Pharmacokinetics and Pharmacodynamics of Topiramate for Weight Loss in Youth: PHARMATOP
Phase: EARLY_PHASE1
Conditions: Obesity, Childhood
Sponsor: University of Minnesota

 
 
O#icial Title “Pharmacokinetics and Pharmacodynamics of Topiramate for Weight Loss in 
Youth: PHARMATOP” 
 
Document Date: 05/03/2024 
 
NCT04986631 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Pharmacokinetics and Pharmacodynamics of Topiramate for Weight Loss 
in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
Page 1 of 43 
 
ANCILLARY REVIEWS 
 
Which ancillary reviews do I need and when do I need them? 
Refer to HRP-309 for more information about these ancillary reviews. 
Select yes or 
no 
Does your study… 
If yes… 
Impact on 
IRB Review 
☐ Yes 
☒ No 
 
Include Gillette resources, staff 
or locations 
Gillette Scientific review and Gillette 
Research Administration approval is 
required.  Contact: 
research@gillettechildrens.com   
Required 
prior to IRB 
submission 
☒ Yes 
☐ No 
Involve Epic, or Fairview 
patients, staff, locations, or 
resources? 
The Fairview ancillary review will be 
assigned to your study by IRB staff 
Contact: ancillaryreview@Fairview.org 
Approval 
must be 
received 
prior to IRB 
committee/ 
designated 
review.   
 
Consider 
seeking 
approval 
prior to IRB 
submission. 
☒ Yes 
☐ No 
Include evaluation of drugs, 
devices, biologics, tobacco, or 
dietary supplements or data 
subject to FDA inspection? 
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assigned to your study by IRB staff 
Contact: medreg@umn.edu  
 
See: 
https://policy.umn.edu/research/indide  
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Require Scientific Review? Not 
sure? See guidance on next 
page. 
 
Documentation of scientific merit must 
be provided.   
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Relate to cancer patients, 
cancer treatments, cancer 
screening/prevention, or 
tobacco? 
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☐ No 
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(x-ray imaging, 
radiopharmaceuticals, external 
beam or brachytherapy) 
Complete the AURPC Human Use 
Application and follow instructions on 
the form for submission to the AURPC 
committee. 
Contact: barmstro@umn.edu  
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from these 
committees 
must be 
received 
prior to IRB 
approval;  
 
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groups 
each have 
their own 
application 
process.  
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Resonance Research (CMRR) 
as a study location? 
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review  
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recombinant or synthetic 
nucleic acids, toxins, or 
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Include the use of human fetal 
tissue, human embryos, or 
embryonic stem cells? 
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instructions and guidance 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Pharmacokinetics and Pharmacodynamics of Topiramate for Weight Loss 
in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
Page 2 of 43 
 
☒ Yes 
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Include PHI or are you 
requesting a HIPAA waiver? 
If yes, HIPCO will conduct a review of 
this protocol. 
Contact: privacy@umn.edu  
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☐ No 
Use data from the Information 
Exchange (IE)? 
The Information Exchange ancillary 
review will be assigned to your study by 
IRB staff 
Contact: ics@umn.edu  
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must be 
received 
prior to IRB 
approval. 
 
These 
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application 
process but 
additional 
information 
from the 
study team 
may be 
required. 
 
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tissue for research? 
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MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Pharmacokinetics and Pharmacodynamics of Topiramate for Weight Loss 
in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
Page 3 of 43 
 
PROTOCOL COVER PAGE 
 
 
 
Protocol Title 
Pharmacokinetics and Pharmacodynamics of Topiramate for 
Weight Loss in Youth: PHARMATOP 
Principal 
Investigator/Faculty 
Advisor 
Name: Eric Bomberg, MD, MAS 
Department: Pediatrics  
Telephone Number: 651-341-8252 (cell) 
Email Address: bombe002@umn.edu  
Student 
Investigator 
Name: N/A 
Current Academic Status (Student, Fellow, Resident): 
  
Department: 
Telephone Number: 
Institutional Email Address: 
Scientific 
Assessment 
Nationally-based, federal funding organizations 
IND/IDE # (if 
applicable) 
Exempted, IND# 157547 
IND/IDE Holder 
 
Investigational Drug 
Services # (if 
applicable) 
5867 
Version 
Number/Date: 
Version 17.0; 2024May03 
 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Pharmacokinetics and Pharmacodynamics of Topiramate for Weight Loss 
in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
Page 4 of 43 
 
REVISION HISTORY 
Revision # 
Version Date 
Summary of Changes 
Consent Change? 
1 
1/17/2022 
1. Specified body composition 
measures from Tanita scale 
2. Change to medication 
dispensing schedule 
3. Change to surveys 
administered  
4. Change to physical exam 
requirements 
5. Added incentive to return 
electronic prescription 
bottle  
Yes 
2 
2/14/2022 
Medication adherence at Week 2 
and Week 4 will be done verbally 
during the telephone call 
 
4 
2/28/2022 
1. Changes to exclusion 
criteria 
2. Revises the recruitment 
plan for the study 
3. Medication compliance will 
be assessed by pill count at 
in-person study visits as an 
additional measure of 
adherence 
Yes 
5 
3/24/2022 
Revises the statistical section of 
the protocol 
No 
6 
4/21/2022 
Adds the use of a recruitment flyer 
to be used by clinicians recruiting 
for this study.  
No 
7 
6/16/2022 
• Revises the study exclusion 
criteria with regard to ADHD 
medications. 
• Allows a physical exam, as long 
as it was performed by a CPOM 
faculty member, performed in 
the pediatric weight 
management clinic or 
performed by a pediatric 
endocrinologist within 30 days 
of the Screening/Baseline visit, 
to be used for this project 
 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Pharmacokinetics and Pharmacodynamics of Topiramate for Weight Loss 
in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
Page 5 of 43 
 
• Clarifies that an individual with 
a high PHQ-9 or positive C-SSRS 
who have a mental health 
provider or whose primary care 
provider manages mental 
health, alerted of the change 
• allows an individual who is 
properly trained to conduct the 
Tanner staging. 
8 
07/08/2022 
Makes updates per the IRB’s 
continuing renewal review: 
Adds in pregnancy testing to be 
performed at all in-person visits 
 
Yes 
9 
10/07/2022 
Revises the study exclusion criteria 
and adds a survey for females of 
childbearing potential to the final 
study visit.  Includes a plan for 
participants who develop suicidal 
ideation while enrolled in the 
study. 
Yes 
10 
10/18/2022 
Revises section 18.2 of the 
protocol to conform to the 
changes made in protocol version 
9 (managing participants who 
manage suicidal ideation). 
No 
11 
03/31/2023 
Revises the study exclusion criteria 
No 
12 
04/13/2023 
Notes that we may encounter a 
child who is comfortable with 
speaking English, but whose 
parent is more comfortable 
speaking Spanish.  A Spanish 
language parental consent is being 
submitted for use in those 
instances. 
Yes 
13 
05/04/2013 
Revises section 9.2 to add in how 
we plan to communicate with 
Spanish speaking parents. 
No 
14 
05/23/2023 
Makes a clarification to the 
exclusion criteria regarding 
glaucoma 
No 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Pharmacokinetics and Pharmacodynamics of Topiramate for Weight Loss 
in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
Page 6 of 43 
 
15 
08/21/2023 
Revises section 5.2 of the protocol 
to remove the at home urine 
pregnancy testing.  Clarifies 
section 13.2 of the protocol to 
note that urine pregnancy tests 
will be done at screening/baseline, 
Week 6, Week 10 and Week 14 
visits. 
No 
16 
11/22/23 
Adds a PHQ-9 and C-SSRS to the 
visit at Week 6.  Names Dr. 
Bomberg as the medical monitor 
for the study and Dr. Brooke 
Sweeney as the external medical 
monitor.  Adds that the study team 
may contact the participant’s 
existing mental health provider in 
the event a participant presents 
with acute suicidal 
ideation/behavior at a study visit.  
Adds a suicide risk assessment at 
weeks 8 and 14, revises the 
protocol to note that topiramate 
cessation without tapering may be 
recommended in the event of an 
emergent medical situation. 
Yes 
17 
01/23/2024 
Makes some clarification to the 
study exclusion criteria 
No 
18 
05/03/2024 
Revises sections 8.3, 13.2 and the 
schedule of events to note that 
urine pregnancy testing will be 
conducted but that serum 
pregnancy tests are also 
acceptable. 
Yes 
 
 
 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Pharmacokinetics and Pharmacodynamics of Topiramate for Weight Loss 
in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
Page 7 of 43 
 
 
 
Table of Contents 
 
1.0 
Objectives 
10 
2.0 
Background 
10 
3.0 
Study Endpoints/Events/Outcomes 
12 
4.0 
Study Intervention(s)/Investigational Agent(s) 
13 
5.0 
Procedures Involved 
15 
6.0 
Data and Specimen Banking 
20 
7.0 
Sharing of Results with Participants 
21 
8.0 
Study Population 
22 
10.0 Local Number of Participants 
27 
11.0 Local Recruitment Methods 
27 
12.0 Withdrawal of Participants 
29 
13.0 Risks to Participants 
30 
14.0 Potential Benefits to Participants 
33 
15.0 Statistical Considerations 
33 
16.0 Health Information and Privacy Compliance 
34 
17.0 Confidentiality 
37 
18.0 Provisions to Monitor the Data to Ensure the Safety of Participants 
37 
19.0 Provisions to Protect the Privacy Interests of Participants 
38 
20.0 Compensation for Research-Related Injury 
38 
21.0 Consent Process 
39 
22.0 Setting 
39 
23.0 Multi-Site Research 
39 
24.0 Coordinating Center Research 
39 
25.0 Resources Available 
39 
26.0 References 
40 
 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Pharmacokinetics and Pharmacodynamics of Topiramate for Weight Loss 
in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
Page 8 of 43 
 
ABBREVIATIONS/DEFINITIONS 
%BF 
Percent Body Fat 
%BMIp95 
Percent of the 95th Body Mass Index Percentile 
%EBMIL 
Percent Excess Body Mass Index Loss 
%TBWL 
Percent Total Body Weight Loss 
AE 
Adverse Event 
AEBQ 
Adult Eating Behavior Questionnaire 
AHC-IE 
Academic Health Center – Information Exchange 
AUC 
Area Under the Curve 
BEVQ-15 
Beverage Intake Questionnaire 15 
BF 
Body Fat 
BIA 
Bioelectrical Impedance 
BMI 
Body Mass Index 
BPIC 
Best Practices Integrated Informatics Core 
CA 
Carbonic Anhydrase 
CHIS 
California Health Interview Survey  
COWA 
Controlled Oral Word Association 
CPOM 
Center for Pediatric Obesity Medicine 
CRF 
Case Report Form 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
CTSI 
Clinical and Translational Science Institute  
DCRU 
Delaware Clinic Research Unit 
DF 
Degrees of Freedom 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
DSMB 
Data Safety Monitoring Board 
DYFAS 
Dimensional Yale Food Addiction Scale 2.0 for Children 
EBMIL 
Excess Body Mass Index Loss 
EDE-Q 
Eating Disorder Examination Questionnaire  
I 
Electronic Health Record 
FCQ-T-r 
Food Craving Questionnaire – Trait -Reduced 
FDA 
Food and Drug Administration 
FPG 
Fasting Plasma Glucose 
FPI 
Fasting Plasma Insulin 
GABA 
Gamma Aminobutyric Acid 
GLP1-RA 
Glucagon-Like Peptide-1 Receptor Agonist 
HDL 
High Density Lipoprotein 
GWAS 
Genome-Wide Association Study 
HOMA-IR 
Homeostatic Model Assessment – Insulin Resistance 
HST 
Health Science Technology 
ID 
Identification 
iDXA 
Dual X-ray Absorptiometry  
Kg 
Kilograms 
LDAP 
Lightweight Directory Access Protocol 
LDL 
Low Density Lipoprotein 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Pharmacokinetics and Pharmacodynamics of Topiramate for Weight Loss 
in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
Page 9 of 43 
 
LSM 
Lifestyle Modification 
MHP 
Mental Health Provider 
MN-POC 
Minnesota Pediatric Obesity Consortium 
MRN 
Medical Record Number 
MSV 
MilliSievert  
NIH 
National Institutes of Health 
NLME 
Non-Linear Mixed Effects 
NONMEM 
Non-Linear Mixed Effects Modeling 
OFV 
Objective Function Value 
PAQ-A 
Physical Activity Questionnaire for Adolescents  
PD 
Pharmacodynamics 
PHI 
Protected Health Information 
PHQ-9 
Patient Health Questionnaire – 9 
PK 
Pharmacokinetics 
POPPK 
Population Pharmacokinetics  
PWMC 
Pediatric Weight Management Clinic 
RED-5 
Reward Based Eating Drive Scale Xt5 
SAE 
Serious Adverse Event 
SCM 
Stepwise Covariate Model 
SD 
Standard Deviation 
T2DM 
Type 2 diabetes mellitus 
TB 
Toolbox 
TBWL 
Total Body Weight Loss 
TOPMed 
Trans-omics for Precision Medicine 
TWL 
Total Weight Loss 
UMGC 
University of Minnesota Genomics Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Pharmacokinetics and Pharmacodynamics of Topiramate for Weight Loss 
in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
Page 10 of 43 
 
 
1.0 
Objectives 
Introduction: 
Pediatric severe obesity is the fastest growing obesity category in the United States, and anti-
obesity pharmacotherapies are promising adjuncts to lifestyle modification (LSM) for the 
treatment of this disease. While anti-obesity pharmacotherapies have overall been associated 
with weight loss, there is substantial variability in their individual-level effectiveness. While some 
patients lose a significant amount of weight with anti-obesity pharmacotherapies, others lose 
little or even gain weight.   
Due to this well-recognized variability in individual-level response, the National Institutes of 
Health (NIH) has recognized the importance of using precision medicine approaches in order to 
optimize treatments for pediatric severe obesity. Pharmacometrics, which uses mathematical 
models to study medication dose-exposure (e.g., blood drug concentrations)-response 
relationships, is an emerging science that can help determine optimal dosing regimens based 
upon patient-specific characteristics. Pharmacometrics quantitates the interplay between 
pharmacokinetics (PK; drug dose-exposure associations) and pharmacodynamics (PD; drug 
exposure-response associations). Population PK (popPK), a type of PK, can be used to quantitate 
variability in drug exposure among individuals in order to help inform recommendations on 
therapeutic individualization (i.e., through tailored dosing). In this study, we will use popPK/PD 
modeling to characterize associations between anti-obesity pharmacotherapy dose, exposure, 
and changes in weight and weight-related outcomes in youth with severe obesity.  
We will be focusing on topiramate because this medication is commonly prescribed for weight 
loss in youth with severe obesity and has been associated with highly variable individual-level 
effectiveness. The weight loss achieved with topiramate occurs through several purported 
mechanisms including reductions in appetite, food cravings, and binge eating, and adverse 
alterations in taste for carbonated beverages. It is hypothesized that some of the individual-level 
effectiveness of this medication on weight loss response is secondary to patient-specific 
differences in these factors. In a 3.5-month pragmatic-based prospective cohort study (n=65), 
we will develop a popPK model using sparse sampling by drawing a series of topiramate 
concentration measures over time in order to begin determining patient-specific factors that 
contribute to topiramate exposure variability. We will also identify associations between 
topiramate exposure, changes in eating behaviors, and weight loss outcomes through PD models 
using regression techniques. We hypothesize that patient-specific characteristics (i.e., age, body 
mass index (BMI), and sex) will explain some variability in topiramate exposure in youth, and that 
higher topiramate exposure will be associated with greater improvements in weight loss 
response and eating behaviors among youth prescribed this medicine for the treatment of 
pediatric severe obesity.  
2.0 
Background 
2.1 Significance of Research Question/Purpose:  
Pediatric severe obesity (defined as age- and sex-adjusted BMI ≥1.2 times the 95th percentile 
and/or BMI ≥35 kg/m2) is the fasting growing obesity category, affecting ~6% of US youth.1-3 As 
most youth with severe obesity fail to achieve clinically significant and durable weight loss with 
LSM alone,4 anti-obesity pharmacotherapies are promising adjuncts to LSM in this population. 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Pharmacokinetics and Pharmacodynamics of Topiramate for Weight Loss 
in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
Page 11 of 43 
 
While anti-obesity medications are overall associated with weight loss, there is substantial 
variability in their individual-level effectiveness in terms of their impact on weight reduction and 
improvements in cardiometabolic risk factors and eating behaviors.5-7 Indeed, some prescribed 
these medications lose a substantial amount of weight, while others lose little or even gain 
weight.6 As severe pediatric obesity is associated with considerable risk for the development of 
future obesity-related health sequelae including hypertension, type 2 diabetes mellitus (T2DM), 
and cardiovascular disease, identifying determinants of the variable response seen with anti-
obesity pharmacotherapies, which can be achieved through precision medicine approaches, is 
critical.  
The goal of precision medicine is to optimize therapeutic benefit and minimize risk by selecting 
treatment based on one’s personalized characteristics.8 A 2018 NIH-sponsored workshop on 
precision medicine approaches for the treatment of severe obesity in adolescents identified, 
among other issues, the importance of optimizing anti-obesity medication dosing based upon 
one’s metabolism.9 Pharmacometrics is an emerging science that may help to accomplish this. In 
brief, pharmacometrics is the study of drug dose-exposure (e.g., blood drug concentration)-
response relationships, and is used to quantitate interplays between PK (drug dose-exposure 
associations) and PD (drug exposure-response associations). PopPK, a type of PK model, is used 
to quantify variability in drug exposure among individuals. Combined PopPK/PD studies can help 
identify factors that influence the variability in drug exposure and, therefore, can be used to help 
determine individualized dosing regimens.10-11 Indeed, popPK/PD studies have helped explain 
some of the differential response to anti-obesity pharmacotherapies in adults, and have been 
used to identify individualized dosing regimens to a wide variety of medicines in both pediatrics 
and adults.12-13 
Topiramate, Food and Drug Administration (FDA) approved for the treatment of seizures (in 
children and adults) and prevention of migraines (in adults), is commonly prescribed for weight 
loss as an adjunct to LSM in youth with severe obesity.14 Its central purported mechanisms for 
weight loss include increasing gamma-aminobutyric acid (GABA) and decreasing glutamate and 
dopamine secretion, subsequently decreasing appetite, food cravings, and binge eating; and 
carbonic anhydrase (CA) inhibition which can adversely alter taste for carbonated beverages.15 
Weight loss associated with topiramate is highly variable, as evidenced by studies showing a 
clinically significant mean 5-7% weight loss after 6-12 months, however, with standard deviations 
(SDs) consistently greater than mean weight loss.16-22  
Because of its ubiquitous use in obesity management and known variability in weight loss 
efficacy, topiramate serves as an ideal model medication to begin our exploration of drug dose-
exposure-response relationships to anti-obesity pharmacotherapies in youth with severe 
obesity. In a 3.5-month pragmatic-based prospective study of youth started on topiramate, we 
will develop a popPK model by serially measuring topiramate concentrations over time (every 2-
4 weeks for a total of 4 measures) in order to determine patient-specific characteristics that 
contribute to drug exposure variability. Specifically, we will statistically test the importance of 
age, sex, BMI, and other baseline characteristics as significant determinants of drug exposure. 
We will also determine associations between topiramate exposure, weight loss outcomes (i.e. 
BMI reduction, changes in other body weight metrics), and changes in eating behaviors (i.e. 
appetite, satiety, binge eating tendencies, food cravings, carbonated and/or sugar-sweetened 
beverage consumption) through PD models that utilize regression techniques.  
 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Pharmacokinetics and Pharmacodynamics of Topiramate for Weight Loss 
in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
Page 12 of 43 
 
2.2 Preliminary Data:  
In a retrospective cohort study we showed 
that, among 28 youth with severe obesity 
prescribed topiramate plus LSM for weight loss 
in our pediatric weight management clinics 
(PWMCs), the average BMI reduction was 4.9% 
after 6 months; however, the SD was 5.8%.22 
This suggests that, while the combination of 
topiramate and LSM leads to weight loss on 
average, the individual-level response is highly 
variable, and some individuals may even gain 
weight on this regimen. While this particular 
study was small and not powered to explore 
possible predictors of weight loss response, 
>475 youth have since been prescribed 
topiramate in our PWMCs. A review of this 
data (unpublished) similarly shows a highly 
variable response to topiramate plus LSM, 
which can be seen early as 12 weeks and out to 
1 year after starting treatment (Figure 1). 
2.3 Existing Literature:  
While we have not generated preliminary data directly supporting our study hypotheses, 
previous studies by others have used popPK/PD modeling to identify drug dose-exposure-
response relationships in children and adults without obesity receiving topiramate for epilepsy 
treatment.23-25 Specifically, using popPK, Takeuchi et al. found that, for seizure management, 
topiramate dose adjustments were necessary to reach effective concentrations based upon 
weight status and concomitant use of other antiepileptic medicines.23 In a PD study, Vovk et al. 
found no relation between topiramate concentration and seizure frequency in children and 
adults with epilepsy.24 No studies have previously used popPK/PD to determine topiramate dose-
exposure-response relationships in terms of this medication’s effects on weight loss and weight-
related outcomes despite its frequent use for these purposes.  
PopPK/PD studies have also been used to determine associations between dose, exposure, and 
weight loss outcomes to other anti-obesity pharmacotherapies. For example, among adults 
prescribed liraglutide (a glucagon-like peptide 1 receptor agonist (GLP1-RA) used for T2DM and 
obesity treatment) plus LSM for weight loss, higher baseline body weight and male sex have been 
associated with lower liraglutide exposure, and higher liraglutide exposure has been associated 
with greater weight loss.12-13 This suggests a possible need for differential liraglutide dosing based 
on the patient-specific characteristics of baseline body weight and sex in adults with obesity.  
3.0 
Study Endpoints/Events/Outcomes 
3.1 Primary Endpoint/Event/Outcome:  
Our overall goal is to determine associations between topiramate dose and exposure, and 
topiramate exposure and weight-related outcomes, in youth with severe obesity prescribed this 
medication for weight management. Towards this end, our study has two primary objectives: 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Pharmacokinetics and Pharmacodynamics of Topiramate for Weight Loss 
in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
Page 13 of 43 
 
1. To determine sources of variability in topiramate exposure using popPK modeling: We 
hypothesize that patient-specific characteristics including age, sex, and baseline BMI 
(primary predictors for popPK) will explain some variability in topiramate exposure, 
assessed by metrics including area under the concentration-time curve (AUC, primary 
outcome for popPK), among youth with severe obesity. 
2. To determine associations between topiramate exposure and 3-month BMI change using 
PD modeling: We hypothesize that higher topiramate exposure (primary predictor for 
PD) will be associated with greater 3-month BMI reduction, as assessed by percent 
change in BMI from baseline (primary outcome for PD), in youth with severe obesity.  
3.2 
Secondary Endpoint(s)/Event(s)/Outcome(s): 
Our study has several secondary objectives: 
1. To determine associations between topiramate exposure and other weight loss 
outcomes, including total weight loss (TWL; kg), percent total body weight loss (%TBWL), 
percent excess BMI loss (%EBMIL), and reduction in percent of the 95th BMI percentile 
(%BMIp95). We hypothesize that higher topiramate exposure, assessed by metrics 
including AUC, will be associated with greater 3-month total weight loss, increased 
%TBWL and %EBMIL, and greater reductions in %BMIp95 in youth with severe obesity. 
2. To determine how topiramate exposure affects eating behaviors in youth severe obesity. 
We hypothesize that higher topiramate exposure will be associated with reduced 
hunger, binge eating, food cravings, and consumption of sugar-sweetened and/or 
carbonated beverages; and increased satiety, all measured via validated questionnaires 
and compared to baseline measures, in youth with severe obesity. 
3. To determine associations between topiramate exposure and changes in cardiometabolic 
risk factor labs. We hypothesize that higher topiramate exposure will be associated with 
greater 3-month improvements in insulin sensitivity (measured by homeostatic model 
assessment – insulin resistance (HOMA-IR) and hemoglobin A1c) and lipid levels 
(including increased HDL and lower LDL and triglycerides) in youth with severe obesity.  
4. To determine associations between body fat percentage and topiramate exposure, and 
to determine if body fat percentage is a better predictor of topiramate exposure 
compared to BMI. We hypothesize that increased percent body fat (%BF) as assessed by 
dual x-ray absorptiometry (iDXA) and bioelectrical impedance (BIA) will be associated 
with decreased topiramate exposure, and that %BF will correlate more strongly with 
topiramate exposure compared to BMI in youth severe obesity.  
4.0 
Study Intervention(s)/Investigational Agent(s) 
4.1 
Description:  
Overview: 
We will perform a 3.5-month prospective cohort study consisting of adolescents (12 to <18 years 
old) with severe obesity prescribed topiramate, and designed to be analyzed by nonlinear mixed-
effects (NLME) approaches. We will quantitate relationships between PK parameters and 
patient-specific factors using popPK modeling in order to better predict topiramate exposure. 
Specifically, we will evaluate the importance of baseline factors including age, sex, and BMI as 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Pharmacokinetics and Pharmacodynamics of Topiramate for Weight Loss 
in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
Page 14 of 43 
 
significant determinants of topiramate exposure. Our quantification of topiramate exposure will 
then allow us to establish topiramate exposure-weight loss outcome relationships using PD 
modeling. This can eventually help us determine optimal topiramate dosing strategies in youth 
with severe obesity prescribed this medication for weight management.  
We will recruit study participants primarily from our PWMCs among adolescents with severe 
obesity who are deemed by prescribing physicians as appropriate candidates to receive 
topiramate for the indication of weight management. Additional study participants may be 
recruited among those who contact CPOM (after receiving recruitment letters for CPOM studies), 
are interested in participating in a study that specifically involves the initiation of an active anti-
obesity pharmacotherapy at study onset (versus possibility of receiving a placebo), and who 
qualify (meet inclusion/exclusion criteria). Study participants will be consented and assented 
prior to enrollment, and study visits will take place in the Delaware Clinical Research Unit (DCRU). 
This is an open-label study and, therefore, all participants will be prescribed topiramate. During 
the first two weeks, all participants will be titrated up to topiramate 75 mg daily (the most 
commonly used dose in our PWMC) or their maximum-tolerated dose. They will then remain on 
this dose for the next 3 months until study completion. During the study, participants will receive 
LSM and undergo a series of anthropometric and laboratory assessments (including topiramate 
levels and labs evaluating for insulin resistance and lipids), and questionnaires that assess eating 
behaviors.  
Topiramate and Dosing:  
Topiramate is 2,3:4,5-di-O-isopropylidene-β-D-fructopyranose sulfamate. The molecular formula 
is C12H21NO8S and its molecular weight is 339.4. Topiramate is a white to off-white crystalline 
powder with a bitter taste. It is freely soluble in methanol and acetone, sparingly soluble in pH 9 
to pH 12 aqueous solutions, and slightly soluble in pH 1 to pH 8 aqueous solutions.  Its structural 
formula is: 
 
 
 
          Figure 2: Molecular Structure of Topiramate 
 
The precise mechanism of action of topiramate on chronic weight management is not known. 
However, central purported mechanisms for weight loss include increasing GABA and decreasing 
glutamate and dopamine secretion, subsequently decreasing appetite, food cravings, and binge 
eating; and CA inhibition, which can adversely alter the taste of carbonated beverage.15 
Based on data from weight loss studies in youth and adults; safety data from several pediatric 
studies; and instructions on FDA-approved labels, topiramate will be initiated at 25 mg daily and 
escalated to 50 mg after one week and 75 mg after two weeks.21,26-30 75 mg daily is the most 
often prescribed dose in our PWMCs, and was safe and well tolerated in CPOM’s previous trial 
examining topiramate for BMI reduction in this population.30 We will also follow generative 
verbal fluency during this study with the Controlled Oral Word Association (COWA) test, sensitive 
for phonetic fluency and used in multiple topiramate studies.31-33 Patients not tolerating dose 
escalation will be reduced to the 50 or 25 mg dose (depending upon tolerability) for the 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Pharmacokinetics and Pharmacodynamics of Topiramate for Weight Loss 
in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
Page 15 of 43 
 
remainder of the trial, per protocol from our previous trial (only occurred in one of 30 of 
participants).30  
4.2 
Drug/Device Handling:  
This study is open-label and, therefore, no placebo will be utilized. The topiramate used in this 
study will be managed by the University of Minnesota Investigational Drug Service (IDS) 
Pharmacy and will be dispensed according to their operating policies. The IDS specializes in 
storing and dispensing medications for clinical trials. Study physicians will write a prescription in 
order for IDS to dispense the medication. IDS is in a secure facility (behind two locked doors) and 
maintains refrigerators and freezers with temperature tracking to assure that the drugs utilized 
in studies maintain stability. IDS will keep detailed records on the receipt of topiramate (including 
lot numbers) and detailed records on the dispensing of product to each participant 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.  
4.3 
Biosafety: N/A 
4.4 
Stem Cells: N/A 
4.5 
Fetal Tissue: N/A 
5.0 
Procedures Involved 
5.1 
Study Design:  
This will be a 3.5-month open-label, pragmatic-based study to determine associations between 
topiramate dose, exposure, weight loss outcomes (i.e., BMI reduction, improvements in 
cardiometabolic risk factor labs), and eating behaviors (i.e., hunger, satiety, binge eating, food 
craving, consumption of sugar-sweetened and/or carbonated beverages) in youth with severe 
obesity prescribed this medication for weight management. The study cohort will be recruited 
primarily among youth receiving care through our PWMCs. Additional  study participants may be 
recruited among those who contact CPOM (after receiving recruitment letters for CPOM studies), 
are interested in participating in a study that specifically involves the initiation of an active anti-
obesity pharmacotherapy at study onset (versus possibility of receiving a placebo), and who 
qualify (meet inclusion/exclusion criteria). We will recruit youth ages 12 to <18 years old. The 
schedule of events (Table 1) shows the data that will be collected at each study visit. Following 
topiramate initiation, adherence will be assessed every other week by review of electronic 
prescription bottles, and side effects will be assessed throughout the study at in-person study 
visits or via phone calls.  
 
 
 
 
 
 
 

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in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
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Table 1: Schedule of Events 
 
Screening/Baseline 
Week 6 
Week 8 
Week 10 
Week 14 
Visit Number 
1 
2 
3 
4 
5 
Review Inclusion/Exclusion Criteria1 
x 
 
 
 
 
Consent/Assent 
x 
 
 
 
 
Demographics2 
x 
 
 
 
 
Physical Exam3 
x 
 
 
 
x 
Tanner Staging3 
x 
 
 
 
 
BMI/Anthropometrics4 
x 
x 
 
x 
x 
Blood Pressure/Heart Rate 
x 
x 
 
x 
x 
Pregnancy Testing and questionnaire14 
x 
x 
 
x 
x14 
Safety Labs5 
x 
x 
 
 
 
Cardiometabolic Risk Labs (fasting)6 
x 
 
 
 
x 
Genotyping7 
x 
 
 
 
 
Topiramate concentration  
 
x 
x 
x 
x 
iDXA (body composition)8 
x 
 
 
 
 
Bioelectrical Impendence Anaysis9  
x 
x 
 
x 
x 
Eating Behavior and Physical Activity Questionnaires10 
• 
Hunger/Satiety Visual Analog Scales 
• 
AEBQ 
• 
FCQ-T-r 
• 
dYFAS 
• 
RED-5 
• 
PAQ-A 
x 
x 
 
 
x 
Sugar Consumption11 
• 
BEVQ-15 
x 
x 
 
 
x 
Eating Disorder Examination Questionnaire (EDE-Q) 
x 
x 
 
 
x 
Depression and Suicide Screening12 
• 
PHQ-9 
• 
C-SSRS 
x 
x 
x 
x 
x 
Neurocognitive Testing13 
• 
COWA 
• 
NIH-TB List Sorting Working Memory Test 
• 
NIH-TB Pattern Comparison Test 
x 
x 
 
x 
x 
Lifestyle Counseling 
x 
x 
 
 
 
Registered Dietician Visit 
x 
x 
 
 
 
Drug Dispensing 
x 
 
x 
 
 
Adherence    
ß Assessed at in person visits via electronic prescription bottles and pill 
count and at weeks 2 and 4 via phone call à 
Side Effects, Inter-current Illnesses, Concomitant Medications Review           
 
ß Assessed weeks 6, 8, 10, and 14 at study visit; weeks 2, and 4 via phone 
call à 
1 Will be reviewed by study principal investigator and/or co-investigator 
2 Demographics including age, sex, race/ethnicity 
3  Physical exam does not need to be repeated if one was done by CPOM faculty, in the pediatric weight management clinic, or by a pediatric 
endocrinologist within 30 days prior to Screening/Baseline visit.  Tanner determined by Marshall-Tanner criteria examining breast and pubic hair 
development (girls) or genitalia and pubic hair (boys); to be performed by a trained professional. 
4 Height, weight, BMI, waist circumference, hip circumference 
5 Creatinine (to assess renal function) and bicarbonate (to assess for presence of metabolic acidosis) 
6 Lipids (total, LDL-, HDL-cholesterol, triglycerides), glucose, insulin, hemoglobin A1c.  
7 DNA collection via salivary collection kits  
8 iDXA to include total and regional body fat measures 
9 Performed using Tanita scale 
10 Including hunger/satiety Visual Analog Scales, Adult Eating Behavior Questionnaire (AEBQ), Food Craving Questionnaire-Trait-Reduced (FCQ-T-r), 
Dimensional Yale Food Addiction Scale 2.0 for Children (dYFAS), Reward Based Eating Drive Scale X5 (RED-5), and Physical Activity Questionnaire 
for Adolescents (PAQ-A) 
11 Assessed via the Beverage Intake Questionnaire 15 (BEVQ-15) 
12  PHQ-9 to be conducted at Baseline/Screening, Week 6 and Week 10.  Columbia-Suicide Severity Rating Scale (C-SSRS) to be conducted at all visits  
13 Controlled Oral Word Association (COWA) test, NIH-TB List Sorting Working Memory Test and NIH-TB Pattern Comparison Test  
14 Urine pregnancy preferred, but serum may be utilized. Females who undergo pregnancy testing will be asked to complete a questionnaire about their 
experience at the Week 14 visit 
 

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in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
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5.2 
Study Procedures:  
Anthropometric Measurements and Body Fat Composition: 
Height and weight will be measured using a calibrated, wall-
mounted stadiometer and an electronic scale, respectively. 
Measurements will be obtained with participants in light clothing 
and 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 then be 
calculated by standard convention: weight in kilograms divided 
by height in meters, squared. Waist circumference will be 
measured at end-expiration midway between the base of the rib 
cage and the superior iliac crest. Hip circumference will be 
measured at the maximal protuberance of the buttocks. 
Total percent body fat, visceral fat, and lean mass will be determined by dual energy x-ray 
absorptiometry (iDXA, GE Healthcare). The scanning table accommodates body sizes of up to 204 
kg. Our group has done some of the early work regarding validation of iDXA visceral fat in children 
and adolescents.34 As an additional measure of body composition, we will also utilize a DC-430U 
Tanita® scale (Tanita Corporation of America Inc, Arlington Heights, IL), which is an FDA-cleared 
bioelectrical impedance analysis device that calculates fat, muscle, water, and bone mass (Figure 
3). This measurement will be obtained in light clothing, and without shoes and socks. Specific 
measures obtained via the Tanita scale will include weight, fat percent (with desirable range), fat 
mass (with desirable range), fat free mass, and body mass index.  
Pubertal Development, Blood Pressure, and Blood Analyses: 
Pubertal stage (Tanner stage) will be determined at the baseline/screening visit by trained 
pediatricians using Marshall-Tanner criteria examining breast and pubic hair development for 
girls and genitalia and pubic hair development for boys.35-36 This will not be performed if this 
exam was previously performed by a pediatric weight management clinic provider and/or 
pediatric endocrinologist within the last 30 days prior to the baseline/screening visit, with results 
available in the EHR.  
Blood pressure measurements will be obtained manually on the same arm using the same cuff 
size and equipment. Standardized procedures will be employed as described previously.37 
Individual cuff size will be determined by measuring the arm circumference midway between the 
acromial process and the bony olecranon. Sitting blood pressure and heart rate will be measured 
after the participant has been resting quietly for 10 minutes. Measurements will be made three 
consecutive times (3-minute intervals). The final two of three measurements will be averaged.  
Cardiometabolic risk factor labs will be drawn fasting (≥12 hours) and will include measurements 
of plasma glucose (FPG), plasma insulin (FPI), hemoglobin A1C, and lipids (total-, LDL-, HDL-
cholesterol, and triglycerides). These will all be assayed in Fairview Diagnostics Laboratories 
(Minneapolis, MN – a Center for Disease Control and Prevention certified laboratory). The fasting 
insulin and glucose measures will be used to determine a HOMA-IR, a commonly used surrogate 
Figure 3: Tanita® Scale 

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Pharmacokinetics and Pharmacodynamics of Topiramate for Weight Loss 
in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
Page 18 of 43 
 
marker of insulin resistance in children and adults,38 which will be calculated per standard 
convention: 
  
 
 
Topiramate levels will be drawn at 6, 8, 10, and 14 weeks, corresponding to 4, 6, 8, and 12 weeks 
after the participant has reached 75 mg daily (or the maximum tolerated dose). All topiramate 
samples will be spun at 10,000 x g for 10 minutes, 5 to <120 minutes after blood draw, and frozen 
(-80°C) until analysis per standard protocol.39 We will measure topiramate concentrations by a 
previously validated liquid chromatography-mass spectrometry (LCMS) assay in the lab of Dr. 
Angela Birnbaum (Department of Experimental and Clinical Pharmacology, College of Pharmacy, 
University of Minnesota).39  
DNA Collection and Genotyping:  
DNA salivary collection kits (Oragene, Ontario, Canada) will be used to collect DNA. All samples 
returned will be stored at room temperature until processing. DNA extraction, quantification, 
and genotyping will be performed by the University of Minnesota Genomics Center (UMGC) 
following standard procedures. Genotyping will be performed using the InfiniumTM Global 
Screening Array-24 v2.0 BeadChip (Illumina, San Diego). Inclusion criteria for SNPs will be a minor 
allele frequency >1%, call rate >98%, and Hardy-Weinberg equilibrium (p>1E-5). We will then 
impute all samples to the Trans-Omics for Precision Medicine (TOPMed) reference panel using 
the Michigan Imputation server.   
Eating Behaviors/Features and Physical Activity Questionnaires: 
Eating behaviors/features and physical activity questionnaires are summarized in Table 2. We 
will obtain self-report ratings (average over the preceding week) for appetite and satiety on 15-
cm visual analog scales anchored with “not at all” to “extremely.” This method has been 
validated for use in appetite research40 and was utilized by Sysko et al. in a study of adolescents 
with severe obesity.41 An additional self-reported appetite and satiety measure will be the Adult 
Eating Behavior Questionnaire (AEBQ; note: in our experience, the self-report version (AEBQ) is 
more appropriate for adolescents compared to the child version (CEBQ)).42  
Food craving will be measured with the Food Craving Questionnaire-Trait-Reduced (FCQ-T-r) and 
food addiction with the Dimensional Yale Food Addiction Scale 2.0 for Children (dYFAS).43-44 Binge 
eating behaviors/features will be measured with the Reward Based Eating Drive Scale X5 (RED-
5), in addition to the Eating Disorder Examination Questionnaire (EDE-Q).45-46 Dietary intake of 
sugar-sweetened and/or carbonated beverages will be measured via questions from the 
Beverage Intake Questionnaire 15 (BEVQ15).47 Finally, physical activity will be measured with the 
Physical Activity Questionnaire for Adolescents (PAQ-A).48  
 
 
 

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in Youth: PHARMATOP 
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Safety-Related Assessments: 
Please see Table 1. A creatinine and bicarbonate to assess for renal disease and metabolic 
acidosis will be performed at baseline and one month after topiramate has reached the 
maximum dose in this study (75 mg or maximum-tolerated dose). We will require all female 
participants to confirm use of two forms of contraception if sexually active.   
We will monitor for depression, suicidal behavior and ideation, acute secondary angle closure 
glaucoma, renal stones, cognitive impairment, decreased bicarbonate indicating metabolic 
acidosis, and elevated creatinine. Changes in neurocognitive function (verbal fluency) and 
working memory will be evaluated using the Controlled Oral Word Association (COWA) test and 
the NIH-TB List Sorting Working Memory Test, and NIH TB Pattern Comparison Processing Test, 
respectively, at each in-person study visit, aside from the week 8 blood draw-only visit.49-50 Of 
note, the COWA is sensitive for phonetic fluency and has been used in multiple studies involving 
topiramate.51-53  
Participants will be assessed for depression with the Patient Health Questionnaire-9 (PHQ-9) at 
the Screening/Baseline, Week 6 and Week 10 visits.  Participants will be assessed for suicide with 
Table 2: Eating Behavior/Features, Physical Activity, Neurocognitive Testing, and Safety Questionnaires 
Type of Questionnaire 
Name of Questionnaire 
What Questionnaire 
Measures 
Number of 
Questions 
Visit 
Performed 
Eating Behaviors/Features 
Visual Analog Scales 
Hunger, satiety 
2 
1, 2, 5 
Adult Eating Behavior 
Questionnaire (AEBQ) 
Hunger, satiety, 
emotional eating, 
hedonic eating 
35 
1, 2, 5 
Food Craving 
Questionnaire-Trait – 
Reduced (FCQ-T-r) 
Food craving 
15 
1, 2, 5 
Dimensional Yale Food 
Addiction Scale 2.0 for 
Children (dYFAS) 
Food addiction 
13 
1, 2, 5 
Reward Eating Drive 
Scale X5 (RED-5) 
Binge eating features 
5 
1, 2, 5 
Beverage Questionnaire 
(BEVQ15) 
Sugar beverage 
intake 
15 
1, 2, 5 
Physical Activity  
Physical Activity 
Questionnaire for 
Adolescents (PAQ-A) 
Physical activity 
9 
1, 2, 5 
Neurocognitive Testing 
Controlled Oral Word 
Association 
Verbal fluency 
3 
1, 2, 4, 5 
NIH-TB List Sorting 
Working Memory Test  
Working memory  
N/A  
(up to 7 minutes 
to complete) 
1, 2, 4, 5 
NIH-TB Pattern-
Comparison Processing 
Test 
Processing Speed 
N/A (up to 1.5 
minutes to 
complete) 
1, 2, 4, 5 
Safety Questionnaires 
Eating Disorder 
Examination 
Questionnaire (EDE-Q) 
Eating disorders 
28 
1, 2, 5 
Patient Health 
Questionnaire-9 (PHQ-9) 
Depression 
9 
1,2, 4 
Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
Risk for Suicidality 
Up to 10 
1, 2, 3, 4, 5 

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in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
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the Columbia-Suicide Severity Rating Scale (C-SSRS) at all visits.54-55 A participant will be referred 
to a mental health provider (MHP) or primary care provider if the participant has a PHQ-9 score 
of ≥15, any suicidal behavior, or any suicidal ideation of type 4 or 5 on the C-SSRS and a member 
of the study team may contact a participant’s existing mental health provider if a participant 
presents with acute suicidal ideation/behavior at a study visit. The decision as to whether the 
participant will be allowed to continue in the trial will be made by the local medical monitor (Dr. 
Eric Bomberg) in consultation with the MHP or primary care provider after the referral clinical 
visit.  Participants who already have an existing mental health provider and/or are followed by 
their primary care provider for mental health will have their mental health provider and/or 
primary care provider alerted if the participant has a PHQ-9 score of >15 or any suicidal behavior 
or suicidal ideation of type 4 or 5 on the C-SSRS. 
Eating disorders will be evaluated using the eating disorder examination-questionnaire (EDE-
Q).46 Any participant endorsing vomiting, laxative use, and/or diuretic use for weight control (via 
the EDE-Q by standard scoring procedures), will be interviewed by a pediatric behavioral 
psychologist using the Eating Disorders Module of the Structured Clinical Interview for Diagnostic 
and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). If disordered eating is 
present upon clinical interview, the participant will be removed from the study and referred to 
an eating behavior specialist for clinical follow-up. If no eating disorder is present, the participant 
may continue in the study.  
5.3 
Study Duration:   
14 weeks, including 2 weeks of topiramate titration up to 75 mg daily (or maximum tolerated 
dose; as described in Section 4.1) followed by 12 weeks on topiramate.  
5.4 
Use of radiation:  
The iDXA consists of exposure to 0.01 mSv. In comparison, a resident of the State of Minnesota 
receives approximately 3 mSv from natural background radiation as a result of living in 
Minnesota. There are no other sources of radiation in this study.  
5.5 
Use of Center for Magnetic Resonance Research: N/A 
6.0 
Data and Specimen Banking 
6.1 
Storage and Access:  
Blood Samples:  
Blood samples for lipids (total-, HDL-, and LDL-cholesterol and triglycerides), glucose, insulin, and 
hemoglobin A1c will be sent to the Fairview Diagnostics Laboratory (which is CLIA licensed) after 
collection of the sample.  
DNA Specimens:  
The DNA specimens (saliva kits) will be stored in the Pediatric Research BioBank until processing, 
located in the 717 Delaware Building. These specimens will then be transferred to the University 
of Minnesota Genomics Center for DNA extraction, quantification, and genotyping. After 
completion of these steps, specimens will then be transferred back to the Pediatric Research 
BioBank, where they will be banked for future use. We will bank these samples indefinitely. DNA 

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in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
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specimens will only be handled by the study personnel including the study investigator, co-
investigators, and coordinator(s).  
Electronic Health Record (EHR) Data Storage and Access:  
Identifiable information from the EHR will only be accessed through the AHC-IE, which is a 
secured data shelter, and only via UMN-issued encrypted password-protected computers. Only 
study investigators will have access to the data, and sharing of the data will only be via the ACE-
IE secured data shelter, UMN Box, and REDCap. We will work with UMN Best Practices Integrated 
Informatics Core (BPIC) for EHR data gathering, storage, and preparation for analysis.  
6.2 
Data:  
Results from the Fairview Diagnostics Laboratories will be posted to the patient’s chart and will 
also be logged into REDCap. The data will be kept with a unique identification (ID) link. The 
principal investigator will retain the link to the patients’ names, which will be stored in the ACE-
IE and only accessed via UMN-issued encrypted password-protected computers. Data, including 
results from Fairview Diagnostics Laboratories, will be entered into a REDCap database on the 
secure web interface with data checks used during data entry to ensure data quality. REDCap is 
a widely-used, powerful, reliable, and well-supported system. REDCap includes a complete suite 
of features to support HIPAA compliance, including a full audit trail, user-based privileges, and 
integration with the institutional Lightweight Directory Access Protocol (LDAP) server. The 
database and web server are both housed on secure servers operated by UMN Health Sciences 
Technology (HST). The servers are in a physically secure location on the UMN campus and are 
backed up nightly, with the backups stored in accordance with the HST retention schedule of 
daily, weekly, and monthly tapes retained for 1 month, 3 months, and 6 months, respectively. 
The HST servers provide a stable, secure, well-maintained, and high capacity data storage 
environment. Access to the study’s data in REDCap will be restricted to members of the study 
team by username and password.  
6.3 
Release/Sharing:  
Access to the study data REDCap will be restricted to the members of the study team by 
username and password. 
7.0 
Sharing of Results with Participants 
7.1 
Sharing results:  
Given the pragmatic nature of this study, participants will receive laboratory test results, which 
will be shared by a study team member. However, for the genetic analysis (DNA collection and 
genotyping), only aggregate results will be shared with participants as described below.  
7.2 
Sharing of genetic testing:  
7.2.1 Disclosure of results:  
Only aggregate results of the genetic analyses (DNA collection and genotyping) will be 
shared with participants. We are not planning to disclose individual results of genetic 
testing to participants.  
7.2.2 If returning results to participants: 

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in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
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• 
Aggregate or individual results: Aggregate.  
• 
Laboratory results: N/A 
• 
Plan for return of results to participants: Results will be returned via a study website 
after publication of the study results.  
• 
Types of results to be returned to participants: Participants will not be provided with 
complete datasets. We will return lay summaries of the publications to the 
participants. 
7.2.3 Future analysis of genotypes: N/A  
8.0 
Study Population 
8.1 
Inclusion Criteria:  
• 
Body Mass Index (BMI) ≥1.2 times the 95th percentile (age and sex-adjusted) and/or 
BMI ≥ 35 kg/m2 
• 
Ages 12 to <18 years old 
• 
If recruited from PWMC: Deemed appropriate candidates to receive topiramate 
(without contraindications) for weight loss by an obesity medicine specialist at the 
University of Minnesota 
8.2 
Exclusion Criteria:  
• 
History of metabolic/bariatric surgery 
• 
Obesity associated with a diagnosed genetic disorder (i.e. monogenic obesity, 
Prader-Willi, Bardet-Biedl syndrome) 
• 
Clinically diagnosed hyperthyroidism or uncontrolled hypothyroidism as 
determined by local medical monitor (Dr. Eric Bomberg) (who is a board certified 
endocrinologist) 
• 
History of acute angle closure glaucoma.  Individuals with other types of glaucoma 
will need approval from the participant’s ophthalmologist to be enrolled. 
• 
History of nephrolithiasis  
• 
History of a seizure disorder (aside from febrile seizures) 
• 
Major psychiatric disorder as determined by local medical monitor  
• 
History of bulimia nervosa or anorexia nervosa 
• 
History of suicide attempt within one year of the screening visit  
• 
History of active suicidal ideation or self-harm within 30 days of the screening visit  
• 
Current or recent (< 6 months prior to enrollment) use of topiramate or 
phentermine/topiramate 
• 
Current or recent (< 6 months prior to enrollment) use of other anti-obesity 
medication(s) defined as metformin, orlistat, phentermine, liraglutide/semaglutide 
(or other GLP1-RAs), naltrexone, and/or combination naltrexone/bupropion 
(monotherapy use of bupropion is not an exclusion), unless participant has been 
on stable doses for ≥ 6 months. Of note, if a dose of phentermine was increased 
from 15 mg daily to 18.75 mg daily during this period, it is not considered a dose 
increase.   

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in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
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• 
Current or recent (< 6 months prior to enrollment) use of medication(s) associated 
with weight gain (e.g. oral steroids, anti-psychotics), unless participant has been on 
stable doses of such medication(s) for ≥ 6 months 
• 
Current or recent (< 6 months prior to enrollment) use of long-acting stimulant 
medications, unless participant has been on stable doses of such medication for ≥ 6 
months.  In terms of short-acting ADHD stimulant medications, the PI will 
determine eligibility based on weight and dose (no studies have shown this 
contributes to weight outcomes).  
• 
Baseline bicarbonate < 18 mmol/L 
• 
Baseline creatinine > 1.2 mg/dL 
• 
Females: pregnant, planning to become pregnant, or, if sexually active, unwilling to 
use 2+ acceptable contraceptive methods during the study period 
8.3 
Screening:  
Patients seen in the University of Minnesota PWMCs who are deemed appropriate candidates 
to receive topiramate (without contraindications) for weight loss by an obesity medicine 
specialist will be referred for this study.  
Screening/Baseline Visit (Visit 1): 
Participants will be asked to present at this visit after having fasted for ≥12 hours. At this visit, 
the participant’s parent/legal guardian will be taken through the consent process and will sign 
the parental consent form, and the participant will be asked to sign the assent form, after all 
have had the opportunity to learn about the study and ask any questions they may have. The 
participant will then undergo the following: 
• 
Review of inclusion/exclusion criteria 
• 
Demographics including age, sex, self-reported race/ethnicity, home address, total family 
combined income, parents’ level of education and employment status 
• 
Physical exam and tanner stage. The physical examination will not need to be repeated if 
performed by a CPOM faculty member, pediatric weight management provider, and/or 
pediatric endocrinologist within the last 30 days before Screening/Baseline visit.  A trained 
professional can perform the Tanner staging. 
• 
BMI/Anthropometrics: height, weight, waist and hip circumference, and BMI  
• 
Blood pressure and heart rate 
• 
Pregnancy test for females  
• 
Contraceptive counseling 
• 
Review of medications 
• 
Blood draw for safety labs (creatinine and bicarbonate) and cardiometabolic risk labs (lipids, 
glucose, insulin, and A1c)  
• 
Genotyping (via saliva collection) 
• 
iDXA (body composition) 
• 
Bioelectrical impedance analysis (via Tanita Scale) 
• 
Eating behavior and physical activity questionnaires (hunger/satiety visual analog scales, 
AEBQ, FCQ-T-r, dYFAS, RED-5, BEVQ-15, PAQ-A)  
• 
Safety questionnaire for eating disorders (EDE-Q) 

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in Youth: PHARMATOP 
VERSION DATE: 05/03/2024 
 
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• 
Depression and suicide screening (PHQ-9 and C-SSRS).  Participants whose tests show that 
they have active suicidal ideation will be referred to their own mental health provider, have 
a mental health referral generated or be referred to the emergency department 
• 
Neurocognitive testing (COWA test, NIH-TB List Sorting Working Memory Test, NIH-TB 
Pattern Comparison Processing Speed Test)  
• 
Lifestyle and registered dietician counseling  
 
Week 2 (± 7 days from enrollment): 
• 
Side effects, inter-current illnesses, medication review and adherence (via phone call) 
 
Week 4 (± 7 days from enrollment): 
• 
Side effects, inter-current illnesses, medication review and adherence (via phone call) 
 
Week 6 (± 7 days from enrollment; Visit 2):  
• 
BMI/Anthropometrics 
• 
Blood pressure and heart rate 
• 
Blood draw for safety labs (creatinine and bicarbonate) 
• 
Pregnancy test for females 
• 
Topiramate concentration 
• 
Bioelectrical impedance analysis (via Tanita Scale) 
• 
Eating behavior and physical activity questionnaires (hunger/satiety visual analog scales, 
AEBQ, FCQ-T-r, dYFAS, RED-5, BEVQ-15, PAQ-A) 
• 
Safety questionnaire for eating disorders (EDE-Q) 
• 
Depression and suicide screening (PHQ-9 and C-SSRS) 
• 
Neurocognitive testing (COWA test, NIH-TB List Sorting Working Memory Test and NIH-TB 
Pattern Comparison Processing Speed Test)  
• 
Lifestyle and registered dietician counseling  
• 
Side effects, inter-current illnesses, medication review 
• 
Adherence (via electronic prescription bottle review and counting pills) 
 
Week 8 (± 7 days from enrollment; Visit 3; lab draw only): 
• 
Topiramate concentration 
• 
Side effects, inter-current illnesses, medication review (via phone call or in-person) 
• 
Adherence (via electronic prescription bottle review and counting pills) 
• 
Suicide screening (C-SSRS) 
• 
Drug dispensing 
 
Week 10 (± 7 days from enrollment; Visit 4): 
• 
BMI/Anthropometrics 
• 
Blood pressure and heart rate 

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• 
Pregnancy test for females 
• 
Topiramate concentration 
• 
Bioelectrical impedance analysis (via Tanita Scale) 
• 
Depression and suicide screening (PHQ-9 and C-SSRS) 
• 
Neurocognitive testing (COWA test, NIH-TB List Sorting Working Memory Test, NIH-TB 
Pattern Comparison Processing Speed Test)  
• 
Side effects, inter-current illnesses, medication review 
• 
Adherence (via electronic prescription bottle review and counting pills) 
Week 14 (± 7 days from enrollment; Visit 5): 
• 
Physical exam, performed by a trained pediatrician 
• 
BMI/Anthropometrics 
• 
Blood pressure and heart rate 
• 
Blood draw for cardiometabolic risk labs (lipids, glucose, insulin, and A1c) 
• 
Pregnancy test for females and questionnaire about the testing 
• 
Topiramate concentration 
• 
Bioelectrical impedance analysis (via Tanita Scale) 
• 
Safety questionnaire for eating disorders (EDE-Q) 
• 
Eating behavior and physical activity questionnaires (hunger/satiety visual analog scales, 
AEBQ, FCQ-T-r, dYFAS, RED-5, BEVQ-15, PAQ-A) 
• 
Neurocognitive testing (COWA test, NIH-TB List Sorting Working Memory Test, NIH-TB 
Pattern Comparison Processing Test)  
• 
Side effects, inter-current illnesses, medication review 
• 
Suicide screening (C-SSRS) 
• 
Adherence (via electronic prescription bottle review and counting pills) 
 
9.0 
Vulnerable Populations 
9.1 Vulnerable Populations:  
Population / Group 
Identify whether any of the 
following populations will be 
targeted, included (not 
necessarily targeted) or excluded 
from participation in the study.  
Children 
Targeted Population 
Pregnant women/fetuses/neonates 
Excluded from Participation 
Prisoners 
Excluded from Participation 
Adults lacking capacity to consent 
and/or adults with diminished 
capacity to consent, including, but 
Excluded from Participation 

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not limited to, those with acute 
medical conditions, psychiatric 
disorders, neurologic disorders, 
developmental disorders, and 
behavioral disorders 
Non-English speakers 
Included/Allowed to Participate 
Those unable to read (illiterate) 
Excluded from Participation 
Employees of the researcher 
Excluded from Participation 
Students of the researcher 
Excluded from Participation 
Undervalued or disenfranchised 
social group 
Included/Allowed to Participate 
Active members of the military 
(service members), DoD personnel 
(including civilian employees) 
Excluded from Participation 
Individual or group that is 
approached for participation in 
research during a stressful situation 
such as emergency room setting, 
childbirth (labor), etc. 
Excluded from Participation 
Individual or group that is 
disadvantaged in the distribution of 
social goods and services such as 
income, housing, or healthcare. 
Included/Allowed to Participate 
Individual or group with a serious 
health condition for which there are 
no satisfactory standard treatments. 
Included/Allowed to Participate 
Individual or group with a fear of 
negative consequences for not 
participating in the research (e.g. 
institutionalization, deportation, 
disclosure of stigmatizing behavior). 
Excluded from Participation 
Any other circumstance/dynamic 
that could increase vulnerability to 
Excluded from Participation 

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coercion or exploitation that might 
influence consent to research or 
decision to continue in research. 
 
9.2 Additional Safeguards:  
At least one parent signature is required for permission for a minor to enroll in the study. 
Children ages 8 to <18 years old will be asked to document their agreement by signing an 
assent form. The research will not involve wards of the state or any other agency, institution, 
or entity. All consent and assent will be documented.  
It is possible that the parent of a child may not be comfortable with reading and speaking 
English and would prefer that the consent be available in Spanish.  For that reason, we have 
had the parental consent translated into Spanish.  As most of the children we encounter are 
comfortable with speaking and reading English, we will not be translating the assent form at 
this time.  We have two native Spanish speakers on our team who can help with answering 
questions that might arise with the parent at visits. 
 
10.0 Local Number of Participants 
10.1 
Local Number of Participants to be Consented:  
All participants will be consented locally. The approximate number of participants we plan to 
enroll is 65. The lowest number that will allow for data analysis is 40, and the maximum that 
might agree to participate is 80.  
11.0 Local Recruitment Methods 
11.1 
Recruitment Process:  
One of the primary strengths of this study is its pragmatic nature. Our 3.5-month duration (2 
weeks to increase topiramate to maximum dose, followed by 3 months on this dose) for this 
study was chosen because the FDA, as well as most obesity management guidelines,1-3 
recommend that pharmacotherapies used for obesity treatment either be altered or 
discontinued after 3 months if response is insufficient. For example, the FDA recommends that 
for adults on the combination of phentermine 7.5 mg/topiramate 46 mg daily, if weight loss is 
<5% at 3 months, then the dose should be titrated up to the maximum-strength dose of 
phentermine 15 mg/topiramate 92 mg daily. Most patients prescribed an anti-obesity 
medication are, therefore, generally on the medication for at least 3 months on the same dose 
assuming they do not develop adverse effects to the treatment. In this sense, this study largely 
entails the addition of measures including anthropometrics (e.g. height, weight, BMI), blood 
draws, and questionnaires onto routine clinical care being performed in our and other weight 
management clinics. We believe that this will substantially facilitate recruitment for our study.  
At the Center for Pediatric Obesity Medicine (CPOM), we have strong recruitment infrastructure. 
For this study, participants will primarily be recruited directly from our PWMCs by providers and 
support staff within the clinics. Additional participants may be recruited among those who 
contact CPOM (after receiving recruitment letters for CPOM studies), are interested in 

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participating in a study that specifically involves the initiation of an active anti-obesity 
pharmacotherapy at study onset (versus possibility of receiving a placebo), and who qualify 
(meet inclusion/exclusion criteria). Inclusion in the study will be determined by the enrollment 
criteria. There is a vast number of potentially eligible participants. Our PWMCs generally have 
≥3,000 patient visits per year, a number that is continuing to rise with the recent expansion of 
our clinical capacity and volume (four new obesity medicine specialists hired in the last few years; 
seven total obesity medicine providers). Further, ≥500 youth to date have been prescribed 
topiramate through our clinics and, with our recent clinical expansion, this number is expected 
to continue to substantially grow. Given our clinical volume and our established recruitment 
infrastructure, we do not anticipate problems with recruiting the cohort during the study 
duration.  
If recruitment is below target for any reason, we can utilize partner institutions within the 
Minnesota Pediatric Obesity Consortium (MN-POC) for assistance with recruitment. Member 
institutions of MN-POC include the University of Minnesota, Mayo Clinic, Children’s Hospitals 
and Clinics of Minnesota, and Park Nicollet/Health Partners, collectively representing a large 
portion of the pediatric medical care provided in the state of Minnesota. All MN-POC institutions 
are within reasonable driving distance of the University of Minnesota, and most refer patients to 
our PWMCs for obesity management already.  
11.2 
Identification of Potential Participants:  
From the PWMC, youth with severe obesity will be identified by PWMC providers as appropriate 
candidates to receive topiramate. The study PI (Dr. Bomberg) is a PWMC provider and is, 
therefore, in regular communication with other PWMC providers. Additional participants may 
be recruited among those who contact CPOM (after receiving recruitment letters for CPOM 
studies), are interested in participating in a study that specifically involves the initiation of an 
active anti-obesity pharmacotherapy at study onset (versus possibility of receiving a placebo), 
and who qualify (meet inclusion/exclusion criteria). After identification, potential participants 
will be given an IRB-approved recruitment letter about the project. Interested participants will 
be asked to contact the study team, and up to five follow-up phone calls will be made by study 
staff if the potential participant leaves a message. Further, with verbal parental permission, 
PWMC providers will also contact the study team about potential participants identified. The 
only information provided to the study team prior to official enrollment will include name and 
contact information.  
11.3 
Recruitment Materials:  
Recruitment letters will be created for this study and approved by the IRB before use.  
Appropriately certified staff within the PWMC may approach potential participants and 
speak to them about the study and provide them with a flyer with a QR code that 
connects them to the research coordinator and indicates a preferred method of 
communication (email, phone or text). 
11.4 
Payment:  
While this study is largely pragmatic in nature in the sense that it largely entails the addition of 
measures including anthropometrics, blood draws, and questionnaires onto routine clinical care 
being performed in PWMCs, we still recognize the additional commitment needed from the 

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participant and family members. Therefore, the children who participate in this study will receive 
payment for the visits they complete.  Payments will be made by the Greenphire ClinCard.   
• 
Screening/baseline visit: $50 
• 
Week 6 visit: $35 
• 
Week 8 visit (blood draw only): $25 
• 
Week 10 visit: $40 
• 
Week 14 visit: $50 
• 
Return of electronic prescription bottle (Visit 14): $25 
• 
Total: $225 
12.0 Withdrawal of Participants 
12.1 
Withdrawal Circumstances:  
Participants will be allowed to withdraw from the study at any time. Those who wish to withdraw 
may notify the research team in writing or by telephone. Participants may also be withdrawn 
from the study at any time based upon investigator judgement.  Finally, in the event that a 
participant has a serious adverse event that is deemed related to the study medication and/or 
procedures by either the external or internal medical monitor (Dr. Brooke Sweeney and Dr. Eric 
Bomberg, respectively), the participant will be required to immediately discontinue the 
intervention. 
12.2 
Withdrawal Procedures:  
As it is generally recommended that patients choosing to discontinue topiramate be weaned off 
of this medication, we will recommend for any participant choosing to withdraw from the study, 
or being withdrawn as described above, the following weaning schedule (consistent with clinical 
practice in the PWMC): 
• 
Take 50 mg daily for one week, followed by: 
• 
Take 25 mg daily for one week, and then discontinue.  
In the event of an emergent medical situation, it may be recommended to cease topiramate 
without tapering the dose.  For those participants that choose to withdraw, we will not plan to 
collect any additional data beyond that point, as the primary data of import in this study is 
topiramate concentration levels.  
12.3 
Termination Procedures:  
It will be noted in the participant enrollment log that the participant has discontinued 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. 
Given the pragmatic nature of this study, including the fact that most participants recruited will 
be from our PWMCs and will continue to be followed through our PWMCs (if they so desire) after 
their participation in this study has terminated, many participants completing this study may 
continue to take topiramate after study completion. In that case, per usual clinical practice the 
medication will be prescribed by the participant’s PWMC provider. For those not yet followed in 
the PWMC who are interested in continuing topiramate and/or being followed in our clinics, 
appointments in the PWMC will be established for continuation of topiramate and ongoing 
clinical management. All additional follow up in the PWMC will continue as per usual clinical 

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practice. If a participant elects to discontinue topiramate after study completion, we will use the 
same withdrawal procedure as described in Section 12.2, and additional topiramate will be 
provided by the IDS for this purpose.  
 
13.0 Risks to Participants 
13.1 
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 iDXA scans involve exposure to a very low dose of 
ionizing radiation. The average amount of radiation that the average person would receive from 
the iDXA used in this study is less than 1% (0.01 mSv) of that received from natural sources of 
radiation by a Minnesota resident in one year (3 mSv).   
Neuropsychological assessments (questionnaires): Potential risks related to the questionnaires 
include emotional distress related to thinking about and recording eating behavior symptoms, 
as well as possible “test fatigue.”  
Risk from salivary collection (spitting into a tube or having saliva collected with a swab): There 
are no known health risks to participants related to the collection of saliva. 
Personal Information: There is a risk that personal information could accidentally be released to 
someone other than study staff.  We keep all personal information in computer databases 
protected by passwords or in locked file cabinets.  Only study staff will have access to these 
documents and files.  All individuals with the ability to access protected health data have 
completed HIPAA and Collaborative Institutional Training Initiative (CITI) training. 
DNA/Genotyping: We are requesting consent to store and process DNA. We will be performing 
genotyping through the use of a genome-wide association (GWAS) chip.  Results from a GWAS 
chip rarely imply much about an individual’s risk of disease.  Rather, GWAS can identify regions 
of linkage disequilibrium containing potentially causal events.  We will also be requesting consent 
for sequencing DNA.  When this is done, it is similar to a fingerprint and is thus unique.  All 
precautions will be taken to protect participant privacy and confidentiality.  All genetic 
information will be stored in a secure database that is only labelled with an identification 
number.  Only the investigators and the study team members will have access to this data as 
needed to carry out their study-related duties.  DNA extraction, quantification, genotyping, and 
sequencing studies will be performed by the UMGC, which also has strict privacy rules in place 
to protect participant identity.  Nevertheless, it is possible that someone in the future could 
identify a participant based on this unique genetic information.  The DNA analysis will occur after 
all participant visits have occurred for the study. Any leftover saliva samples will be returned to 
the study team. The saliva sample collected can only be initially processed for approximately five 
years. Any saliva that remains after the sample is analyzed will be put back into storage 
indefinitely and may be used for future research projects. .   
Expected Adverse Events – Topiramate: A majority of patients tolerate topiramate well and have 
no adverse events. Adverse events, if they do occur, are generally mild to moderate in intensity. 
The following have been identified as the most common potential adverse events related to 
topiramate: paresthesia (tingling in the hands, feet, and/or face), dysgeusia (altered or metallic 

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taste), fatigue, dizziness, somnolence, nervousness, psychomotor slowing, difficulty with 
memory and/or concentration/attention, cognitive problems, confusion, mood problems, fever, 
infection, and flushing. In our experience, the most common side effect is transient irritability 
and rarely do patients discontinue topiramate due to side effects. Of note, we will be following 
generative verbal fluency during the study with the COWA test and working memory via the NIH-
TB List Sorting Working Memory Test and Pattern Comparison Processing Speed Test. According 
to the package insert, the following additional adverse reactions to topiramate have been 
identified: 
• 
Acute myopia and secondary angle closure glaucoma 
• 
Oligohidrosis and hyperthermia 
• 
Metabolic acidosis 
• 
Suicidal behavior and ideation.  Participants who have active suicidal ideation will be referred 
to their own mental health provider, have a mental health referral generated or be referred 
to the emergency department.    
• 
Fetal toxicity 
• 
Kidney stones 
• 
Seizure precipitation with sudden withdrawal 
• 
Hyperammonemia and encephalopathy 
• 
Hypothermia 
 
13.2 
Reproduction Risks:  
Topiramate can cause fetal harm in pregnant women. Available data indicate an increased risk 
in oral clefts (cleft lip with or without cleft palate) with first trimester exposure to topiramate. 
When multiple species of pregnant animals received topiramate at clinically relevant doses, 
structural malformations, including craniofacial defects, and reduced fetal weights occurred in 
offspring. Therefore, all female participants who are sexually active must agree to use two forms 
of birth control during their time in the study. Females of childbearing potential will have 
pregnancy tests at baseline/screening (during which visit they also complete the iDXA scan) and 
at the Week 6, Week 10 and Week 14 visits. Urine pregnancy tests will be used as often as 
possible, but a serum pregnancy test may also be conducted.  If a patient becomes pregnant 
while taking topiramate, treatment will be discontinued immediately and the patient will be 
apprised of the potential hazard to a fetus again at that time. 
13.3 
Risks to Others: N/A 
13.4 
Definition of Adverse Events (AE):  
An adverse event is any untoward medical occurrence in a clinical study participant that is 
temporally associated with the use of a medicinal product, whether or not it is considered related 
to the medicinal product. An adverse event can be any unfavorable and unintended sign, 
including an abnormal laboratory finding, symptom or disease (new or exacerbated), temporally 
associated with the use of a medicinal product. 
13.5 Definition of a Serious Adverse Event (SAE):  
A serious adverse event is an AE that fulfills at least one of the following criteria: 
• 
Results in death 

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• 
Is life-threatening 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent disability/incapacity 
• 
Is a congenital anomaly/birth defect 
13.6 
Classification of an Adverse Event: 
Severity of Event: The severity of all AEs will be assessed by the internal safety monitor using the 
following grading system: 
• 
Grade 1: Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
• 
Grade 2: Moderate: minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living 
• 
Grade 3: Severe: medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily life 
• 
Grade 4: Life-threatening: urgent intervention indicated 
• 
Grade 5: Death related to adverse event 
Relationship to Study Intervention: All AEs must have their relationship to study intervention 
assessed by the clinician who examines and evaluates the participant based on temporal 
relationship and his/her clinical judgment. The degree of certainty about causality will be graded 
using the categories below.  In a clinical study, the study product must always be suspected. 
• 
Unrelated: clearly not related to the investigational agent(s) 
• 
Unlikely: doubtfully related to the investigational agent(s) 
• 
Possible: may be related to the investigational agent(s) 
• 
Probable: likely related to the investigational agent(s) 
• 
Definite: clearly related to the investigational agent(s) 
Expectedness:  The internal safety monitor will be responsible for determining whether an AE is 
expected or unexpected. An AE will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the risk information previously described for the 
study intervention. 
 
13.7 Time Period and Frequency for Event Assessment and Follow-Up:   
All AEs will be captured on the appropriate case report form (CRF). Information to be collected 
includes event description, time of onset, clinician’s assessment of severity, relationship to 
topiramate (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 in the study must be 
documented appropriately regardless of relationship. All AEs will be followed to adequate 
resolution. 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE. 
The study staff will record all reportable events with start dates occurring any time after 
informed consent is obtained until the last day of study participation. As described in Section 

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5.1, at each study encounter study staff will inquire about the occurrence of AEs/SAEs since the 
last encounter. Events will be followed for outcome information until resolution or stabilization. 
The PI will notify the IRB and external medical monitor (Dr. Brooke Sweeney) of any SAE that 
meets the definition of being an unanticipated problem that involves risk to subjects or others 
(UPIRTSO) within five days of knowledge of the event. The DSMB will be provided with AE and 
SAE information prior to their review of the study, at least every six months. 
14.0 Potential Benefits to Participants 
14.1 
Potential Benefits:  
We believe the potential benefits to the participants outweigh the risks in this study. We expect 
that most, if not all, participants will experience some degree of weight loss and improvements 
in eating behaviors during the study. Since data from studies in youth receiving topiramate have 
shown an overall reduction in BMI with topiramate plus LSM, it is reasonable to expect similar 
results in this proposed study focused on characterizing associations between topiramate dose, 
exposure, and weight loss outcomes in youth with severe obesity.   
 
15.0 Statistical Considerations 
15.1 
Data Analysis Plan:  
PopPK analysis will be conducted using NONMEN® following best practice guidelines set forth by 
Byon et al.56 We will assume that the structural model of topiramate follows a one-compartment 
model with 1st-order absorption and elimination per previous topiramate studies.23-25 Topiramate 
concentrations (collected 4, 6, 8, and 12 weeks after 75 mg or maximum-tolerated topiramate 
dose reached) will be modeled using non-linear mixed effects (NLME). Topiramate exposure 
(assessed by area under the curve (AUC)), as well as additional variables including apparent 
clearance, volume of distribution, and inter-individual variability will be estimated with popPK, 
described in Section 15.3. The effects association of topiramate exposure (AUC) on weight loss 
outcomes (BMI reduction, changes in eating behaviors and cardiometabolic risk labs) will be 
performed using linear regression with robust estimation for confidence intervals and p-values. 
We will also explore potential non-linear relationships with cubic splines. 
15.2 
Power Analysis:  
In line with the goals of this pilot study, our sample size was chosen to strike a balance between 
recruitment, feasibility, potential attrition, and the amount of data deemed necessary to inform 
the aims and design of a subsequent NIH R01. Results from previous simulations and statistical 
methods for repeated measures outcomes using sparse sampling in popPK suggest that bias and 
precision are acceptable as sample sizes approach 50.57-59 Assuming 25% drop-out, higher than 
usual for CPOM clinical trials (10-15%), we will recruit 65 participants. The power will depend on 
the range of values observed for the exposure predictor (AUC). Based on the variability observed 
from a pilot study of similar dose and age, and allowing for drop-out of as many as 15, we will 
have 80% power for an association of 4.75kg per 20 mcg*h/ml.60  
15.3 
Statistical Analysis:  
Pharmacokinetic Modeling (dose-exposure relationships): 
Topiramate concentrations will be modeled using a non-linear mixed effects (NLME) regression 

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implemented in NONMEM® (ICON Development Solutions, Ellicott City, MD). NLME is robust 
with respect to sparse data sets such as ours, hence appropriate for this analysis. Compartment 
models best describing topiramate will be selected based on diagnostic plots and fall in objective 
function values (OFVs). Covariates known to effect drug disposition (e.g. BMI, sex, race/ethnicity, 
genomics, as determined by a genetic risk score (GRS) will be included in the model-building 
algorithms. An automated stepwise covariate model (SCM) procedure will be used to screen 
covariates.31 The SCM involves forward selection and backward elimination steps: forward 
addition followed by backward deletion. Covariates that upon inclusion reduced the OFV by at 
least 3.84 (statistical significance of p<0.05, based on a Chi-squared distribution (degrees of 
freedom (df) = 1)), will be sequentially added. After stepwise addition of all significant covariates, 
backward deletion will be performed wherein removal of covariates that increase the OFV by at 
least 6.84 (statistical significance of p<0.01 based on a Chi-squared distribution (df = 1)), will be 
considered significant. Final model parameter estimates and their 95% confidence intervals will 
be qualified by re-estimation using a nonparametric bootstrap approach generating 1,000 
bootstrap datasets. Parameter estimates are rank ordered and the values at the 2.5% and 97.5% 
of the rank order are used as the lower and upper bounds of the bootstrap 95% confidence 
interval. The 50th percentile (median) is used as the bootstrap parameter estimate.31  
Pharmacodynamic Modeling (exposure-response relationships): 
The association of topiramate exposure (AUC) on weight loss outcomes (BMI reduction, changes 
in eating behaviors and cardiometabolic risk labs) will be performed using linear regression, 
adjusting for model covariates, with robust estimation for confidence intervals and p-values. We 
will also explore potential non-linear relationships utilizing cubic splines. 
15.4 
Data Integrity:  
Despite our best efforts, it is possible that some data will be missing, which could limit 
interpretation of the 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 use a last observation carried 
forward approach for participants on whom we do not have a final measurement. Observations 
obtained during interim visits will be used for these analyses, and additional sensitivity analyses.  
16.0 Health Information and Privacy Compliance 
16.1 
Select which of the following is applicable to your research: 
☐ My research does not require access to individual health information and 
therefore assert HIPAA does not apply.   
 
☒ I am requesting that all research participants sign a HIPCO approved HIPAA 
Disclosure Authorization to participate in the research (either the standalone 
form or the combined consent and HIPAA Authorization). 
☐ I am requesting the IRB to approve a Waiver or an alteration of research 
participant authorization to participate in the research. 

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Appropriate Use for Research: N/A 
☐ 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. 
16.2 
Identify the source of Private Health Information you will be using for your 
research (Check all that apply)   
☒ I will use the Informatics Consulting Services (ICS) available through CTSI 
(also referred to as the University's Information Exchange (IE) or data 
shelter) to pull records for me 
☒ I will collect information directly from research participants. 
☐ I will use University services to access and retrieve records from the Bone 
Marrow Transplant (BMPT) database, also known as the HSCT 
(Hematopoietic Stem Cell Transplant) database. 
☒ I will pull records directly from EPIC. 
☐ I will retrieve record directly from axiUm / MiPACS 
☐ I will receive data from the Center for Medicare/Medicaid Services  
☐ I will receive a limited data set from another institution  
☐ Other.  Describe: N/A 
16.3 
Explain how you will ensure that only records of patients who have agreed to 
have their information used for research will be reviewed.  
All participants in this study will be recruited directly from our PWMCs among patients who are 
receiving care by PWMC providers. Therefore, study staff will not have access to records of other 
individuals, including those who have not agreed to have their information used for research.   
16.4 
Approximate number of records required for review: >1,000 
16.5 
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.  
☒ 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.  

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Participants will receive telephone calls and emails regarding the study. The details of 
the telephone calls that this study requires is outlined in the consent forms. Emails that 
contain protected health information (PHI) will be sent to the participant/parent via a 
secure, encrypted manner.  
16.6 
Explain how the research team has legitimate access to patients/potential 
participants: This has been explained in other sections of the protocol.  
16.7 
Location(s) of storage, sharing and analysis of research data, including any links 
to research data (check all that apply).   
☒ In the data shelter of the Information Exchange (IE)  
 ☒ Store 
☐ Analyze 
☐ Share 
☐ In the Bone Marrow Transplant (BMT) database, also known as the HSCT 
(Hematopoietic Stem Cell Transplant) Database  
 ☐ Store 
☐ Analyze 
☐ Share 
☒ In REDCap (recap.ahc.umn.edu)  
 ☒ Store 
☒ Analyze 
☒ Share 
☐ In Qualtrics (qualtrics.umn.edu) 
 ☐ Store 
☐ Analyze 
☐ Share 
☒ In OnCore (oncore.umn.edu)  
 ☒ Store 
☐ Analyze 
☐ Share 
☒ In the University’s Box Secure Storage (box.umn.edu) 
 ☒ Store 
☒ Analyze 
☒ Share 
☐ In an AHC-IS supported server. Provide folder path, location of server and IT 
Support Contact: 
 ☐ Store 
☐ Analyze 
☐ Share 
☐ In an AHC-IS supported desktop or laptop.  
Provide UMN device numbers of all devices:  
 ☐ Store 
☐ Analyze 
☐ Share 
☐ Other. Describe:  
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 

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☐I will use a server not previously listed to collect/download research data 
☐I will use a desktop or laptop not previously listed 
☐I will use an external hard drive or USB drive (“flash” or “thumb” drives) not 
previously listed  
☐I will use a mobile device such as an tablet or smartphone not previously listed 
16.8 
Consultants. Vendors. Third Parties. N/A 
16.9 
Links to identifiable data:  
Absolute confidentiality will be maintained. All data will be stored in locked offices and will not 
be released without consent of participants. Blood samples that are sent to laboratories will be 
identified only by study identification number, never by name. Similarly, DNA samples both in 
CPOM and those sent to UMGC will be identified only be study identification, never by name.  
Data to be used in scientific presentations or publications will not contain participant identifiers. 
16.10 Sharing of Data with Research Team Members.  
Study team members will have access to UMN Box, RedCAP, OnCore, and the ACE-IE. 
16.11 Storage and Disposal of Paper Documents:  
All paper documents will be stored in locked offices and will not be released without participant 
consent.  
 
17.0 Confidentiality 
17.1 
Data Security:  
Absolute confidentiality will be maintained. All data will be stored in locked offices and will not 
be released without consent of participants. Blood samples that are sent to laboratories will be 
identified only by study identification number, never by name. Similarly, DNA samples both in 
CPOM and those sent to UMGC will be identified only be study identification, never by name.  
Data to be used in scientific presentations or publications will not contain participant identifiers. 
18.0 Provisions to Monitor the Data to Ensure the Safety of Participants 
18.1 
Data Integrity Monitoring. 
The study will undergo regular monitoring (at least annually) of the facility, staff, and study 
documents by clinical research associates in the University of Minnesota Clinical Trials 
Monitoring Service, which specializes in regulatory compliance for clinical trials associated with 
the FDA. 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. 

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18.2 
Data Safety Monitoring. 
An internal medical monitor (Dr. Eric Bomberg) will review all adverse events and serious adverse 
events regularly throughout the study. In addition, an independent (not involved in the study) 
external medical monitor (Dr. Brooke Sweeney) will review all serious adverse events regularly 
throughout the study. A data and safety monitoring board (DSMB) will be established, which will 
include at least one adult obesity medicine specialist or endocrinologist, one pediatric obesity 
medicine specialist or pediatric endocrinologist, and one biostatistician. DSMB members will not 
be affiliated with the study. The DSMB will meet regularly (frequency to be determined by DSMB 
members but no less than every six months) during the study to review data and evaluate 
participant safety.  
A charter for the DSMB will be developed and approved by its members along with a plan for 
frequency of data review prior to the commencement of the study. Review materials for the 
DSMB will be prepared and presented by the study biostatistician, Dr. Kyle Rudser. 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 assigned NIH 
Program Director and the IRB. Important charges of the DSMB will be to closely monitor progress 
and timelines related to recruitment goals, fidelity to the protocol (e.g. regularly review the 
number and types of protocol deviations), and to closely monitor the quality and integrity of the 
data. The DSMB will communicate any concerns relevant to these issues of study conduct to the 
PI and note specific recommendations for improvement in meeting reports.  
In the event that a participant has a serious adverse event that is deemed related to topiramate 
(this is an open-label study; all participants will receive topiramate) and/or procedures by either 
the internal or external medical monitor, the participant will be required to discontinue the 
intervention following the withdrawal procedures as outlined in Section 12.2. The overall study 
may be stopped at any time at the request of the PI, internal or external medical monitor and/or 
the DSMB. Participants may be removed from the study if suicidal ideation is present at any time 
during the trial or if any clinically significant changes (at the discretion of the internal or external 
medical monitor) in mood and/or depression are observed (see Section 5.2). Patients will be 
instructed that they may withdraw from the study at any time and for any reason. 
19.0 Provisions to Protect the Privacy Interests of Participants 
19.1 
Protecting Privacy:  
We understand that the decision to participate in clinical research is personal. Potential 
participants do not need to decide during a PWMC visit if they would like to participate in clinical 
research. During the PWMC visit, potential participants will be offered written information about 
the study and asked if it is okay for our study team to reach out for further details. Participants 
will be told that taking part in clinical research is not mandatory, and their participation in this 
study is entirely optional. See HIPCO ancillary review for further details. 
19.2 
Access to Participants: Please refer to the recruitment section.  
20.0 Compensation for Research-Related Injury 
20.1 
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 

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such injuries will be billed in the ordinary manner, to the participant or to their insurance 
company.  Participants will be encouraged to contact the study team if they think that they have 
suffered a research related injury. 
20.2 
Contract Language: N/A 
21.0 Consent Process 
21.1 
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 forms will be given to the participants and the parents/guardians. 
21.2 
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.  
21.3 
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.   
21.4 
Non-English Speaking Participants:  
We do not plan on enrolling non-English speaking participants at this time.  
21.5 
Participants Who Are Not Yet Adults (infants, children, teenagers under 18 
years of age): 
This study will enroll participants who are under the age of 18, and they will be asked to sign an 
IRB-approved assent form. Their parents/guardians will be asked to sign a parental consent form. 
Individuals who sign an assent form but turn 18 during the course of the study will be asked to 
sign a consent form and HIPAA to indicate that they are still willing to participate in the study 
once they reach the age of majority. A copy of the consent form will be given to the participant. 
21.6 
Cognitively Impaired Adults, or adults with fluctuating or diminished capacity to 
consent: N/A 
21.7 
Adults Unable to Consent: N/A 
22.0 Setting 
22.1 
Research Sites: University of Minnesota (CPOM, Delaware Clinical Research Unit 
(DCRU)) 
22.2 
International Research: N/A  
23.0 Multi-Site Research: N/A 
24.0 Coordinating Center Research: N/A 
25.0 Resources Available 

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25.1 
Resources Available:  
Funding to perform this study will be obtained from the National Institutes of Health as part of 
Dr. Bomberg’s K23 Career Development Award grant (DK125668: Precision Medicine Approaches 
to Obesity Pharmacotherapy in Youth with Severe Obesity).   
For this study, participants will primarily be recruited directly from our PWMCs by providers and 
support staff within the clinics. Our PWMCs have ≥3,000 patient visits a year, a number that has 
been increasing with the recent expansion of our clinical capacity and volume (four new obesity 
medicine specialists hired over the last few years; currently seven total providers). Further, well 
over 500 youth to date have been prescribed topiramate for weight management in our clinics, 
a number that is also increasing with our clinical expansion. In addition, CPOM providers an 
extremely strong recruitment and retention infrastructure, and has retained 85-90% of 
participants in prior pharmacotherapy trials that were far longer durations than the 3.5 months 
proposed in this study.61-63   
 
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