficit hyperactivity disorder 
AE 
Adverse event 
ALT 
Alanine transaminase 
AST 
Aspartate aminotransferase 
BIS/BAS 
Behavior Inhibition and Behavioral Activation System 
BMI 
Body mass index 
BMIz 
Body mass index z-score 
BPIC 
Best Practices Integrated Informatics Core 
BPM 
Beats per minute 
BRIEF-2 
Behavioral Rating Inventory of Executive Function 
CDI-2 
Children’s Depression Inventory 
CEBQ 
Child Eating Behavior Questionnaire 
CI 
Confidence interval 
CPOM 
Center for Pediatric Obesity Medicine 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTSI 
Clinical and Translational Science Institute 
DBP 
Diastolic blood pressure 
DXA 
Dual x-ray absorptiometry 
DSMB 
Data and safety monitoring board 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Heart rate 
ICH GCP 
International Conference on Harmonisation-Good Clinical Practice 
ICS 
Informatics Consulting Services 
IDS 
Investigational Drug Service 
IE 
Information Exchange 
LDX 
Lisdexamfetamine 
LOC 
Loss of control 
mSv 
Millisievert 
NICHQ-Vanderbilt 
National Institute for Children’s Health Quality-Vanderbilt Scale 
NIDDK 
National Institute of Diabetes and Digestive and Kidney Diseases 
NDS-R 
Nutrition Data System for Research 
PALS 
Pediatric Adapted Liking Survey 
Peds QL 
Pediatric Quality of Life Survey 
PWMC 
Pediatric Weight Management Clinic 
QOL 
Quality of life 
QR 
Quick response 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SDS 
System Dynamics Statistics 
SOP 
Standard operating procedure 
%BMI95p 
BMI 95th percentile 
U.S. 
United States 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Lisdexamfetamine for the Treatment of Severe Obesity in Children Aged 
6 to 12 Years 
 
VERSION DATE: 19Sep2025 
 
Page 8 of 50 
 
 
1.0 
Objectives 
1.1 Purpose: This will be a single site, 24-week double-blind, randomized, placebo-
controlled pilot and feasibility clinical trial designed to estimate the treatment 
effect and tolerability of lisdexamfetamine (VyvanseTM) for the treatment of 
severe obesity in children ages 6 to < 12 years.  After careful screening, all eligible 
participants (n=44) will be randomized, 1:1, to either lisdexamfetamine plus 
lifestyle therapy or placebo plus lifestyle therapy for 24 weeks of intervention.  
Participants and their parent/guardian will attend 8 in-person and 6 virtual visits.  
Participants will undergo regular assessments of anthropometrics, blood 
pressure, heart rate, and side effects and interval assessments of body 
composition, bone age, Tanner stage, laboratory tests, and questionnaires.   
2.0 
Background 
2.1 Significance of Research Question/Purpose:  
Childhood severe obesity is a highly prevalent, serious, and chronic disease. 
Severe obesity in children (defined as a body mass index [BMI] ≥120 percent of 
the 95th age- and sex-specific percentile) is one of the most important public 
health challenges of the 21st century.1  Affecting nearly 5% of the 6-11 year olds in 
the U.S.,2 severe obesity, particularly in this early life phase, is a serious and 
chronic disease.  The physical and psychological health sequelae of childhood 
obesity are substantial, including high rates of metabolic syndrome (50-61%), 3,4 
non-alcoholic fatty liver disease (11-28%),5 obstructive sleep apnea (11-78%),6 
depression (10-27%),7 and low quality of life.8,9  Furthermore, multiple studies 
indicate that obesity in childhood almost universally persists into adolescence and 
adulthood.10-12 For instance, one longitudinal study reported that 85% of 7-year 
olds with obesity became adults with obesity.13  Unsurprisingly, the consequences 
of obesity in childhood on future adult health and productivity are staggering and 
include increased rates of type 2 diabetes, coronary artery disease, hypertension, 
and many cancers,14 as well as reduced education attainment and employment.15 
Thus, there is an urgency to intervene on obesity early and aggressively in 
childhood when there is a window of opportunity to improve, or even normalize, 
growth trajectories in order to reduce the immense social and financial burden 
childhood obesity has on society. 
Lifestyle therapy alone has limited efficacy; adjunct anti-obesity medication 
may improve outcomes.  While the cornerstone of obesity treatment in children 
is lifestyle therapy, the effectiveness 16-18 and long-term durability 19,20 of this 
singular strategy is questionable, even in young populations.  This has been 
demonstrated in multiple randomized controlled studies, as in real world 
settings.21 Even the gold standard of pediatric obesity treatment, family-based 
therapy, resulted in only 1/3 of children achieving a healthy weight.18  Underlying 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Lisdexamfetamine for the Treatment of Severe Obesity in Children Aged 
6 to 12 Years 
 
VERSION DATE: 19Sep2025 
 
Page 9 of 50 
 
poor outcomes of lifestyle therapy is the failure of this approach to appropriately 
address the pathophysiology of obesity.  Accordingly, anti-obesity medications, 
which target pathophysiology,22 are recommended as an adjunct to lifestyle 
therapy when lifestyle therapy alone is insufficient for limiting weight gain or 
ameliorating comorbidities.23-25 Indeed, this approach of combining anti-obesity 
medications with lifestyle therapy, when employed early in childhood, before 
puberty when obesity is all but “ingrained,” has the potential to slow weight gain, 
thereby improving growth trajectories. 
Presently, however, no anti-obesity medications are approved by the U.S. Food 
and Drug Administration (FDA) for children under 12 years of age.  Liraglutide, a 
glucagon-like peptide-1 receptor agonist, is in a phase 3 study for the treatment 
of obesity in children 6-11 years of age, but its widespread utilization is likely to 
be low because it is expensive (approximately $15,000 annually), administered by 
daily injection, and unfamiliar to most pediatricians.  Identification of safe, 
effective, easy to use, and affordable anti-obesity medications for children with 
obesity has the prospect of dramatically improving the outcomes of this high-risk 
population, ultimately leading to a reduction in future morbidity and 
accompanying, staggering health care costs, and premature mortality.  One such 
class of medications that may meet these criteria are psychostimulants such as 
amphetamine and methylphenidate.  Psychostimulants are FDA-approved for the 
indication of attention deficit hyperactivity disorder (ADHD) in children ≥ 6 years 
of age and are the second most frequently prescribed medication class in the 
pediatric population.26 Psychostimulants have a long-standing, well-described 
safety profile27 and because of their favorable impact on weight, they may serve 
as a useful adjunct to lifestyle therapy. 
Psychostimulants may be an effective adjunct to lifestyle therapy. 
Pharmacological treatments for obesity target homeostatic and non-homeostatic 
energy regulatory mechanisms.  Homeostatic mechanisms induce food intake and 
decrease energy expenditure when energy reserves are depleted.  This 
“physiologic hunger” is controlled by numerous hormones and neurotransmitters 
such as leptin, insulin, and norepinephrine.  In contrast, non-homeostatic 
mechanisms involve reward, cognition, and emotional factors of eating, and are 
primarily driven by dopamine activity.28-30 Dopamine is implicated in mediating 
the reinforcing value of food, and reduced brain dopamine activity is associated 
with both obesity and with pathological food intake, such as binge eating.31 
Psychostimulants are both norepinephrine and dopamine re-uptake inhibitors 
and therefore may be especially effective for weight management because they 
address both homeostatic and non-homeostatic pathways (see Figure 1). 
Numerous studies indicate that psychostimulant treatment is associated with 
reduced weight gain in children with ADHD.  A recent meta-analysis of 8 studies 
including nearly 5,000 children and adolescents with ADHD showed that 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Lisdexamfetamine for the Treatment of Severe Obesity in Children Aged 
6 to 12 Years 
 
VERSION DATE: 19Sep2025 
 
Page 10 of 50 
 
psychostimulant treatment, for at least 6 months, was associated with a 
consistent, significant pre-post difference in weight z-score of 0.33 (95% CI: 0.22-
0.44, p <0.0001).32 A subset of this meta-analysis, including only those studies 
that provided outcomes out to 18-24 months, showed a pre-post difference in 
weight z-score of 0.46 (95% CI: 0.29-0.62, p <0.0001).  Although these findings are 
modest, though clinically significant, several large studies observed that children 
with higher baseline BMIs 33-34 and younger age 35 experience greater weight 
reduction.  Combined with lifestyle therapy, the magnitude of change in BMI due 
to psychostimulants is likely to be much higher, particularly when considering 
their mechanisms of action. 
 
 
Figure 1.  Potential mechanisms by which lisdexamfetamine leads to BMI reduction.  Homeostatic 
mechanisms are shown in green.  Non-homeostatic mechanisms are shown in blue.  Obesogenic 
behaviors are shown in orange. 
 
There are likely multiple mechanisms by which psychostimulants promote weight 
loss (see Figure 1).  One mechanism may be by their direct effect on appetite 
reduction and subsequent decrease in food intake, given their noradrenergic 
properties.  This is supported by two studies that measured the acute effect of a 
common psychostimulant, methylphenidate, on eating in individuals with obesity 
who did not also have ADHD.  In one of these studies, 22 adolescents with obesity 
received a single acute dose of methylphenidate or placebo before a test meal.  
The methylphenidate group compared to the placebo group consumed 
significantly less calories from fat (167 vs 203 kcal) and carbohydrate (311 vs 389 
kcal).36 In the other study, 9 adults were treated with a single dose of 
methylphenidate or placebo in a within-subject double blind laboratory study.  
Compared with placebo, those who had pre-meal methylphenidate consumed 
34% fewer calories.37 It is also conceivable that via its noradrenergic properties, 
psychostimulants may increase resting energy expenditure, which may directly 
lead to BMI reduction.  While this has been demonstrated in a small (n=14) study 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Lisdexamfetamine for the Treatment of Severe Obesity in Children Aged 
6 to 12 Years 
 
VERSION DATE: 19Sep2025 
 
Page 11 of 50 
 
of healthy adults,38 where resting energy expenditure increased by 7% over 
baseline after an acute dose of a psychostimulant, another study in children 
(n=31)39 had null findings. 
Other proposed mechanisms by which psychostimulants may promote weight 
loss are related to non-homeostatic processes including reward, cognition, and 
emotional factors, which are determined largely by dopaminergic pathways.  
These processes are controlled, in part, by executive functioning, which is 
positively affected by psychostimulants.40-42 Executive functioning is an umbrella 
term that refers to a set of cognitive processes that aid in managing behavior, 
emotions, and thoughts with regard to a future goal or outcome.  Executive 
functioning emerges in early childhood, continues to develop throughout 
adolescence, and plays a key role in self-regulation.  Extensive literature supports 
a robust association between deficits in executive functioning and obesity.43-45 
Indeed, deficits in executive functioning lead to dysregulated eating patterns 
including more emotional overeating, more binge eating, and higher intake of 
high calorie snacks, as well as difficulty with delay of gratification for both food 
and non-food rewards.44  Executive function skills are also needed to facilitate 
physical activity behaviors, such as sport or complex motor movements.46  Finally, 
via dopaminergic pathways, psychostimulants may directly improve reward 
processing1 and thereby decrease reward-based eating. In summary, by 
improving executive functioning and reward processing, psychostimulants may 
increase a child’s ability to successfully engage in goal directed behavior such as 
healthy eating, reduced binge eating and reward-based eating, and regular 
physical activity, which in turn may lead to BMI reduction.   
Lisdexamfetamine (LDX) may be better than other psychostimulants for treating 
obesity in children.  The two primary types of psychostimulants are 
amphetamine-based, such as lisdexamfetamine (LDX), and methylphenidate-
based, such as Ritalin.  LDX is a long-acting (12 hour) psychostimulant that is 
dosed once daily.  Multiple studies suggest that amphetamine-based 
psychostimulants,49 and LDX in particular,50 compared to methylphenidate-based 
psychostimulants perform better for ADHD treatment.  Furthermore, LDX 
compared to other psychostimulants may be associated with more weight loss.  In 
a head-to-head study of LDX versus a long-acting methylphenidate compound for 
treating ADHD in adolescents, those treated with LDX compared to 
methylphenidate experienced more frequent decreased appetite (53% vs 42%) 
and decreased weight (21% vs 13%).51  Thus, it is possible that LDX, through its 
superior impact on improving ADHD symptoms, including executive dysfunction, 
may also have a superior effect on weight reduction compared to other 
psychostimulants. 
In addition to ADHD, LDX, unlike other psychostimulants, is also FDA-approved for 
the indication of binge eating disorder in adults and may therefore be useful for 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Lisdexamfetamine for the Treatment of Severe Obesity in Children Aged 
6 to 12 Years 
 
VERSION DATE: 19Sep2025 
 
Page 12 of 50 
 
decreasing binge eating behaviors (and perhaps subsequent weight) in affected 
children.  Binge eating disorder is characterized by recurrent episodes of 
consumption of larger amounts of food in a discrete period of time than is typical 
for most people, accompanied by a sense of loss of control over the food 
consumption and psychological distress.2  A corollary to this eating disorder in 
children is loss of control (LOC) eating.  LOC eating is described as the experience 
of LOC over what or how much one eats, regardless of the amount of food 
consumed.3  Binge/LOC eating is highly prevalent in the pediatric population, 
affecting 22-31% of children and adolescents with overweight and obesity,4 and is 
consistently associated with adverse physiological and psychological outcomes.5  
Furthermore, it has been proposed that binge/LOC eating may mediate the 
relationship between poor executive function and weight gain.6  Perhaps not 
surprising is that in the phase 3 study of adults randomized to 11 weeks of LDX or 
placebo for binge eating disorder where weight loss was only a safety outcome 
and obesity was not an inclusion criteria, the mean weight loss was 4.9 kg for the 
treatment arm and 0.1 kg for the placebo arm.7  
 
Finally, other advantages of LDX include its long half-life compared to other 
psychostimulants, which is associated with reduced abuse potential8 and the fact 
that the manufacturer’s patent has expired in February 2023, thus paving the way 
for less expensive, generic formulations.  The latter is particularly important 
because many insurance plans do not cover anti-obesity medications so families 
must resort to paying out-of-pocket for their needed obesity treatment.   It 
should also be noted that phentermine, the most commonly prescribed anti-
obesity medication in adults, is also an amphetamine derivative.9  However, 
although it is inexpensive, phentermine, in contrast to LDX, is only FDA-approved 
for 12 weeks of use rather than chronic use.  Further, phentermine has relatively 
weaker dopaminergic properties.  For these reasons, it seems logical to examine 
LDX, not phentermine, for the treatment of childhood obesity. 
 
A.5. Tolerability of LDX for the treatment of severe obesity in children is 
unknown 
Although psychostimulants, including LDX, have a long-standing, well-established 
safety profile,10 the relative tolerability of these medications in children who do 
not have ADHD has yet to be established.  Aside from decreased appetite, the 
most common side effects of psychostimulants in children with ADHD include 
insomnia, upper abdominal pain, and irritability.  Particularly relevant to patients 
with obesity are the impact of psychostimulants on blood pressure, heart rate 
and linear growth, the effects of which tend to be dose dependent in children 
with ADHD.10  Clinical trials of LDX for the treatment of ADHD in children report 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Lisdexamfetamine for the Treatment of Severe Obesity in Children Aged 
6 to 12 Years 
 
VERSION DATE: 19Sep2025 
 
Page 13 of 50 
 
mean increases in systolic blood pressure of 2-4 mm Hg and in heart rate of 3-7 
bpm.11  The clinical significance of this effect on the cardiovascular system is 
uncertain, especially for children with obesity who may be at higher risk of having 
underlying cardiovascular impairment such as hypertension.  Importantly, in 
adults with obesity treated with phentermine, also a noradrenergic agent, blood 
pressure tends to decrease as a function of weight loss.12  Thus, measuring the 
impact of LDX on blood pressure and heart rate in children with obesity is critical 
for assessing its utility as an adjunct treatment for obesity in this population.  
Regarding linear growth, psychostimulants have been shown to have adverse 
effects on height velocity at various stages of childhood, including pre-
puberty.13,14 However, final adult height does not appear to be impacted.15  
Similarly, obesity can effect growth and has been associated with taller stature 
during childhood but decreased growth velocity in adolescence; the net result 
again is no association between childhood weight status and adult height.16 That 
said, as both psychostimulant use and obesity can affect growth velocities during 
the pre- and peri-pubertal periods, the net effect of both of these simultaneously 
during this stage of development is unclear and warrants further investigation. 
 
2.2 Preliminary Data: To our knowledge, no randomized controlled trials have 
examined psychostimulants as an adjunct to lifestyle therapy for BMI reduction in 
children with obesity. At the University of Minnesota Pediatric Weight 
Management Clinic, where off-label use of medications for the treatment of 
obesity is guided by protocols developed by our team of pediatric obesity 
medicine physicians, we have used LDX as an adjunct to lifestyle therapy for the 
treatment of obesity in patients.  We identified 65 patients, >6 years of age with 
severe obesity, who were treated with LDX plus our standard of care lifestyle 
therapy for at least 3 months.  The mean absolute change in the percent of the 
95th BMI percentile (%BMIp95) was -4.68 and -6.35 percentage points at 3- and 6-
months, respectively (see Figure 2).  In a sub-analysis including only patients ages 
> 6 to < 12 years (n=37), the mean absolute change in %BMIp95 was -5.94 and -
8.41 percentage points at 3- and 6-months, respectively.   

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Lisdexamfetamine for the Treatment of Severe Obesity in Children Aged 
6 to 12 Years 
 
VERSION DATE: 19Sep2025 
 
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Figure 2.  Change in %BMIp95 from baseline to 3- and 6-months with 
LDX and lifestyle therapy. 
 
2.3 Existing Literature: Several case series and retrospective medical chart reviews 
describe the results of treating hypothalamic obesity (most often from brain 
tumors) in children with psychostimulants.  These reports demonstrated BMI 
stabilization or reduction with dextroamphetamine or methylphenidate.17-20  A 
case series of children with monogenic obesity due to mutations in leptin 
receptor or melanocortin-4 receptor also demonstrated favorable BMI outcomes 
with methylphenidate treatment.21  
3.0 
Study Endpoints/Events/Outcomes 
3.1 Primary Endpoint/Event/Outcome: To estimate the treatment effect of LDX + 
lifestyle therapy vs. placebo + lifestyle therapy on changes in BMI (%BMIp95), 
body fat, cardiometabolic health and quality of life (QOL) from baseline to 24 
weeks.  We hypothesize that LDX compared to placebo will result in a greater 
mean decrease in %BMIp95 and body fat, improved cardiometabolic health and 
QOL at 24 weeks. 
3.2 Secondary Endpoint(s)/Event(s)/Outcome(s): To generate estimates of the 
tolerability and safety of LDX used for the treatment of severe obesity in children.  
We hypothesize that at least 80% of participants will tolerate an LDX dose of at 
least 30 mg per day (the recommended starting dose) and that the LDX group 
compared to the placebo group will not demonstrate clinically significant 
increases in blood pressure or heart rate. 

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We will also examine the potential mechanisms by which LDX affects BMI in 
children with obesity, including its effect on executive functioning, reward 
processing, appetite, resting energy expenditure, and health behaviors (diet, 
eating behaviors, and physical activity). Study Intervention(s)/Investigational 
Agent(s) 
3.3 Description:  
LDX:  LDX, a psychostimulant prodrug of dextroamphetamine, is FDA-approved 
for ADHD in children ≥6 years of age and for binge eating disorder in adults.  It is 
available in capsules of 10, 20, 30, 40, 50, 60, and 70 mg.  It is orally administered 
once daily and has a half-life of 12 hours. After a single dose, the 
pharmacokinetics are linear between 30 and 70 mg in children ages 6-12 years, 
and both the clinical efficacy for ADHD symptoms and weight loss side effects are 
dose dependent.22  Following single doses of 30 mg to 70 mg, the weight/dose 
normalized area under the curve and maximal concentration values are the same 
in 6-12 year olds compared to adults.  Per the package insert, the recommended 
starting dose for children ≥6 years of age with ADHD is 30 mg daily.  The dose is 
adjusted by 10 or 20 mg increments at weekly intervals up to a maximum of 70 
mg daily.  The target dose is one that balances the clinical efficacy with 
tolerability.  For binge eating disorder in adults, the recommended dose is 50-70 
mg daily.  To operate conservatively and allow for maximum tolerability, we will 
start at 30 mg daily for 2 weeks, then 40 mg daily for 2 weeks, then 50 mg daily 
for 2 weeks, then 60 mg daily for 2 weeks, then 70 mg daily for the remaining 14 
weeks.  We will not use a forced titration schedule.  That is, for patients who do 
not tolerate the full dose escalation schedule, we will maintain the dose at the 
maximum tolerated dose for the remainder of the trial. Also, we will not escalate 
the dose after week 10, which is the end of the planned dose escalation schedule.   
A participant’s dose may be decreased for medication intolerance anytime during 
the trial; the dose will be reduced by 10 mg at weekly intervals until a tolerable 
dose is achieved.  If a participant cannot tolerate the smallest dose, 10 mg, then 
drug/placebo will be discontinued but the participant will remain in the trial.  This 
flexible dosing will allow for maximal time on medication.  Placebo capsules that 
are identical in appearance to the LDX capsules will be made by the University of 
Minnesota Investigational Drug Service Pharmacy, which will manage all trial 
product.       
Lifestyle Therapy:  Lifestyle therapy will focus on dietary and physical activity 
modification supported by behavior change strategies.  The standardized 
curriculum will be based on a behavioral conceptualization of effective weight 
management that emphasizes: 1) identifying behaviors in need of change; 2) 
setting goals for change; 3) monitoring progress; 4) modifying environmental cues 
to facilitate change; and 5) modifying consequences to motivate change (e.g. 
positive reinforcement for goal attainment).  Each session will be delivered by an 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Lisdexamfetamine for the Treatment of Severe Obesity in Children Aged 
6 to 12 Years 
 
VERSION DATE: 19Sep2025 
 
Page 16 of 50 
 
RD-trained research coordinator, who will follow a standardized format including 
a review of progress, new material, and a summary/plan for the upcoming 
session.  A total of 13 sessions, each 30-60 minutes in length, will be delivered 
every 2 weeks, 7 in-person and 6 virtually (delivered by a secure virtual platform).  
Virtual visits may be conducted with the parent/guardian alone (without 
participant present) to allow for more flexibility in scheduling and to minimize 
time away from school. 
3.4 Drug/Device Handling:  
LDX will be purchased commercially. The University of Minnesota Investigational 
Drug Service (IDS) Pharmacy will be asked to prepare a matching placebo.  Trial 
product will be managed by IDS and will be dispensed according to their 
operating policies.  The IDS office specializes in storing and dispensing 
investigational drugs for clinical trials.  Study physicians will write a prescription in 
order for IDS to dispense the study medication.  IDS is a secure facility (behind 
two locked doors) and maintains refrigerators and freezers with temperature 
tracking to assure that the drugs utilized in this study will maintain stability.  IDS 
will keep detailed records on the receipt of investigational product (including lot 
numbers) and detailed records on the dispensing of the product to each subject 
enrolled in the study.  IDS is also equipped to destroy any medication that is 
returned at the end of the study when all drug accountability has been 
completed.  The participants and their parents will be instructed on how to 
administer the medication and the dose escalation.  Study staff members will 
perform drug accountability at each visit and estimate a percentage of missed 
doses as additional forms of compliance tracking. 
3.5 
Biosafety: Not applicable.  
3.6 
Stem Cells: Not applicable. 
3.7 
Fetal Tissue: Not applicable. 
 
4.0 
Procedures Involved 
4.1 Study Design: This will be a 24-week, randomized, double-blind, placebo-
controlled pilot and feasibility clinical trial of LDX plus lifestyle therapy versus 
matching placebo plus lifestyle therapy.  We will enroll 44 children who have 
previously failed to lose weight with lifestyle therapy per parent report.   

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Figure 3.  Clinical Trial Framework 
 
The schedule of events shows the data that will be collected at each study visit.  
All participants will receive reimbursement for completing study visit 
assessments.   
 
 

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Page 18 of 50 
 
Screening 
Baseline/ 
Randomization 
+21d7 
Week 2 + 3d 
Week 4 + 3d 
Week 6 + 3d 
Week 8 + 3d 
Week 10 + 3d 
Week 12 + 7d 
Week 14 + 7d  
Week 16 + 7d 
Week 18 + 7d 
Week 20 + 7d 
Week 22 + 7d 
Week 24 + 7d 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, including chemical dependency 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, weight, blood pressure and heart rate 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Physical exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tanner stage 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Basic metabolic panel5, TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test1 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Suicide and Depression Screen 
• C-SSRS  
• CDI-2 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Bone age 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Indirect calorimetry 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Fasting blood tests 
• Lipids 
• Glucose 
• Insulin 
• HbA1c 
• AST 
• ALT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
DXA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Diet recall 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
Accelerometry2 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Questionnaires 
• Peds QL 
• NIH Toolbox 
• BRIEF-2 
• NICHQ-Vanderbilt 
• CEBQ 
• VAS of Hunger 
• CBES 
• BIS/BAS6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Planned dose escalation (mg) 
 
30 
40 
50 
60 
70 
 
 
 
 
 
 
 
 
Dispense study medication 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Compliance check 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Review 
• AEs 
• Barkley Rating Scale4 
• Con Meds 
• Intercurrent Illness 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lifestyle therapy (in-person) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Lifestyle therapy (virtual) 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
1. 
Blood or urine pregnancy tests can be conducted at the Screening and Week 24 visits.  Urine pregnancy tests will be done at the 
Baseline/Randomization. Week 4, Week 8, Week 12, Week 16 and Week 20 visits. 
2. 
Accelerometer will be worn 24/hours x 7 days between screening and baseline and again for 24/hours x7 days between Week 20 
and Week 24 
3. 
Participant may be given a placebo test capsule to ensure they are able to swallow the capsules for the study 
4. 
Barkley Rating Scales will be performed every two weeks during the dose escalation through Week 10 and then at the in person 
visits (Weeks 12, 16, 20 and 24). 
5. 
Basic metabolic panel to consist of anion gap, calcium, chloride, bicarbonate, creatinine, glucose, potassium, sodium, urea 
nitrogen 
6. 
Only BAS will be utilized 
7. 
Baseline/Randomization must occur within 21 days of the date blood was drawn at the Screening visit. 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Lisdexamfetamine for the Treatment of Severe Obesity in Children Aged 
6 to 12 Years 
 
VERSION DATE: 19Sep2025 
 
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4.2 Study Procedures:  
● 
Height, weight, blood pressure, heart rate and pubertal development.  
Height and weight will be measured by 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.  Blood pressure will be 
obtained on the same arm using the same cuff size and equipment 
according to standardized procedures and the internal standard operating 
procedure.  Tanner stage will be determined by trained personnel.  
● 
Medical history and history of chemical dependency.  Participants will be 
asked about their medical history at the screening visit and will be asked if 
they have a history of chemical dependency. 
● 
Bone age.  To estimate the maturity of the participant’s skeleton, an x-ray of 
the left wrist will be taken. 
● 
Resting energy expenditure.  Resting energy expenditure will be measured 
by indirect calorimetry after participants have been fasting for > 12 hours.  
Metabolic data will be collected using a ventilated hood.  Participants will 
be instructed not to engage in intentional exercise or consume caffeine on 
the day prior to testing.  Participants will be instructed to take their study 
medication the morning of their 24-week visit. Resting gas exchange 
measurements will be collected using a Parvo Medics TrueOne 2400 
Metabolic Cart (Sandy,UT).  After a 30-minute resting session, room air will 
be drawn through the hood at a rate of 25-40 L/min to match participant’s 
respiration (dilution method).  VO2 and VCO2 values will be collected over a 
30-minute period in a semi-supine position to estimate resting metabolic 
rate.  An estimate of metabolic rate will consist of an average of the 30-
minute collection period minus the first 5-minutes and any movement 
and/or abnormal respiration.  The metabolic cart will be calibrated for gas 
analyses and volume prior to each testing session. 
● 
Blood analyses.  Safety labs consisting of a basic metabolic panel and TSH at 
screening.  Fasting blood (> 12 hours) will be collected for measurement of 
lipids (total-, LDL-, and HDL-cholesterol and triglycerides), glucose, insulin, 

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PROTOCOL TITLE: Lisdexamfetamine for the Treatment of Severe Obesity in Children Aged 
6 to 12 Years 
 
VERSION DATE: 19Sep2025 
 
Page 20 of 50 
 
hemoglobin A1c, ALT and AST (Fairview Diagnostics Laboratories, 
Minneapolis, MN). 
● 
DXA scan.  Total percent body fat, visceral fat, and lean mass will be 
determined by dual energy x-ray absorptiometry.  The scanning table 
accommodates body sizes of up to 204 kg.   
• 
Diet recall.  Will be measured with two multi-pass 24-hour diet recalls on non-
consecutive days using the Nutrition Data System for Research (NDS-R, 
Nutrition Coordinating Center, University of Minnesota).66  The first set of two 
recalls will be completed at the screening and baseline visits.  A second set of 
two 24-hour diet recalls will be completed over the phone at week 22 and in 
person at week 24.  Respondents will use the Food Amounts Booklet to 
estimate portion sizes. Quality assurance checks will be conducted on at least 
10% of recalls according to NDS-R standard protocols.  Key dietary intake 
variables include total energy intake, percent calories from fat, Healthy Eating 
Index, and intake of specific food types (e.g., sugar-sweetened beverages).   
• 
Accelerometry. Objectively measured participant physical activity and sleep 
will be assessed using ActiGraph (GT3X+) accelerometers (ActiGraph LLC, 
Pensacola, FL), which provides reliable and valid assessments of physical 
activity in school-aged children.68-70 Children will be asked to wear the 
accelerometer 24 hours/day for 2 seven-day sessions (between screening and 
baseline/randomization and between weeks 20 and 24), with the exception 
of water activity (e.g., bathing). The ActiGraph GT3X+ measures acceleration 
in three individual orthogonal planes using a vertical axis, horizontal axis and 
a perpendicular axis and is set to collect data at a 40-Hertz frequency. The 
minimum valid wear time criteria are four days (3 weekdays, 1 weekend day) 
of at least 6 hrs of activity between 5:00am and 11:59pm.  Devices will be 
wrist worn, as recent studies have found better compliance with wrist-worn 
actigraph70 without compromising measurement of physical activity.71 
Minutes spent in moderate-to-vigorous physical activity will be primary 
activity endpoint of interest. Vigorous, moderate, light, and sedentary activity 
will also be calculated using ActiLife software. Child sleep will also be 
measured using the same wrist-worn ActiGraph (GT3X-BT) device, which has 
been shown to have acceptable reliability and validity in sleep-wake 
detection compared with laboratory-based polysomnography.72 Nighttime 
sleep efficiency defined as the portion of time dedicated to sleep that is spent 
asleep, sleep latency, sleep duration, and awakenings after sleep onset will 
be examined.  All indexes will be calculated using ActiLife software. A 7-day 
sleep diary will also be maintained by the parent.  Parents will be given small 
gifts to provide to the child (stickers, pens, markers) to give to the child upon 
completion of wearing the ActiGraph for a 7-day period. 
● 
Questionnaires.  Appetite will be gauged by a visual analog scale obtained in 
a fasting state 73,74 and by the Child Eating Behavior Questionnaire (food 

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PROTOCOL TITLE: Lisdexamfetamine for the Treatment of Severe Obesity in Children Aged 
6 to 12 Years 
 
VERSION DATE: 19Sep2025 
 
Page 21 of 50 
 
responsiveness subscale).75  Executive Function will be assessed with brief 
subtests of the NIH Toolbox (including Flanker test of inhibition, 
Dimensional Change Card Sorting Test of cognitive flexibility and List Sorting 
Working Memory Test), and the parent report Behavioral Rating Inventory 
of Executive Function (BRIEF)-2.  ADHD will be measured by the NICHQ 
Vanderbilt Assessment Scale.  Reward responsiveness will be measured by 
the parent-reported Behavioral Inhibition System/Behavioral Approach 
System (BIS/BAS) scales for children.  Specifically, we will use the 13-item 
BAS subscales.  Reward based eating will be measured by the Child Eating 
Behavior Questionnaire (enjoyment of food subscale)75 and Pediatric 
Adapted Liking Survey.76  Binge eating will be measured by the Children’s 
Binge Eating Scale, a 7-item structured, interviewer administered scale 
validated to measure binge eating disorder in children ages 5-13 years.67 
● 
Quality of Life will be measured by the parent report on the Peds QL.77  
● 
Tolerability and Safety Outcomes.  The feasibility of conducting the larger 
clinical trial will depend on whether or not participants can tolerate LDX at 
doses that are effective for inducing BMI reduction.  We will define 
tolerability as being able to tolerate a dose of at least 30 mg daily (the 
recommended starting dose) for the duration of the study.  Importantly we 
will also measure outcomes of children taking doses less than 30 mg daily 
(i.e., 20 mg or 10 mg) as this information will be important for informing the 
dosing of the larger, definitive trial.  We anticipate that participants taking 
LDX will have side effects at the same rate as patients who take LDX for the 
treatment of ADHD, so we will not define tolerability as not having any side 
effects whatsoever.  Rather, the parent/guardian and participant will 
subjectively decide if the side effects, if present, are severe enough to 
warrant discontinuation of the study medication or reducing the dose below 
30 mg daily.  From an objective standpoint, every two weeks during dose 
escalation and every 4 weeks for the remainder of the study we will 
administer the Barkley’s Side Effect Rating Scale which was developed 
specifically to monitor side effects from psychostimulants.  This 
questionnaire, completed by the parent/guardian (and sometimes with the 
child’s help) requests feedback on 17 items on a 9-point Likert scale 
including typical physical side effects (e.g., decrease appetite, insomnia, 
stomachaches, and headaches) and behavioral symptoms (e.g., irritability, 
anxiety).78. Other measures of tolerability will include incidence of 
developing stage 1 hypertension and tachycardia, measured by blood 
pressure and heart rate.  Stage 1 hypertension is defined as SBP and/or DBP 
>95th percentile on three separate occasions and will be confirmed by a 24-
hour ambulatory blood pressure monitor.79  Tachycardia in childhood is 
defined as heart rate > 120 bpm at rest measured on three separate 
occasions.80 

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● Lifestyle therapy.  Lifestyle therapy will focus on dietary and physical 
activity modification supported by behavior change strategies.  The 
standardized curriculum will be based on a behavioral conceptualization 
of effective weight management that emphasizes: 1) identifying 
behaviors in need of change; 2) setting goals for change; 3) monitoring 
progress; 4) modifying environmental cues to facilitate change; and 5) 
modifying consequences to motivate change (e.g., positive 
reinforcement for goal attainment).  Each session will be delivered by an 
RD-trained research coordinator, who will follow a standardized format 
including a review of progress, new material, and a summary/plan for 
the upcoming session.  A total of 13 sessions, each 30-60 minutes in 
length, will be delivered every 2 weeks, 7 in-person and 6 virtually 
(delivered by a secure virtual platform).  Virtual visits may be conducted 
with the parent/guardian alone (without participant present) to allow 
for more flexibility in scheduling and to minimize time away from school. 
4.3 Study Duration: Individuals will be enrolled in the study for up to 27 weeks, 
including 24 weeks of intervention and up to 3 weeks between screening and 
start of intervention. 
We anticipate that it will take 2.5 years to recruit and enroll the 44 participants 
needed for this pilot trial and that data collection will be completed after 3.5 
years.  We anticipate it will take 1 year to analyze the data. 
4.4 Use of radiation 
This study will consist of two bone age x-rays and two DXA scans, all of which will 
utilize ionizing radiation.  None of these tests are considered part of standard 
medical care.  The DXA scans each consist of exposure to 0.01 mSv.  The bone age 
x-rays each consist of exposure to 0.001 mSv.  A participant who completes both 
DXA scans and both bone age x-rays will be exposed to 0.42 mSv.  The average 
amount of radiation that the average person would receive from these procedures 
is less than 2% of that received from natural sources of radiation by a Minnesota 
resident in one year.  Parents will be asked if their child has participated in a 
research study that used radiation within the past 12 months so that the amount 
of radiation the child has been exposed to can be reviewed.  
4.5 Use of Center for Magnetic Resonance Research: Not applicable. 
5.0 
Data and Specimen Banking 
Not applicable. 
6.0 
Sharing of Results with Participants 
6.1 Laboratory results will be posted to the participant’s medical record.  
6.2 Sharing of genetic testing:  Not applicable. 

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7.0 
Study Population 
7.1 Inclusion Criteria:  
• 
Children ages 6 to < 12 years at study entry. 
• 
Severe obesity defined as BMI > 1.2 times the 95th percentile at the screening 
visit. 
• 
Prior failed attempt of lifestyle therapy per parent/guardian report. 
• 
Written informed consent of parent/legal guardian and written assent of 
participant 
 
7.2 Exclusion Criteria:  
• 
Contraindications to lisdexamfetamine, including current or recent (< 14 
days) use of monoamine oxidase inhibitor and known hypersensitivity to 
amphetamine products. 
• 
Family history of sudden death or ventricular arrhythmia in any first or 
second degree relative with any of the following: sudden or unexplained 
death including sudden infant death syndrome, cardiomyopathy, heart 
transplant, familial arrhythmia (such as Wolff-Parkinson-White syndrome, 
long QT interval, or implantable defibrillator). 
• 
Any history of fainting or seizure from exercise, startle or fright 
• 
Clinically significant congenital or structural heart disease or arrhythmia. 
• 
BMI < 1.2 times the 95th percentile at the baseline/randomization visits 
• 
Hypertension defined as SBP and/or DBP >95th percentile (on 3 separate 
occasions) at the screening OR baseline/randomization visits. 
• 
Tachycardia defined HR >120 bpm (on 3 separate occasions) at the screening 
OR baseline/randomization visits. 
• 
Current or recent (< 3 months) use of psychostimulant or sympathomimetic 
amine. 
• 
History of chemical dependency. 
• 
Diabetes mellitus (type 1 or 2). 
• 
Current or recent (< 3 months) use of anti-obesity medication(s). 
• 
Previous bariatric surgery. 
• 
Recent initiation or change in dose (< 3 months prior) of anti-hypertensive or 
lipid medication(s). 
• 
TSH > 1.5x ULN. 
• 
AST or ALT > 3x ULN. 
• 
Fasting glucose ≥ 126 mg/dL 
• 
History of mania, schizophrenia, bipolar disorder, or psychosis. 
• 
Unstable depression or anxiety that has required hospitalization in the past 
12 months. 
• 
Any history of suicide attempt. 

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• 
Columbia Suicide Severity Rating Scale (C-SSRS) with a score of Moderate or 
High at the screening or baseline/randomization visits. 
• 
Children’s Depressive Inventory 2 (CDI-2) score ≥ 70 (based on parent or 
child report) at the screening or baseline/randomization visits. 
• 
Concomitant use of tricyclic antidepressants, selective serotonin reuptake 
inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), 
lithium, fentanyl, tramadol, triptans, tryptophan, buspirone, and St. John’s 
wort at any time during the study. 
• 
Refusal to use adequate contraception (double barrier method or stable 
hormonal contraception plus single barrier method, tubal ligation, or 
abstinence) in girls of childbearing potential. 
• 
Inability to swallow test capsule (participants will have two opportunities) 
 
7.3 Screening (in person visit): 
At this visit the participant’s parent/legal guardian and the participant will be 
taken through the consent process and sign the parental consent form and the 
assent forms after they have had the opportunity to learn about the study and 
ask any questions that they may have.  The participant will undergo the following: 
• Review of inclusion/exclusion criteria 
• Review of medical history including chemical dependency 
• Demographic information collection 
• Height, weight, blood pressure and heart rate 
• Physical exam 
• Tanner staging 
• ECG 
• Fasting blood draw for basic metabolic panel, TSH, lipids, glucose, insulin, 
HbA1c, AST and ALT 
• Urine collection for pregnancy test  
• Suicide and depression screening (C-SSRS and CDI-2) 
• Diet recall 
• Demonstration of ability to swallow capsule 
 
An accelerometer will also be worn for one week (7 days x 24 hours/day) 
between the screening and baseline visit. The parent will be provided with a sleep 
log and small gift to give the child upon completion.  This visit may be broken into 
two parts, to give participants who have difficulty swallowing the capsule an 
opportunity to practice at home (by swallowing tic tacs, etc.) and return for a 
second attempt. 
 
 

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Baseline/Randomization (in person visit): 
• Height, weight, blood pressure and heart rate 
• Bone age x-ray 
• Indirect calorimetry 
• DXA scan (with urine pregnancy test for females) 
• Suicide and depression screening (C-SSRS and CDI-2) 
• Questionnaires 
• Diet recall 
• Medication/placebo dispensed and medication log provided to parent 
• Review adverse events, concomitant medications, intercurrent illness and 
Barkley Side Effect Rating Scale 
• In-person lifestyle therapy visit and offer of a portion plate 
 
Week 2 (virtual visit): 
• Compliance check  
• Review adverse events, concomitant medications, intercurrent illness and 
Barkley Side Effect Rating Scale 
• Dose escalation (if tolerated)  
• Virtual lifestyle therapy visit 
 
Week 4 (in person visit): 
• Height, weight, blood pressure and heart rate 
• Urine pregnancy test  
• Suicide and depression screening (C-SSRS and CDI-2) 
• Compliance check and return unused study medication 
• Review adverse events, concomitant medications, intercurrent illness and 
Barkley Side Effect Rating Scale 
• Dose escalation (if tolerated) and study drug dispensing 
• In-person lifestyle therapy visit 
 
Week 6 (virtual visit): 
• Compliance check 
• Review adverse events, concomitant medications, intercurrent illness and 
Barkley Side Effect Rating Scale 
• Dose escalation (if tolerated)  
• Virtual lifestyle therapy visit 
 
Week 8 (in person visit): 
• Height, weight, blood pressure and heart rate 
• Urine pregnancy test 
• Suicide and depression screening (C-SSRS and CDI-2) 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Lisdexamfetamine for the Treatment of Severe Obesity in Children Aged 
6 to 12 Years 
 
VERSION DATE: 19Sep2025 
 
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• Compliance check and return unused study medication 
• Dose escalation (if tolerated) and study drug dispensing  
• Review adverse events, concomitant medications, intercurrent illness and 
Barkley Side Effect Rating Scale 
• In-person lifestyle therapy visit 
 
Week 10 (virtual visit): 
• Compliance check 
• Review adverse events, concomitant medications, intercurrent illness and 
Barkley Side Effect Rating Scale 
• Virtual lifestyle therapy visit 
 
Week 12 (in person visit): 
• Height, weight, blood pressure and heart rate 
• Urine pregnancy test 
• Suicide and depression screening (C-SSRS and CDI-2) 
• Compliance check and return unused study medication 
• Study drug dispensing  
• Review adverse events, concomitant medications, intercurrent illness and 
Barkley Side Effect Rating Scale 
• In-person lifestyle therapy visit 
 
Week 14 (virtual visit): 
• Compliance check 
• Review adverse events, concomitant medications, and intercurrent illness  
• Virtual lifestyle therapy visit 
 
Week 16 (in person visit): 
• Height, weight, blood pressure and heart rate 
• Urine pregnancy test 
• Suicide and depression screening (C-SSRS and CDI-2) 
• Compliance check and return unused study medication 
• Study drug dispensing  
• Review adverse events, concomitant medications, intercurrent illness and 
Barkley Side Effect Rating Scale 
• In-person lifestyle therapy visit 
 
 

MEDICAL PROTOCOL (HRP-590) 
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6 to 12 Years 
 
VERSION DATE: 19Sep2025 
 
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Week 18 (virtual visit): 
• Compliance check 
• Review adverse events, concomitant medications, intercurrent illness and  
• Virtual lifestyle therapy visit 
 
Week 20 (in person visit): 
• Height, weight, blood pressure and heart rate 
• Urine pregnancy test 
• Suicide and depression screening (C-SSRS and CDI-2) 
• Compliance check and return unused study medication 
• Study drug dispensing  
• Review adverse events, concomitant medications, intercurrent illness and 
Barkley Side Effect Rating Scale 
• In-person lifestyle therapy visit 
• Instructions for Accelerometer and sleep log 
 
Week 22 (virtual visit): 
• Compliance check 
• Review adverse events, concomitant medications, intercurrent illness and 
Virtual lifestyle therapy visit 
• Dietary recall  
 
Week 24 (in person visit): 
• Height, weight, blood pressure and heart rate 
• Tanner stage 
• Bone age x-ray 
• Indirect calorimetry 
• DXA scan (with pregnancy test for females) 
• Suicide and depression screening (C-SSRS and CDI-2) 
• Fasting blood draw for lipids, glucose, insulin, HbA1c, AST and ALT 
• Questionnaires 
• In-person lifestyle therapy visit 
• Dietary recall 
• Compliance check and return unused study medication 
• Review adverse events, concomitant medications, intercurrent illness and 
Barkley Side Effect Rating Scale 
 
 

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8.0 
Vulnerable Populations 
8.1 Vulnerable Populations:  
 
Population / Group 
Identify whether any of the 
following populations will be focus 
of the research (targeted), 
included, but not necessarily the 
focus or excluded from 
participation in the study. 
Children 
Primary focus of the research 
Pregnant women/fetuses/neonates 
Excluded 
Prisoners 
Excluded 
Adults lacking capacity to consent 
and/or adults with diminished 
capacity to consent, including, but 
not limited to, those with acute 
medical conditions, psychiatric 
disorders, neurologic disorders, 
developmental disorders, and 
behavioral disorders 
Excluded 
Non-English speakers 
Excluded 
Those unable to read (illiterate) 
Excluded 
Employees of the researcher 
Excluded 
Students of the researcher 
Excluded 
Undervalued or disenfranchised 
social group 
included but not the focus 
Active members of the military 
(service members), DoD personnel 
(including civilian employees) 
Excluded 
Individual or group that is 
approached for participation in 
research during a stressful situation 
Excluded 

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such as emergency room setting, 
childbirth (labor), etc. 
Individual or group that is 
disadvantaged in the distribution of 
social goods and services such as 
income, housing, or healthcare. 
Included but not the focus 
Individual or group with a serious 
health condition for which there are 
no satisfactory standard treatments. 
Excluded 
Individual or group with a fear of 
negative consequences for not 
participating in the research (e.g. 
institutionalization, deportation, 
disclosure of stigmatizing behavior). 
Included but not the focus 
Any other circumstance/dynamic 
that could increase vulnerability to 
coercion or exploitation that might 
influence consent to research or 
decision to continue in research. 
Excluded 
 
8.2 Additional Safeguards, if any, to ensure inclusion is appropriate: Not applicable. 
9.0 
Local Number of Participants 
9.1 Local Number of Participants to be Consented: 65 (Our goal is to randomize 44 
participants.  From previous experience, we expect no more than 15% to fail in-
person screening after consent is obtained.) 
10.0 Local Recruitment Methods 
10.1 Recruitment Process: Recruitment will be achieved by a number of methods.  
These include mailing letters or sending electronic messages to potentially eligible 
participants within the MHealth Fairview Health System and our research 
partners, Children’s Hospitals and Clinics of Minnesota and Health Partners/Park 
Nicollet health system.  Direct recruitment of University of Minnesota Pediatric 
Weight Management clinic patients by Center for Pediatric Obesity Medicine 
CPOM clinician-scientists will also be conducted. 
10.2 Identification of Potential Participants: Participants will be identified by using       
the University of Minnesota CTSI, Best Practices Integrated Informatics Core 
(BPIC) to identify patients in the MHealth Fairview health system based on age 

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and BMI.   Both the recruitment mailing and the electronic messages will request 
that the interested parties contact the research staff for additional information.  
If the interested party and the research staff do not connect on the first try, the 
research staff will attempt to contact the interested parties with up to three 
follow-up phone calls and/or three emails. 
10.3 Recruitment Materials: A recruitment letter and recruitment flyers will be created 
for this study and approved by the IRB before use.   
10.4 Payment: Participation in this study is time intensive for the subject and their 
family members.  Payment will be made by the Greenphire ClinCard to the parent 
on the following schedule: 
● 
Baseline visit: $75 for the visit and $25 when the accelerometer is returned 
● 
Week 4: $75 
● 
Week 8: $75 
● 
Week 12: $75 
● 
Week 16: $75 
● 
Week 20: $75 
● 
Week 24 visit: $100 for the visit and $50 when the accelerometer is 
returned 
 
Participants who complete all of the virtual lifestyle therapy visits will receive a 
$100 bonus at the Week 24 visit.  Therefore, participants will be eligible to 
receive a total reimbursement/compensation of $725.   
 
11.0 Withdrawal of Participants 
11.1 Withdrawal Circumstances: Participants will be allowed to withdraw from the 
study at any time.  Participants will be asked to return for one final visit and to 
return any study medication.  Participants may be withdrawn from the study at 
any time based upon investigator judgement. 
11.2 Withdrawal Procedures: Any participant who is removed from the study by the 
principal investigator will be asked to return for one final visit to assess adverse 
events and to collect any unused study medication and do a final study 
medication compliance. 
11.3 Termination Procedures: It will be noted in the subject enrollment log that the 
participant has been discontinued from the study and the date of the last study 
related visit.  No additional data will be collected after that time.  Data that has 
already been collected can be used in the study analysis. 
 
 

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11.4  
12.0 Risks to Participants 
12.1 Foreseeable Risks:  
Risks of blood sampling:  There is a minimal risk of bruising, fainting and infection 
associated with blood draws. 
Risks of exposure to ionizing radiation:  The DXA scans and the bone age scans 
involve exposure to a very low dose of ionizing radiation.  The average amount of 
radiation that the average person would receive from the bone age scan and DXA 
scans used in this study is less than 2% (3 mrem) of that received from natural 
sources of radiation by a Minnesota resident in one year (300 mrem). 
Risks of Lisdexamfetamine: Adverse reactions occurring in >5% and at a rate at 
least twice that of placebo in children include anxiety, dry mouth, diarrhea, 
nausea, vomiting, upper abdominal pain, irritability, insomnia and dizziness.  
Rarely reported adverse events include hypertension and tachycardia.  
Additionally, suppression of linear growth is a known class effect, though final 
adult height is not impacted. 
• 
Although not recommended as a routine practice, baseline ECG will be obtained on all 
participants to screen for underlying arrhythmia. If SBP and/or DBP is ≥95th percentile or 
≥130/80 (whichever is lower), blood pressure will be measured again on a separate visit 
within 2 weeks. If BP remains elevated on 3 separate visits, the participant will undergo 
a 24 hour ambulatory blood pressure monitor (ABPM) to confirm or rule out a diagnosis 
of hypertension.  
 
If elevated BP emerges and is confirmed on 2 additional occasions during 
lisdexamfetamine dose escalation, further dose escalation will halt until the results 
of a 24 hour ABPM are available. 
 
If hypertension is confirmed, lisdexamfetamine dose will be reduced until blood 
pressure normalizes.  
 
• If SBP and/or DBP is ≥95th percentile+12 mmHg or ≥140/90 (whichever is lower) 
and the participant is symptomatic, lisdexamfetamine will be discontinued and 
the participant will be referred to emergent care.  
• If heart rate is ≥140 bpm, an EKG will be obtained and the participant will be 
assessed for the need for emergent or non-emergent medical intervention, 
including the need to reduce or discontinue lisdexamfetamine dose.  
 
Risks of indirect calorimetry:  Potential risks include feeling claustrophobic from 
the mask/hood. 

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Risks of Accelerometry:  Potential risks include emotional distress from wearing 
the device 24 hours per day. 
Risks of lifestyle therapy:  Potential risks related to lifestyle therapy is sadness or 
frustration related to difficulty adhering to dietary and activity plans.  Participants 
may experience injury related to increased physical activity.  In our experience, 
participants tolerate lifestyle therapy without difficulty. 
Risks of neuropsychological assessments and eating questionnaires: Potential risks 
include emotional distress and possible “test fatigue.” 
Risks of changes in mental health status:  Individuals whose C-SSRS levels increase 
to a Moderate or High risk or whose CDI-2 values increase to a level of > 70 (by 
either child or parent report) after the screening and baseline/randomization 
visits will have these values reported to a peds psychologist (either Dr. Gross or 
Dr. Kunin-Batson) and they may be referred to their mental health professional (if 
one is pre-existing) or provided with names of a mental health professional if one 
is not already in place. 
12.2 Reproduction Risks: Exposure to ionizing radiation may cause harm to an unborn 
fetus.  Therefore, all females will have a pregnancy tests before they undergo the 
bone age x-ray or the DXA scan. 
12.3 Risks to Others: Not applicable. 
13.0 Potential Benefits to Participants 
13.1 Potential Benefits: Participation in the study will be restricted to children ages 6 
to <12 years who have severe obesity and have a parent report of failing to lose 
weight with lifestyle therapy.  Participants may benefit from participation in this 
study through close contact with the study staff and counseling on diet and 
physical activity which may result in weight loss.  Participants randomized to 
active treatment will have access to experimental intensified treatment, 
lisdexamfetamine, which has been shown to cause weight loss in children treated 
for ADHD.  The side effect profile of lisdexamfetamine is acceptable and the 
proposed study tests are not more than minimal risk. 
14.0 Statistical Considerations 
Data Analysis Plan: Descriptive analyses of baseline characteristics and outcomes 
will include means and standard deviations, median and range for continuous 
variables and frequencies with percentages for categorical variables.  Safety 
analyses (including Barkley’s Side Effect Rating Scale and incidence of hypertension 
and tachycardia) will be primarily descriptive reporting the number and percentage 
of adverse events during participation in the study. All safety outcomes will be 
evaluated and monitored throughout the study.  Confidence intervals (Cis) and P-
values for all analyses will be based on robust variance estimation.  Statistical 
significance will be considered as p<0.05.  

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Aim 1: Estimate the treatment effect of LDX plus lifestyle therapy vs placebo plus 
lifestyle therapy on changes in BMI (%BMIp95 primary endpoint), body fat, 
cardiometabolic health and quality of life (QOL) from baseline to 24 weeks.  
H1: We hypothesize that LDX compared to placebo will result in a greater mean 
decrease in %BMIp95 and body fat, and improved cardiometabolic health and 
QOL at 24 weeks. 
 
The primary outcome measurement will be absolute change in percent of the BMI 
95th percentile abbreviated %BMIp95.  Although we will report on other metrics 
of BMI change including absolute BMI change and percent BMI change, we chose 
%BMIp95 as the primary outcome measurement because of its clinical utility in 
measuring changes in BMI in young children who have severe obesity and a 
consensus in the research community that expressing BMI change relative to the 
95th percentile is preferred over other metrics such as BMI standard deviation 
score a.k.a. z-score.  The limitation of BMIz is explained by the flattening of BMIz 
curve at values significantly above the 95th percentile, despite the wide variance 
of BMIs in youth with severe obesity, which therefore leads to an 
underestimation of clinically significant improvement in weight status).  The 
primary outcome will be the mean change in %BMIp95 from baseline to 24 weeks 
follow-up compared between treatment groups, while adjusting for baseline 
value for added precision.  See Table 1 for examples of changes in BMI and 
corresponding changes in %BMIp95. 
 
Table 1.  Examples of changes in BMI and corresponding changes in %BMIp95 
Example 
Participant 
Starting 
BMI 
(kg/m2) 
Starting 
%BMIp95 
Ending 
BMI 
(kg/m2) 
Ending 
%BMIp95 
Absolute 
change 
in 
BMI (kg/m2) 
Absolute 
change 
in 
%BMIp95 
6 yo girl 
26.37 
140% of 95th 
percentile 
25.2 
134% of 95th 
percentile 
-1.17 
-6 percentage 
points 
10 yo boy 
39.8 
135% of 95th 
percentile 
28.7 
130% of 95th 
percentile 
-1.1 
-5 percentage 
points 
 
Power Analysis: Given this is a pilot and feasibility study, the sample size is not 
driven by a power analysis stemming from a formal statistical evaluation of a 
hypothesis test associated with the primary endpoint the trial.83 Instead, the 
objectives of this study revolve around identifying key information on execution of 
the study and experience of participants to best inform the design of a subsequent, 
larger study to examine efficacy and effectiveness.  
Secondary endpoints for Aim 1 are also continuous and will be evaluated in a 
similar fashion, with adjustment for baseline value.  These include percent body 
fat, lab measurements of glucose, insulin, lipids (total-, LDL-, HDL-cholesterol, and 

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triglycerides), hemoglobin A1c, ALT, AST, and PedsQL.  We will also report on other 
metrics of BMI change, including absolute BMI change and percent BMI change. 
 
Aim 2: Generate estimates of the tolerability and safety of LDX used for the 
treatment of severe obesity in children.  
 
H2: We hypothesize that at least 80% of participants will tolerate an LDX dose of 
>30 mg daily (recommended starting dose) for 24 weeks and that the LDX group 
compared to the placebo group will not demonstrate clinically significant 
increases in blood pressure or heart rate. 
 
We will define feasibility to conduct the larger trial if, in this pilot study, >80% of 
participants randomized to LDX tolerate a dose of >30 mg daily, the 
recommended starting dose, for 24 weeks and there are no statistically significant 
differences between the LDX group and placebo group in incidence of developing 
stage 1 hypertension or tachycardia. Outcomes will be captured for all regardless 
of tolerability and will inform inclusions/exclusion criteria and dose escalation 
schedule for the subsequent trial. Safety outcomes will be monitored carefully 
and include instances of stage 1 hypertension (defined as SBP and/or DBP ≥95th 
percentile on 3 separate occasions) and confirmed by 24 hour ambulatory blood 
pressure monitor) and tachycardia (defined as heart rate ≥120 bpm at rest 
measured on 3 separate occasions).  The Barkley Side Effect Rating Scale will also 
be measured at every 2 weeks during dose escalation and then every 4 weeks for 
the remainder of the study and will be used to help identify reasons for limited 
tolerability should this occur.  Height velocity in cm/year will be determined by 
the difference in measured height between the baseline and 24-week 
assessments and will be used to calculate a height velocity SDS (z-score).  Given 
the potential for LDX to disrupt sleep and the impact of sleep on obesity, 
participant sleep will be measured objectively using accelerometry with the 
ActiGraph (GT3X-BT) device, which has been shown to have acceptable reliability 
and validity in sleep-wake detection compared with laboratory-based 
polysomnography.72  Nighttime sleep efficiency, defined as the portion of time 
dedicated to sleep that is spent asleep, will be evaluated as the primary sleep 
endpoint of interest, with higher scores representing more efficient sleep.  All 
indexes will be calculated using the ActiLife software.  Participant mental health 
will be monitored by the Columbia-Suicide Severity Rating Scale (C-SSRS) and 
Children’s Depressive Inventory-2 (CDI-2).  
 
Exploratory Aim: Examine potential mechanisms by which LDX reduces BMI in 
children with obesity.  To do this, we will examine the effect of LDX on executive 
functioning skills, reward, appetite, resting energy expenditure and health 
behaviors (diet, eating behaviors, and physical activity).  We expect that over the 

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24-week intervention, LDX compared to placebo will be associated with greater 
gains in executive functioning (measured by BRIEF-2 and NIH Toolbox), reduced 
reward responsiveness (measured by BIS/BAS), and reduced appetite (measured 
by visual analogue scale), which in turn will lead to more BMI reduction.  Further, 
LDX compared to placebo will be associated with increased resting expenditure 
(measured by indirect calorimetry), leading to greater BMI reduction. Finally, we 
hypothesize that LDX compared to the placebo will be associated with greater 
reduction in calorie intake (measured by NDSR), binge eating (measured by 
(measured by CBES) and reward-based eating (measured by CEBQ), and a greater 
increase in physical activity (measured by accelerometry). 
 
The exploratory evaluation of associations between treatment groups and 
exploratory endpoints will follow the same approach as in Aim 1 looking at mean 
differences in change from baseline.  All endpoints are continuous and will have 
baseline measurements which will be used for baseline value adjustment for added 
precision in estimating contrasts between treatment groups and use robust 
variance estimation for the confidence interval and P-value.  The results of these 
analyses will inform the larger definitive study in which these mediating 
relationships could be further defined. 
14.1 Data Integrity: Impacting all aims, despite best efforts, it is possible that some 
data will be missing, which could limit the interpretation and generalizability of 
results.  If the data are missing at random, conditioned on measured covariates, 
then supplementary analyses adjusting for these covariates will produce unbiased 
results.  For potential missing data mechanisms beyond measured covariates, we 
will examine the extent to which results may be affected.  Imputation techniques 
will be considered for missing data issues (e.g., multiple imputation). In particular, 
we will incorporate multivariate imputation by chained equations to handle 
missing data in follow-up visits.85  The imputation models will include baseline 
values and change from baseline.  Additional variables for inclusion in the model 
include age, race, sex, Tanner stage, BMI, and LDX dose.  We will also examine 
results without imputed values.  If the analyses with and without multiple 
imputed values differ substantially, then exploratory analyses will be performed 
to evaluated factors that may have contributed to the differences. 
15.0 Health Information and Privacy Compliance 
15.1 
Select which of the following is applicable to your research: 
☐ My research does not require access to individual health information and 
therefore assert HIPAA does not apply.   
 
X I am requesting that all research participants sign a HIPCO approved HIPAA 

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Disclosure Authorization to participate in the research (either the standalone 
form or the combined consent and HIPAA Authorization). 
☐ I am requesting the IRB to approve a Waiver or an alteration of research 
participant authorization to participate in the research. 
Appropriate Use for Research:  
☐ An external IRB (e.g. Advarra) is reviewing and we are requesting use of the 
authorization language embedded in the template consent form in lieu of the 
U of M stand-alone HIPAA Authorization.  Note: External IRB must be serving 
as the privacy board for this option. 
15.2 
Identify the source of Private Health Information you will be using for your 
research (Check all that apply)   
X I will use the Informatics Consulting Services (ICS) available through CTSI 
(also referred to as the University's Information Exchange (IE) or data 
shelter) to pull records for me 
X I will collect information directly from research participants. 
☐ I will use University services to access and retrieve records from the Bone 
Marrow Transplant (BMPT) database, also known as the HSCT 
(Hematopoietic Stem Cell Transplant) database. 
X I will pull records directly from EPIC. 
☐ I will retrieve record directly from axiUm / MiPACS 
☐ I will receive data from the Center for Medicare/Medicaid Services  
☐ I will receive a limited data set from another institution  
☐ Other.  Describe:  
15.3 
Explain how you will ensure that only records of patients who have agreed to 
have their information used for research will be reviewed. 
We will work with Fairview Research Administration to pull a pool of individuals 
who have agreed, in their electronic medical record, to learn about potential 
research studies.  The data will be placed in the data shelter so that recruitment 
letters and/or emails can be generated and sent to potential participants.  
Individuals who have indicated that they do not want to be contacted about 
research will not be approached. 

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Practitioners within the Pediatric Weight Management Clinic may approach 
patients who they feel might qualify for the study and discuss the study with the 
patient.  The patient may be provided with a flyer with the study name and a 
QR code to submit a request for additional information. 
15.4 
Approximate number of records required for review: >10,000 
15.5 
Please describe how you will communicate with research participants during 
the course of this research.  Check all applicable boxes 
☐ This research involves record review only. There will be no communication 
with research participants. 
☐ Communication with research participants will take place in the course of 
treatment, through MyChart, or other similar forms of communication used 
with patients receiving treatment.  
X Communication with research participants will take place outside of 
treatment settings. If this box is selected, please describe the type of 
communication and how it will be received by participants. Potential 
participants who request information via use of the QR code will be 
contacted via phone or via email.  Potential participants will be asked to 
accept email that is encrypted or, if unwilling, sign the email permission to 
send emails that are not encrypted. 
15.6 
Explain how the research team has legitimate access to patients/potential 
participants: 
This has been explained in other sections of the protocol.  
15.7 Location(s) of storage, sharing and analysis of research data, including any links to 
research data (check all that apply).   
X In the data shelter of the Information Exchange (IE)  
 X Store 
☐ Analyze 
☐ Share 
☐ In the Bone Marrow Transplant (BMT) database, also known as the HSCT 
(Hematopoietic Stem Cell Transplant) Database  
 ☐ Store 
☐ Analyze 
☐ Share 
X In REDCap (recap.ahc.umn.edu)  
 X Store 
☐ Analyze 
☐ Share 
☐ In Qualtrics (qualtrics.umn.edu) 

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 ☐ Store 
☐ Analyze 
☐ Share 
X In OnCore (oncore.umn.edu)  
 X Store 
☐ Analyze 
☐ Share 
X In the University’s Box Secure Storage (box.umn.edu) 
 X Store 
☐ Analyze 
☐ Share 
☐ In an AHC-IS supported server. Provide folder path, location of server and IT 
Support Contact: 
 ☐ Store 
☐ Analyze 
☐ Share 
X In an AHC-IS supported desktop or laptop.  
Provide UMN device numbers of all devices: 20200305, 20200303, 20191753, 
20191752 20191431, 20191182, 20191181, 20190950, 20190949, 20190208, 
20190091, 20181963, 20181819, 20221301 20180940, 20180861, 20180790, 
20180789, 20170466, 20161203, 20160775, 20140912, 20140482, and 20140295. 
 x Store  
x Analyze 
x Share 
☐ Other. Describe:  
Indicate if  data will be collected, downloaded, accessed, shared or stored using a 
server, desktop, laptop, external drive or mobile device (including a tablet 
computer such as an iPad or a smartform (iPhone or Android devices) that you 
have not already identified in the preceding questions 
☐I will use a server not previously listed to collect/download research data 
☐I will use a desktop or laptop not previously listed 
☐I will use an external hard drive or USB drive (“flash” or “thumb” drives) not 
previously listed  
☐I will use a mobile device such as a tablet or smartphone not previously listed 
 
15.8 Consultants. Vendors. Third Parties. None.  
15.9 Links to identifiable data: We will strive to maintain absolute confidentiality.  All 
data will be stored in locked offices and will not be released without consent of 
participants.  Data to be used in scientific presentations or publications will not 
contain identifiers. 
 

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15.10 Sharing of Data with Research Team Members. Team members will have access 
to Box, REDCap and OnCore. 
15.11 Storage of Documents: Electronic documents are stored in password protected 
files that have two-factor authentication.  Paper documents will be stored in 
locked offices and will not be released outside the study team without consent 
of participants. 
15.12 Disposal of Documents: Disposal of paper documents will not happen until six 
years after the study analysis has been completed (to satisfy HIPAA 
requirements) or, in the event the study needs FDA oversight, until two years 
after the closure of the IND for this specific purpose, whichever is longer. 
16.0 Confidentiality 
16.1 Data Security: Absolute confidentiality will be maintained.  All data will be stored 
in locked offices and will not be released outside of the study team without the 
consent of the participant.  Data that is collected will be entered into REDCap and 
OnCore, which re only accessible by the study team via two-factor authentication.  
Data to be used in scientific presentations or publications will not contain 
participant identifiers. 
 
17.0 Provisions to Monitor the Data to Ensure the Safety of Participants 
17.1 Data Integrity Monitoring.  Because this study requires FDA oversight, the study 
will undergo regular monitoring (at least annually) of the facility, staff, and study 
documents by clinical research associates in the University of Minnesota Clinical 
Trials Monitoring Service, which specializes in regulatory compliance for clinical 
trials associated with the Food and Drug Administration.  This service provides 
regulatory monitoring of all research-related activities and is offered free of 
charge through the University of Minnesota Clinical and Translational Science 
Institute (CTSI).  Monitoring of fidelity to the protocol (e.g., protocol deviations) 
will be performed at each monitoring visit.  Monitoring staff will present a 
summary report to the PI after each monitoring session.  If necessary, corrective 
action plans will be devised and implemented by the PI to address deficiencies.  
Monitoring will be initiated shortly after IRB approval (before participants are 
enrolled) and then every six months.  Consent and eligibility will be reviewed on 
100% of subjects.  Data will be reviewed on 10% of participants.  Study monitoring 
will review the findings with the staff at the conclusion of the visit and the staff 
have 10 days to resolve the findings before the final report is generated.  The 
monitoring report will be generated on Day 10 after the visit.  Following written 
Standard Operating Procedures (SOPs), monitors will verify that the clinical trial is 
conducted, and data are generated, and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, 
International Conference on Harmonisation Good Clinical Practice (ICH GCP), and 

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applicable regulatory requirements.  The investigational site will provide direct 
access to source data/documents, and reports for the purpose of monitoring, 
auditing, and inspection by local and regulatory authorities. 
 
17.2 Data Safety Monitoring. An independent Data and Safety Monitoring Board (DSMB) 
will be established to oversee participant safety in the clinical trial and provide 
overall monitoring of interim data and safety issues. An independent medical 
safety officer (medical monitor) with experience in pediatric obesity 
pharmacotherapy will  review  all serious adverse  events.   This  individual  will  also  
serve  on  the  DSMB.    The DSMB will include a pediatric cardiologist, a pediatric 
psychologist and a biostatistician.  DSMB members will not be affiliated with the 
study.  At the first meeting, the DSMB (and medical monitor) will review the 
protocol and potentially recommend modifications.  Subsequently, the DSMB will 
monitor and review recruitment, adverse events, data quality, outcome data, and 
overall trial performance.  The DSMB will have the responsibility to review interim 
data and final data, and recommend whether the protocol should be modified, and, 
at each meeting, whether the study should be continued or should be terminated 
early.  Review materials for the DSMB will be prepared and presented by the study 
biostatistician.  The DSMB and medical monitor will review data every six months 
during the trial, beginning six months after enrollment of the first participant, to 
review data and evaluate participant safety.  A charter for the DSMB will be 
developed and approved by the DSMB members along with a plan for frequency of 
data review prior to the commencement of the trial.  A report from each meeting 
will be sent to the PI and co-investigators advising on the continuation of the study 
and any suggestions for trial improvement.  This report will also be sent to the 
NIDDK program officer.   
 
Adverse events (AEs), inter-current illnesses, and medications will be reviewed and 
documented at each in-person study visit, i.e., monthly throughout the study.  
Additionally, adverse events will be reviewed and documented every two weeks 
during dose escalation.  Participants will be instructed to contact study staff 
immediately if any serious adverse event (SAE) is experienced.   
 
Review of AEs: We will administer a standardized tool, the Barkley’s Side Effect 
Rating Scale, which was developed specifically to monitor side effects from 
psychostimulants.  This questionnaire, completed by the caregiver (and sometimes 
with child’s help) requests feedback on 17 items on a 9-point Likert scale, including 
typical physical side effects (e.g., decreased appetite, insomnia, stomach aches, 
and headaches) and behavioral symptoms (e.g., irritability, anxiety). 
 

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Inter-current Illnesses/Medications:  Participants will also be queried about any 
other new symptoms, inter-current illnesses, clinic or hospital visits, or medication 
changes.  
• All AEs will be captured on the appropriate case report form (CRF).  Information 
to be collected includes event description, time of onset, clinician’s assessment 
of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization 
of the event.  All AEs occurring while on study must be documented 
appropriately regardless of relationship.  All AEs will be followed to adequate 
resolution.  
• Any medical condition that is present at the time that the participant is 
screened will be considered as baseline and not reported as an AE.  However, 
if the study participant’s condition deteriorates at any time during the study, it 
will be recorded as an AE.  
• The study staff will record all reportable events with start dates occurring any 
time after informed consent is obtained until the final study visit.  Any non-
serious AEs that are not resolved at the final visit will be followed for an 
additional 7 days and any serious AEs that are not resolved at the final visit will 
be followed for an additional 30 days after the final visit.  At each study visit, 
the study staff will inquire about the occurrence of AE/SAEs since the last visit.  
Events will be followed for outcome information until resolution or 
stabilization.  
• All adverse events (AEs) will have their relationship to study intervention 
assessed by the PI who will remain blinded to intervention assignment.  The 
degree of certainty about causality will be graded using the categories below. 
In a clinical trial, the study product must always be suspect.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, 
and other possible contributing factors can be ruled out.  The clinical event, 
including an abnormal laboratory test result, occurs in a plausible time 
relationship to study intervention administration and cannot be explained 
by concurrent disease or other drugs or chemicals.  The response to 
withdrawal of the study intervention (dechallenge) should be clinically 
plausible.  The event must be pharmacologically or phenomenologically 
definitive, with use of a satisfactory rechallenge procedure if necessary.  
• 
Probably Related – There is evidence to suggest a causal relationship, and 
the influence of other factors is unlikely.  The clinical event, including an 
abnormal laboratory test result, occurs within a reasonable time after 
administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal (dechallenge).  Rechallenge 
information is not required to fulfill this definition.  

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• 
Potentially Related – There is some evidence to suggest a causal 
relationship (e.g., the event occurred within a reasonable time after 
administration of the trial medication).  However, other factors may have 
contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events).  Although an AE may rate only as “possibly related” 
soon after discovery, it can be flagged as requiring more information and 
later be upgraded to “probably related” or “definitely related”, as 
appropriate.  
• 
Unlikely to be related – A clinical event, including an abnormal laboratory 
test result, whose temporal relationship to study intervention 
administration makes a causal relationship improbable (e.g., the event did 
not occur within a reasonable time after administration of the study 
intervention) and in which other drugs or chemicals or underlying disease 
provides plausible explanations (e.g., the participant’s clinical condition, 
other concomitant treatments).  
• 
Not Related – The AE is completely independent of study intervention 
administration, and/or evidence exists that the event is definitely related to 
another etiology.  There must be an alternative, definitive etiology 
documented by the clinician.  
 
Adverse Event Reporting: The PI will be notified of all AEs within 7 days of 
identification; the PI will be notified of serious AEs (SAEs) within 24-hours of 
identification. A report of all SAEs will be sent to the FDA, the external medical 
monitor, DSMB,IRB, and NIH NIDDK program officer as soon as possible, but no 
later than five working days after the PI’s initial receipt of the information.  Reports 
of all adverse events, both serious and non-serious, will be provided to the external 
medical monitor and DSMB for review at their next regularly scheduled meetings.  
 
Stopping Rules: In the event that a participant has an SAE that is deemed related 
to the study medication and/or procedures by the external medical monitor, 
DSMB, PI, and/or NIDDK, the participant will be required to immediately 
discontinue the study medication. However, the participant may be invited to stay 
in the study for lifestyle therapy if this seems beneficial to the participant and the 
SAE is not related to lifestyle therapy. Participants will be instructed that they may 
withdraw from the study at any time and for any reason. The overall study may be 
stopped at any time at the request of the external medical monitor, DSMB, PI, 
and/or NIDDK. Participants will be instructed that they may withdraw from the 
study at any time and for any reason. 
 
18.0 Provisions to Protect the Privacy Interests of Participants 
18.1 Protecting Privacy: Please see HIPCO ancillary review. 

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18.2 Access to Participants: Please refer to the recruitment section. 
19.0 Compensation for Research-Related Injury 
19.1 Compensation for Research-Related Injury:  
Treatment for injuries that result from participating in the research activity will be 
available.  Those treatments include first aid, emergency treatment and follow-up 
care as needed.  Care for such injuries will be billed in the ordinary manner, to the 
participant or their insurance company.  Participants will be encouraged to 
contact the study team if they think that they have suffered a research related 
injury. 
19.2 Contract Language: Not applicable. 
20.0 Consent Process 
20.1 Consent Process (when consent will be obtained):  
Parental/guardian consent and participant assent will be obtained by a study 
investigator or a designated study coordinator after explaining the study in detail, 
asking the participant and the parents/guardians to explain the purpose, risks and 
benefits, and other details of the study, and giving the participant and 
parents/guardians an opportunity to ask questions.  A copy of the signed consent 
forms will be given to the participants and the parents/guardians. 
20.2 Waiver or Alteration of Consent Process (when consent will not be obtained): 
There is no plan to request a waiver or alteration of the consent process. 
20.3 Waiver of Written/Signed Documentation of Consent (when written/signed 
consent will not be obtained): There is no plan to request a waiver of 
written/signed documentation. 
20.4 Non-English Speaking Participants:  It is typical for the children to be seen in the 
Pediatric Weight Management Clinic to speak English.  At times, the parent feels 
more comfortable with the Spanish language.  Should we receive a large number 
of families where the parent is a native Spanish speaker, we would amend the 
protocol to note that Spanish language parental consent forms will be used after 
IRB approval.  
20.5 Participants Who Are Not Yet Adults (infants, children, teenagers under 18 years 
of age):  Participants who will enroll in this study will be aged 6 to <12 at study 
entry.  Assent will be obtained from children who are aged 8 to <12 at study entry 
and a parent will also be needed to provide consent.  Children aged 6 and 7 will 
not be asked to sign an assent form at study entry, but a verbal dissent to 
participate will be honored.  Participants who turn 8 during the course of the 
study will be asked to sign the assent form.  Participants will not reach the age of 
majority to require adult consent during their enrollment in the study. 
Single parent consent will be secured.  As this study has a potential for benefit, 
we believe it falls under 21CFR46.404 which allows single parent consent. 

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20.6 Cognitively Impaired Adults, or adults with fluctuating or diminished capacity to 
consent:  Not applicable. 
20.7 Adults Unable to Consent:  Not applicable. 
● 
Assent: Children aged 6 to <12 at study entry will be approached about 
participating in the project.  
o 
Children aged 6 to <8 years of age will be asked to consent verbally.  
Dissent will be honored and noted in the record.  Individuals who turn 
8 during the course of the study will be asked to sign an assent form.  
A single parent will be asked to sign a parental consent form. 
o 
Children aged 8 to <12 at study entry will be asked to sign an assent 
form if they would like to participate in the study.  A single parent will 
be asked to sign a parental consent form. 
● 
Dissent: Dissent will be honored from the children who are approached 
about participating in this study.  
21.0 Setting 
21.1 Research Sites 
● 
Study activities will take place at the University of Minnesota within the 
building located at 717 Delaware Street SE.  All research procedures will be 
performed in this building. 
21.2 International Research: Not applicable.  
22.0 Multi-Site Research 
Not applicable.   
 
23.0 Coordinating Center Research 
Not applicable.   
24.0 Resources Available 
24.1 Resources Available:  
● 
When designing the study, the University of Minnesota CTSI, Best Practices 
Integrated Informatics Core (BPIC) identified 2,512 in our health care system 
(MHealth Fairview).  Additionally, the clinician-scientist members of CPOM 
are all active in recruiting their patients from the University of Minnesota 
Pediatric Weight Management Clinics, where 600 new patients with severe 
obesity are seen annually.  By harnessing the support of CPOM and the 
extensive pool of participants, we are confident in our ability to realistically 
recruit and retain the number of participants (n=44) proposed for this 
project. 

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● 
The implementation of research protocols within CPOM involves the PI and 
sub-investigators, the study coordinator, dietician and the regulatory 
manager who have regular meetings to refine the protocol before it opens 
for enrollment.  The study, when close to opening for enrollment, will hold a 
protocol training for the CPOM staff where the protocol will be reviewed.  
Team members who are unable to attend will be provided with a slide deck 
overview of the study to familiarize themselves with the project.  Many 
activities (lifestyle modification, bone age, DXA, ECG, indirect calorimetry, 
questionnaires, blood draws, measurement of height, weight, blood 
pressure and heart rate and the collection of adverse events) are seen in 
most of our projects so staff are quite familiar with procedures that will be 
conducted in this study. 
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