Role of Pharmacotherapy in Counteracting Weight Regain in Adolescents With Severe Obesity
Phase: PHASE2
Conditions: Obesity
Sponsor: University of Minnesota

MEDICAL PROTOCOL WLM-001 
PROTOCOL TITLE:  Role of Pharmacotherapy in Counteracting Weight Regain in 
Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
Page 1 of 63 
 
PROTOCOL COVER PAGE 
 
 
Protocol Title 
Role of Pharmacotherapy in Counteracting Weight Regain in 
Adolescents with Severe Obesity 
Principal 
Investigator 
Name: Aaron S Kelly, PhD 
Department: Pediatrics; Center for Pediatric Obesity Medicine 
Telephone Number: (612) 626-3492 
Email Address: kelly105@umn.edu 
Scientific 
Assessment 
Nationally-based, federal funding organizations 
IND/IDE # (if 
applicable) 
155563 
IND/IDE Holder 
Aaron Kelly, Ph.D. 
Investigational Drug 
Services # (if 
applicable) 
5604 
Version 
Number/Date: 
Version 23.0, 2025Mar27 
 

MEDICAL PROTOCOL WLM-001 
PROTOCOL TITLE:  Role of Pharmacotherapy in Counteracting Weight Regain in 
Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
Page 2 of 63 
 
 
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? 
The regulatory ancillary review will be 
assigned to your study by IRB staff 
Contact: medreg@umn.edu  
 
See: 
https://policy.umn.edu/research/indide  
☐ Yes 
☒ No 
Require Scientific Review? Not 
sure? See guidance on next 
page. 
 
Documentation of scientific merit must 
be provided.   
Contact: hrpp@umn.edu  
☐ Yes 
☒ No 
Relate to cancer patients, 
cancer treatments, cancer 
screening/prevention, or 
tobacco? 
Complete the CPRC application process.  
Contact: ccprc@umn.edu  
☒ Yes 
☐ No 
Include the use of radiation? 
(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  
Approval 
from these 
committees 
must be 
received 
prior to IRB 
approval;  
 
These 
groups 
each have 
their own 
application 
process.  
☐ Yes 
☒ No 
Use the Center for Magnetic 
Resonance Research (CMRR) 
as a study location? 
Complete the CMRR pre-IRB ancillary 
review  
Contact: ande2445@umn.edu  
☐ Yes 
☒ No 
Include the use of 
recombinant or synthetic 
nucleic acids, toxins, or 
infectious agents? 
Complete the IBC application via 
eprotocol.umn.edu 
Contact: 
☐ Yes 
☒ No 
Include the use of human fetal 
tissue, human embryos, or 
embryonic stem cells? 
Contact OBAO for submission 
instructions and guidance 

MEDICAL PROTOCOL WLM-001 
PROTOCOL TITLE:  Role of Pharmacotherapy in Counteracting Weight Regain in 
Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
Page 3 of 63 
 
☒ Yes 
☐ No 
 
Include PHI or are you 
requesting a HIPAA waiver? 
If yes, HIPCO will conduct a review of 
this protocol. 
Contact: privacy@umn.edu  
☒ Yes 
☐ 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  
Approval 
must be 
received 
prior to IRB 
approval. 
 
These 
groups do 
not have a 
separate 
application 
process but 
additional 
information 
from the 
study team 
may be 
required. 
 
☐ Yes 
☒ No 
Use the Biorepository and 
Laboratory Services to collect 
tissue for research? 
The BLS ancillary review will be 
assigned to your study by IRB staff. 
Contact: cdrifka@umn.edu  
☐ Yes 
☒ No 
Have a PI or study team 
member with a conflict of 
interest? 
The CoI ancillary review will be 
assigned to your study by IRB staff 
Contact: becca002@umn.edu  
☒ Yes 
☐ No 
Need to be registered on 
clinicaltrials.gov? 
If you select “No” in ETHOS, the 
clinicaltrials.gov ancillary review will be 
assigned to your study by IRB staff 
Contact: kmmccorm@umn.edu  
☒ Yes 
☐ No 
Require registration in 
OnCore? 
If you select “No” or “I Don’t Know” in 
ETHOS, the OnCore ancillary review will 
be assigned to your study by IRB staff 
Contact: oncore@umn.edu  
Does not 
affect IRB 
approval. 
 
 
 
 

MEDICAL PROTOCOL WLM-001 
PROTOCOL TITLE:  Role of Pharmacotherapy in Counteracting Weight Regain in 
Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
Page 4 of 63 
 
 
REVISION HISTORY 
 
Revision # 
Version Date 
Summary of Changes 
Consent Change? 
1 
2.0 
This protocol amendment adds the following 
items: 
• Adds a 400-meter walk test at four 
timepoints during the study; 
• Allows for test results to be shared with the 
parent upon request; 
• Adds a heart rate measurement at the 
Screening visit. 
 
This protocol amendment revises the following 
items: 
• 
Notes that the safety labs at the Screening 
visit do not need to be repeated if the 
Baseline visit occurs within 30 days of the 
Screening visit; 
• 
Revises the statistical section; 
• 
Revises the exclusion criteria; 
• 
Allows sexually active females to now be 
on one form of contraception; 
• 
Revises the Recruitment section; 
• 
Revises the Compensation section. 
 
This protocol amendment removes the 
ambulatory blood pressure monitoring in a 
subset of participants. 
Yes 
2 
3.0 
Based on feedback from the FDA this protocol 
amendment asks that participants who are 
sexually active to utilize two forms of 
contraception.  Monthly urine pregnancy tests 
will be required from females of childbearing 
potential.  Test kits will be supplied for 
conducting these at home for the timepoints 
where there is no planned in-person visit.  
Amendment also includes increasing the meal 
replacement phase daily calorie count to 1,200 
kcals and provision of a modest monetary 
incentive for completing the monthly lifestyle 
modification counseling sessions.   
Yes 
3 
4.0 
Revises the schedule of events and description 
of visits to note the activities that will take 
place on a monthly basis via telephone.  
  
Yes 
4 
5.0 
Makes revisions to the protocol based on 
suggestions from the FDA.  These changes 
include asking participants who can get 
pregnant to correctly and consistently utilize 
Yes 

MEDICAL PROTOCOL WLM-001 
PROTOCOL TITLE:  Role of Pharmacotherapy in Counteracting Weight Regain in 
Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
Page 5 of 63 
 
Revision # 
Version Date 
Summary of Changes 
Consent Change? 
two forms of contraception and documenting 
this at all visits (in person and telephone).  
Revises the protocol so that adverse events are 
collected starting at the Randomization visit.  
To review concomitant medications at all visits.  
To clarify that discontinuation of Qsymia for 
any reason should include a tapering regimen.  
To add heart rate collection at all study visits. 
We are also adding in payments to families for 
dropping off the urine samples 7 days after the 
baseline, randomization, week 26 and week 52 
visits for those participants who are 
randomized to receive the doubly labeled 
water for energy expenditure tests.  Changes 
the Week 8 visit to be an in-person visit so that 
dose titration of the study medication can 
occur.   Changes the IND holder of the record 
to Aaron Kelly. 
5 
6.0 
Updated the footnotes of the schedule of 
events 
No 
6 
7.0 
Removes the arterial stiffness and heart rate 
variability testing from the project.  Expands 
the recruitment to send out letters to 
individuals who are on the waiting list to be 
seen in the Pediatric Weight Management 
Clinic. 
Yes 
7 
8.0 
Provides safety clarifications regarding 
contraception and PHQ-9 questionnaire 
cutoffs.  Provides a Greenphire Clincard to 
parents who attend long visits (Screening, 
Baseline, Week 25 or Week 52) to help offset 
the cost of a meal. 
Yes 
8 
9.0 
Corrects the protocol to match the currently 
approved parental consent form, adult consent 
form and assent forms. 
No 
9 
10.0 
Study drug supply chain issues have been 
encountered.  This protocol revision will 
develop a plan for tapering doses if supply 
chain issues are not resolved in 3-6 months.  It 
also adds the risk of seizure information to the 
protocol. 
No 
10 
11.0 
Revises the total compensation section. 
Yes 
11 
12.0 
Adds the Minneapolis YWCA as a community 
partnership to section 10.0 of the protocol. 
No 
12 
13.0 
Revises who can conduct Tanner staging 
No 
13 
14.0 
Adds a hemoglobin A1c to be done at 
screening.  Updates the schedule of events and 
section 7.2 of the protocol. 
Yes 

MEDICAL PROTOCOL WLM-001 
PROTOCOL TITLE:  Role of Pharmacotherapy in Counteracting Weight Regain in 
Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
Page 6 of 63 
 
Revision # 
Version Date 
Summary of Changes 
Consent Change? 
14 
15.0 
Updates the schedule of events to note that 
study drug (for the down titration) will be 
dispensed at the Week 52 visit 
Yes 
15 
16.0 
Revises section 3.1 of the protocol to note that 
participants will be asked to strictly follow the 
eating regimen, which will include a total of 
approximately 1,200 kcals per day of 
commercially-available liquid shakes, pre-
packaged frozen entrée meals, two servings of 
fruit, and three servings of vegetables.  
Updates section3.1 for individuals who attend 
a school where no public microwave is 
available and offers a letter to be able to utilize 
a microwave. 
No 
16 
17.0 
Makes clarifications to the study exclusion 
criteria. 
No 
17 
18.0 
Notes that Qsymia is now approved for use in 
adolescents by the FDA. 
Yes 
18 
19.0 
Revises section 4.2 and 17.0 of the protocol to 
align with the new IRB guidance regarding 
suicide risk. 
Yes 
19 
20.0 
Makes revisions to the protocol based on an 
HRPP audit.  Revises sections 6.2 and 16.1 of 
the protocol to note that the analysis of 
samples conducted by a Fairview lab will be 
posted to the participant’s medical record and 
results from other laboratory analyses will not 
be shared.  Clarifies the study exclusion criteria 
(section 7.1 of the protocol) surrounding 
seizure disorders.  Revises the schedule of 
events to individually list tests that are to be 
performed to avoid staff confusion and 
updates the visit detail (this was not brought 
up by the HRPP audit team). 
Yes 
20 
21.0 
Revises section 4.2 and 12.0 of the protocol do 
clarify when comprehensive metabolic panels 
will be undertaken so that they match the 
schedule of events in the protocol.  Adds to 
section 4.2 that additional tests may be done if 
a safety issue is suspected. 
 
We are also revising the enrollment goal to 
about 100 individuals who consent, complete 
the screening visit, complete the baseline visit 
and start the meal replacement therapy 
portion of the project. 
Yes 
21 
22.0 
Revises section 1.1 of the protocol to review 
the history of the review and approval of the 
study drug by the FDA during the course of this 
project. 
Yes 

MEDICAL PROTOCOL WLM-001 
PROTOCOL TITLE:  Role of Pharmacotherapy in Counteracting Weight Regain in 
Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
Page 7 of 63 
 
Revision # 
Version Date 
Summary of Changes 
Consent Change? 
22 
23.0 
Removes use of the BRIEF from the schedule of 
events, and protocol sections 4.2, 7.2 and 12.1 
of the protocol.  Update section 12.1 of the 
protocol with regard to the instance of rash 
(seen in < 2% of patients).  
Yes 
 
 
 

MEDICAL PROTOCOL WLM-001 
PROTOCOL TITLE:  Role of Pharmacotherapy in Counteracting Weight Regain in 
Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
Page 8 of 63 
 
Table of Contents 
1.0 
Objectives .............................................................................................................. 10 
2.0 
Background ............................................................................................................ 11 
3.0 
Study Intervention(s)/Investigational Agent(s) ..................................................... 22 
4.0 
Procedures Involved .............................................................................................. 25 
5.0 
Data and Specimen Banking ................................................................................. 32 
6.0 
Sharing of Results with Participants ...................................................................... 32 
7.0 
Study Population ................................................................................................... 32 
8.0 
Vulnerable Populations ......................................................................................... 40 
9.0 
Local Number of Participants ................................................................................ 41 
10.0 
Local Recruitment Methods .................................................................................. 41 
11.0 
Withdrawal of Participants .................................................................................... 43 
12.0 
Risks to Participants .............................................................................................. 44 
13.0 
Potential Benefits to Participants ........................................................................... 48 
14.0 
Statistical Considerations ...................................................................................... 49 
15.0 
Health Information and Privacy Compliance ........................................................ 51 
16.0 
Confidentiality ....................................................................................................... 54 
17.0 
Provisions to Monitor the Data to Ensure the Safety of Participants .................... 54 
18.0 
Provisions to Protect the Privacy Interests of Participants .................................... 55 
19.0 
Compensation for Research-Related Injury .......................................................... 56 
20.0 
Consent Process ..................................................................................................... 56 
21.0 
Setting .................................................................................................................... 57 
22.0 
Multi-Site Research ............................................................................................... 57 
23.0 
Coordinating Center Research ............................................................................... 57 
24.0 
References ............................................................................................................. 58 
 

MEDICAL PROTOCOL WLM-001 
PROTOCOL TITLE:  Role of Pharmacotherapy in Counteracting Weight Regain in 
Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
Page 9 of 63 
 
ABBREVIATIONS/DEFINITIONS 
ACE-Q Teen 
Adverse Childhood Experiences Questionnaire-Teen 
ADHD 
Attention Deficit Hyperactivity Disorder 
AEBQ 
Adult Eating Behavior Questionnaire 
ALT 
Alanine Transaminase 
AST 
Aspartate Aminotransferase 
A-V 
Atrioventricular 
BMI 
Body Mass Index 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CEBQ 
Child Eating Behavior Questionnaire 
CI 
Confidence Interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CPT-II 
Connors Continuous Performance Test II 
CRF 
Case Report Form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTSI 
Clinical and Translational Science Institute 
DBP 
Diastolic Blood Pressure 
DEBQ 
Dutch Eating Behavior Questionnaire 
DHEAS 
Dehydroepiandrosterone 
DSMB 
Data and Safety Monitoring Board 
DXA 
Dual-Energy X-ray Absorptiometry 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone 
HDL 
High-Density Lipoprotein 
HOMA-IR 
Homeostatic Model Assessment of Insulin Resistance 
IDS 
Investigational Drug Service 
iDXA 
Intelligent Dual-Energy X-ray Absorptiometry 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IWQOL-Kids 
Impact of Weight on Quality of Life-Kids 
LDL 
Low-Density Lipoprotein 
LH 
Luteinizing Hormone 
MPH 
Mental Health Professional 
MN-POC 
Minnesota Pediatric Obesity Consortium 
mSv 
Millisievert 
NIDDK 
National Institute of Diabetes and Digestive Kidney Diseases 
NIH 
National Institutes of Health 
PAQ-A 
Physical Activity Questionnaire for Adolescents 
PedsQL 
Peds Quality of Life Questionnaire 
PHQ-9 
Patient Health Questionnaire 
PP 
Per protocol 
pQCT 
Peripheral Quantitative Computed Tomography 
QEWP-A 
Questionnaire on Eating and Weight Patterns 
RED-5 
Reward Based Eating Drive Scale 
SBP 
Systolic Blood Pressure 
SOC 
Standard of Care 
TSH 
Thyroid Stimulating Hormone 
UPIRTSO 
Unanticipated Problem Involving Risk to Subjects or Others 
U.S. 
United States 
VO2-max 
The maximum volume of oxygen consumed by the body each minute 
during exercise while breathing air at sea level 
 
 

MEDICAL PROTOCOL WLM-001 
PROTOCOL TITLE:  Role of Pharmacotherapy in Counteracting Weight Regain in 
Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
Page 10 of 63 
 
 
1.0 
Objectives 
1.1 Purpose: 
Long-term weight loss maintenance is seldom achieved by individuals with 
obesity owing to numerous biological adaptations occurring in the post-
weight loss setting, including neuroendocrine-mediated changes in 
appetite/satiety and reduction of energy expenditure.  Following weight 
loss, peripheral and central mechanisms respond in a way similar to 
starvation by conveying a sense that energy reserves have dwindled, 
activating a strong counter-response to increase caloric intake.  Moreover, 
metabolic rate drops, further compounding the propensity for weight 
rebound.  Adolescents with severe obesity are not immune to the vexing 
issue of weight regain; therefore, effective and scalable treatments are 
urgently needed.  Pharmacotherapy has the potential to prevent weight 
regain by targeting counter-regulatory mechanisms in the post-weight loss 
setting. The combination of phentermine and topiramate was approved by 
the US FDA for the treatment of obesity in children 12 and older on 
27Jun2022. However, this study was enrolling participants before that 
approval and its use was considered experimental.  For participants who 
enrolled in the study after 27Jun2022, this research falls within the approved 
parameters for use. The mechanisms of action are thought to reduce 
appetite, enhance satiety, and potentially increase energy expenditure, 
making this medication particularly well-suited for the purpose of weight 
loss maintenance since it targets many of the biological adaptations known 
to induce relapse and subsequent weight regain.  Our group has generated 
preliminary data demonstrating that both phentermine and topiramate 
reduce BMI in adolescents with severe obesity and have acceptable safety 
profiles. 
 
In 
this 
clinical 
trial, 
we 
will 
utilize 
combination 
phentermine/topiramate to target counter-regulatory pathways responsible 
for weight regain after meal replacement therapy (structured meals of 
known caloric content) in adolescents with severe obesity with a goal of 
enhancing weight loss maintenance and improving obesity-related 
complications.  Importantly, we will maximize the clinical utility and overall 
impact of our study by comprehensively characterizing the safety of 
phentermine/topiramate (cognition and bone health) as well as examine the 
extent to which this medication counteracts mechanisms of weight regain. 
 
 

MEDICAL PROTOCOL WLM-001 
PROTOCOL TITLE:  Role of Pharmacotherapy in Counteracting Weight Regain in 
Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
Page 11 of 63 
 
 
2.0 
Background 
2.1 Significance of Research Question/Purpose:  
Severe obesity, afflicting ~8% of adolescents in the U.S., is a serious and 
challenging medical and public health problem.1,2  The number and levels of 
cardiovascular risk factors are considerably higher in the context of severe 
obesity compared to milder forms of obesity.3  Approximately 85% of youth 
with severe obesity have ≥1 cardiovascular risk factor.4  Non-alcoholic fatty 
liver disease is highly-prevalent among adolescents with severe obesity with 
estimates nearing 60%.5  Subclinical atherosclerosis and arterial stiffening is 
present in youth with severe obesity at levels similar to those with type 2 
diabetes.6  Youth with severe obesity have high levels of inflammation and 
oxidative stress,7 adverse adipokine profiles,8 and arterial endothelial 
activation.9  Moreover, longitudinal data implicate obesity in childhood as a 
strong predictor of future risk factor clustering and sub-clinical 
atherosclerosis in adulthood.10-12  Risk of developing type 2 diabetes is high 
in youth with severe obesity.13-15  Severe obesity in adolescence is associated 
with chronic disability from a wide range of causes later in life.16  Perhaps 
most disturbing is the poor long-term prognosis for these youth.  
Approximately 90% will have a BMI ≥35 kg/m2 in adulthood.4 Disturbingly, 
severe obesity in adulthood reduces life expectancy by 7-14 years.17   
 
In the field of obesity management, weight loss maintenance has proven to 
be an arduous challenge.  Indeed, long-term weight loss maintenance is 
seldom achieved owing to numerous biological adaptations occurring in the 
post-weight loss setting.  These include, but are not limited to, 
neuroendocrine changes in the gut-brain axis influencing appetite and 
satiety and reduction of energy expenditure.18-20  Following weight loss, 
peripheral and central mechanisms respond in a way similar to starvation by 
conveying a sense that energy reserves have dwindled, activating a strong 
and persistent counter-response to increase caloric intake.19  Moreover, 
metabolic rate decreases, further compounding the propensity for weight 
rebound.18  These counter-regulatory adaptations persist for many years 
following initial weight loss, and in fact might be permanent.20,21   
 
Adolescents with severe obesity (BMI ≥120% above the 95th percentile or 
BMI ≥35 kg/m2) are not immune to the vexing issue of weight regain as 
evidenced by the poor outcomes of interventions using lifestyle modification 
alone.22-25 Indeed, large clinic-based studies from Europe and the U.S. 
reported that only a small fraction of patients were able to achieve and 
maintain clinically-meaningful weight loss with lifestyle modification 

MEDICAL PROTOCOL WLM-001 
PROTOCOL TITLE:  Role of Pharmacotherapy in Counteracting Weight Regain in 
Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
Page 12 of 63 
 
therapy.22,26  Metabolic/bariatric surgery is an effective treatment27 but 
uptake is very low28 and many pediatricians and parents are concerned 
about the irreversible nature of this treatment and worry about the 
possibility of long-term (decades) risks, which are currently unknown.  
Therefore, a large treatment gap exists between lifestyle modification 
therapy and metabolic/bariatric surgery that remains unfilled. 
 
Pharmacotherapy has the potential to prevent weight regain by targeting 
counter-regulatory mechanisms in the post-weight loss setting, with various 
agents demonstrating improved long-term weight loss durability in adults.29-
32 Until recently, orlistat was the only FDA-approved anti-obesity medication 
for adolescents but it is rarely prescribed because of modest efficacy and 
notable side effects.33 The combination of phentermine and topiramate is 
an attractive option owing to its relatively high degree of efficacy compared 
to other medications.32  The combination of phentermine/placebo (under 
the name Qsymia) was approved in June 2022 for adolescents, after our 
study had been started.  Placebo-subtracted weight loss at one and two 
years with phentermine/topiramate is 9% at the top dose in adult trials.34-36 
The mechanisms of action of phentermine/topiramate, which together are 
thought to reduce appetite, enhance satiety, and potentially increase energy 
expenditure, are well-suited for the purpose of weight loss maintenance 
since they target many of the biological adaptations known to induce relapse 
and subsequent regain. 18-20   
 
The rationale for specifically focusing on phentermine/topiramate (vs. other 
medications) to prevent weight regain is supported by its multiple 
mechanisms of action, which are thought to target many of the post-weight 
loss counter-regulatory biological adaptations known to induce relapse.  
These mechanisms include: 1) reducing appetite through inhibition of 
norepinephrine reuptake (phentermine) and reduction of hypothalamic 
glutamate neurotransmission (topiramate) and lowering the levels of 
neuropeptide Y (topiramate); 2) enhancing satiety by slowing gastric 
emptying (combination of phentermine/topiramate); and 3) increasing 
energy expenditure (both phentermine and topiramate independently).37-43  
Through these mechanisms of action, sustained weight loss has been 
demonstrated with phentermine/topiramate treatment in adults.44  While 
other obesity medications target some of these pathways, their respective 
mechanisms of action are generally less comprehensive, and accordingly 
have lower efficacy, ranging from 3-5% placebo-subtracted weight reduction 
at 1 year.45  
 

MEDICAL PROTOCOL WLM-001 
PROTOCOL TITLE:  Role of Pharmacotherapy in Counteracting Weight Regain in 
Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
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In terms of safety, topiramate is FDA-approved in children and adolescents 
for the treatment of seizures and migraine headaches with a reasonable 
safety track-record.  Importantly, we observed no signal of cognitive 
problems in a pilot clinical trial of topiramate for the treatment of obesity.  
Phentermine is FDA-approved for short-term use in ages >16 years old for 
treatment of obesity and is the most widely-prescribed adult obesity 
medication in the U.S.46 And, the combination of phentermine/topiramate 
was recently FDA-approved for the treatment of adolescent obesity.  
Although in a distinct medication class, phentermine is not dissimilar in 
mechanism of action and side effects to many of the stimulant medications 
widely-prescribed for the treatment of ADHD in youth.  Adult data suggest 
no adverse cardiovascular effects or increased risk of addiction potential or 
withdrawal symptoms associated with phentermine use,47,48 and our clinical 
experience with phentermine in adolescents with obesity demonstrated an 
acceptable safety profile.49   
 
2.2 Preliminary Data:  
We present preliminary data demonstrating that phentermine and 
topiramate reduce BMI as respective monotherapies and to a greater degree 
in combination, and have acceptable safety profiles.  Moreover, we and 
others have shown that although meal replacement therapy (structured 
meals of known caloric content) can elicit robust short-term weight loss (6% 
BMI reduction over a few months) in adolescents with severe obesity, weight 
regain is a pervasive problem.50  Therefore, in this clinical trial, we propose 
to combine these interventions in a chronological fashion and utilize 
phentermine/topiramate to target counter-regulatory pathways thought to 
be responsible for weight regain following meal replacement therapy in 
youth with severe obesity.  Participants achieving ≥5% BMI reduction with 
short-term (six weeks) use of meal replacements will be randomized (1:1) to 
phentermine/topiramate or placebo for an additional 52 weeks while 
simultaneously engaging in lifestyle modification therapy.  Based on adult 
outcomes with phentermine/topiramate36, 44 and expected weight regain in 
the placebo group,50 we anticipate a mean placebo-subtracted BMI 
reduction of 8-10% at 52 weeks, a level considered clinically-meaningful in 
adolescents.51    
 
Importantly, this study will also allow us to further investigate the safety of 
phentermine/topiramate.  We will perform in-depth and extensive 
physiological assessments to provide pediatricians with the information they 
need to make a balanced judgement of the benefits/risks of 
phentermine/topiramate treatment for obesity.  The safety-related 

MEDICAL PROTOCOL WLM-001 
PROTOCOL TITLE:  Role of Pharmacotherapy in Counteracting Weight Regain in 
Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
Page 14 of 63 
 
rationale for combination pharmacotherapy is that lower doses of the 
individual constituent medications can be used, which might minimize side 
effects.  However, to our knowledge, no combination medications have yet 
been tested in the pediatric population in a randomized, placebo-controlled 
safety/efficacy trial.     
 
Lastly, we have aimed to maximize the impact of our trial by characterizing 
the mechanisms of action of phentermine/topiramate, uniquely in the 
context of weight loss maintenance, to begin to uncover clues about the 
types of patients most likely to benefit from treatment.  Visual analog scales 
and standardized eating behavior questionnaires will allow us to track and 
quantify changes in appetite and satiety.  Serial assessment of resting 
metabolic rate (via indirect calorimetry) and total energy expenditure (via 
doubly-labeled water in a subset of participants) will elucidate the degree to 
which phentermine/topiramate offsets the counterproductive increase in 
energy efficiency often observed in the context of weight loss.  Although 
hypothesis-generating, results will provide a framework for the design of 
future studies with targeted hypotheses addressing response prediction.  
For example, we may find that patients reporting high levels of appetite and 
poor satiety at baseline respond the most favorably to treatment and/or 
those with the largest initial decrease in resting metabolic rate and/or total 
energy expenditure benefit most in regard to weight loss maintenance.  
Indeed, precision medicine has been identified by the NIH as a high priority 
area for adolescent severe obesity.52   
 
Short-Term Weight Loss with Meal Replacements in Adolescents with Severe 
Obesity 
Meal replacement therapy is an effective short-term treatment for obesity.  
Meta-analyses of adult obesity studies have shown that meal replacements 
reduce body weight to a greater extent than conventional diets.53,54 The 
rationale for the use of meal replacements is that individuals with obesity, 
particularly adolescents,55 often underestimate caloric intake; adherence to 
a strict, predetermined meal regimen removes the “guesswork” from eating.  
Berkowitz et al.50 demonstrated promising short-term weight loss efficacy 
(BMI reduction of ~6%) in adolescents with severe obesity using meal 
replacements for a period of four months.  Despite the positive short-term 
effectiveness, weight regain ensued in most participants.50 Therefore, meal 
replacement therapy appears to be an effective “kick-start” for weight loss; 
however, longer-term outcomes could likely be enhanced with subsequent 
treatments that mitigate the counter-regulatory biological adaptations 
favoring weight regain (i.e., a tool offering individuals a fighting chance to 
keep the weight off).  We conducted an unpublished clinical trial in 

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Adolescents with Severe Obesity 
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adolescents with severe obesity that included a two-month meal 
replacement induction period.  Out of 39 participants, 28 (72%) successfully 
achieved a 5% BMI reduction benchmark.  These results provide evidence of 
the success of short-term meal replacement therapy in our hands and offer 
guidance for the design of the proposed clinical trial (we anticipate 
approximately 70% will achieve the 5% BMI reduction goal).   
 
Table 1 (below) summarizes the mean changes in BMI, body fat percentage, 
select cardiometabolic risk factors, resting metabolic rate, and liver fat 
(expressed as hepatic fat fraction) in participants who were able to reduce 
their BMI by ≥5% during the meal replacement phase of our above-
mentioned unpublished study (and on whom we had complete follow-up 
data, N=26).  Again, our goal in the currently-proposed trial is to evaluate the 
utility of pharmacotherapy in targeting the counter-regulatory pathways 
responsible for weight regain in an effort to “hold the line” on weight loss 
(and improvements in obesity related complications) and ideally further 
enhance it after short-term meal replacement therapy.  In other words, we 
want to sustain and further enhance these benefits. 
 
Table 1.  Mean Changes in BMI, Body Fat, Cardiometabolic Risk Factors, and 
Metabolic Rate 
 
 
 
 
Existing Literature:  
Systematic Clinical Experience with Phentermine Monotherapy in 
Adolescents with Severe Obesity 
In this published retrospective study, we reported on the change in BMI and 
adverse events among adolescents engaging in lifestyle modification 
therapy only (standard of care: SOC) and phentermine monotherapy + SOC 
in our pediatric weight management program where standard protocols for 
phentermine treatment have been implemented.49  
 
Sample Size
Measure
Baseline (SD)
Post-MR (SD)
% change
p-value (paired t-test)
n=26
BMI (kg/m2 )
40.1 (4.0)
37.9 (3.9)
-5.6
<0.001
n=26
Body Fat (%)
48.9 (4.3)
47.9 (5.0)
-2.1
<0.001
n=26
SBP (mmHg)
121 (9)
118 (9)
-2.7
0.032
n=26
TG (mg/dL)
106 (56)
92 (34)
-12.6
0.04
n=26
HDL (mg/dL)
40 (7)
39 (21)
-1.1
0.909
n=26
Insulin (uU/mL)
15 (10)
10 (5)
-33.8
0.02
n=26
RMR (kcal/day)
2059 (365)
1939 (355)
-5.9
0.006
n=10
HFF (%)
11.3 (8.1)
8.3 (7.1)
-27.0
0.027
Abbreviations: BMI = Body mass index; SBP = Systolic blood pressure; TG = Triglyceride; HDL= High-density 
lipoprotein cholesterol; RMR = Resting metabolic rate; HFF = hepatic fat fraction

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We identified 25 patients (mean age 16.1±1.3 years; mean BMI 41.2±6.9 
kg/m2) prescribed phentermine (15 mg/day) + SOC and a comparison group 
of 274 patients matched on age and BMI receiving only SOC.  Phentermine 
treatment was associated with a greater percent change in BMI at one 
month (-1.6% [95% CI (-2.6%, -0.6%); p=0.001), three months (-2.9% [95% CI 
(-4.5%, -1.4%); p<0.001]) and six months (-4.1% [95% CI (-7.1%, -1.0%); 
p=0.009]).  At three months, 40% of the phentermine group achieved ≥5% 
BMI reduction vs. 8.8% in the SOC group; at 6 months, this increased to 
63.6% of the phentermine group vs. 20.8% in the SOC group. 
 
Since publishing this paper, we have updated the analysis with additional 
patients and have slightly expanded the window of follow-up at the six-
month time-point.  We identified 29 patients (mean age 15.8±1.6 years; 
mean BMI 40.7±7.1 kg/m2) prescribed phentermine (15 mg/day) + SOC and 
a comparison group of 920 patients matched on age and BMI receiving only 
SOC.  Phentermine treatment was associated with a greater percent change 
in BMI at one month (-1.7% [95% CI (-2.6%, -0.8%); p<0.001), three months 
(-2.9% [95% CI (-4.1%, -1.7%); p<0.001]) and six months (-3.5% [95% CI (-
5.8%, -1.2%); p=0.004]).  At three months, 36% of the phentermine group 
achieved ≥5% BMI reduction vs. 3.6% in the SOC group; at six months, this 
increased to 57.9% of the phentermine group vs. 6.8% in the SOC group.  
Importantly, there were no statistically- or clinically-significant differences in 
systolic or diastolic blood pressure in the phentermine group. Moreover, 
adult data suggest no increased risk of addiction potential or withdrawal 
symptoms associated with phentermine use.5   
 
Figure 1. Change in BMI with Phentermine vs. Standard of Care 
 
 

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Systematic Clinical Experience with Topiramate Monotherapy in Adolescents 
with Severe Obesity 
In this retrospective study, we reported on the change in BMI and adverse 
events among adolescents prescribed topiramate monotherapy (according 
to our standardized clinical protocol) and lifestyle modification therapy in 
our pediatric weight management program.56 Twenty-eight patients (mean 
age 15.2 ± 2.5 years; mean baseline BMI 46.2 ± 10.3 kg/m2) who were 
prescribed doses of topiramate ranging from 75 to 100 mg daily, were 
included in the analysis.  The six-month percent change in BMI was −4.9, 
[95% confidence interval (−7.1, −2.8), P < 0.001].  At six months, 50% of the 
patients experienced at least 5% reduction in BMI from baseline.  
Intermittent paresthesia (tingling in the extremities) was reported in 2/28 
(7%).  No other adverse events/side effects were reported (including no 
reports of cognitive dulling).  These preliminary results suggest that 
topiramate is associated with clinically-meaningful BMI reduction with a 
reasonable and acceptable safety profile. 
 
A Pilot, Randomized, Placebo-Controlled Trial of Topiramate for Weight Loss 
Maintenance 
We conducted a randomized, placebo-controlled pilot clinical trial 
evaluating the preliminary efficacy and safety of topiramate following short-
term meal replacement therapy in adolescents with severe obesity.57 
Participants completed four weeks of meal replacement therapy followed by 
24 weeks of treatment with either topiramate 75 mg/day or placebo.  Thirty 
adolescents (mean age 15.2 ± 1.7 years, mean BMI 40.3 ± 4.6 kg/m2) 
completed the meal replacement phase and were randomized; 21 
completed the study.  The difference in mean percent change in BMI 
between the topiramate and placebo groups did not reach statistical 
significance (-1.9% [95% CI (-5.2%, +1.5%); P=0.291]).  We learned from this 
trial that the dose of topiramate used (75 mg/day) was probably too low and 
that monotherapy may be insufficient in this population – ultimately setting 
the stage for our plans to evaluate topiramate at a higher dose (92 mg/day) 
and in combination with phentermine (15 mg/day).   
 
Importantly, our primary areas of focus in this pilot trial were safety, 
tolerability, and acceptability.  We employed a comprehensive panel of 
questionnaires and computer-based tests pre and post including: Cambridge 
Neuropsychological Test Automated Battery (CANTAB) (a computerized test 
of motor speed, memory, and attention), and the Connors Continuous 
Performance Test II (CPT II) (a computerized measure of attention and 
impulsivity).  Bone density and geometry were assessed with peripheral 
quantitative computed tomography (pQCT) and DXA.   

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The most common adverse event was paresthesia (tingling in the 
extremities), reported by 25% in the topiramate group and none in the 
placebo group.  Table 2 summarizes the neurocognitive safety results.  There 
were no statistically- or clinically-significant differences between the 
topiramate and placebo group on any of the CANTAB subscales.  For the CPT 
II, only the hit reaction time was different indicating a faster reaction time in 
the topiramate group compared with placebo.  No statistically- or clinically-
significant changes in bone health were observed.  None of the participants 
withdrew due to experiencing adverse events.57  
 
Table 2. Change in Neurocognitive-Related Safety Variables from Randomization to 
24 Weeks 
 
 
These preliminary data suggest that the side effect profile of topiramate is 
acceptable in adolescents.  Although the treatment effect was relatively 
modest, as shown below we expect superior efficacy with combination 
therapy as demonstrated in adults, with additive benefit when phentermine 
is co-administered.  
 
Treatment Effect of Phentermine/Topiramate in Adults 
Phentermine/topiramate was approved by the FDA in 2012 for the 
treatment of obesity in adults.  This orally-administered medication is 
available in mid- (phentermine 7.5 mg; topiramate 46 mg) and high- 
(phentermine 15 mg; topiramate 92 mg) doses, administered once per day.  
In a meta-analysis, phentermine/topiramate was shown to be the most 
effective obesity medication currently available.34 A large dose-ranging trial 
in adults evaluating phentermine and topiramate as monotherapies vs. 
phentermine/topiramate 
demonstrated 
superior 
efficacy 
of 
the 
combination with an acceptable safety profile.58  
 

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Results from a large phase III clinical trial demonstrated placebo-subtracted 
weight loss of >9% with treatment for one year at the top dose.18 Importantly, 
a separate trial demonstrated that the treatment effect is durable out to at 
least two years.35 The most common side effects in these trials were 
paresthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth.  
Improvements were noted in blood pressure, lipids, glucose, insulin, HOMA-
IR, C-reactive protein, and adiponectin. 
 
Figure 2. Percent Body Weight Loss with Phentermine/Topiramate in Adults with 
Severe Obesity 
 
 
 
 
Systematic Clinical Experience with Phentermine/Topiramate Combination 
Therapy in Adolescents with Severe Obesity: Preliminary Safety, Tolerability, 
and Acceptability (unpublished data) 
We performed a chart review of patients treated with phentermine and 
topiramate within our pediatric weight management clinic.  Our healthcare 
providers carefully and systematically assess and document adverse events 
with obesity pharmacotherapy at all follow-up visits according to established 
protocols.  We identified 55 patients (37 females/18 males) ages 11-20 years 
old (mean age 15.4±2.3 years) with a baseline mean BMI of 43.2±10.2 kg/m2.  
The most commonly-prescribed doses were 15 mg/day of phentermine and 
75-100 mg/day of topiramate.  The mean duration of combination treatment 
was 11.1±10.3 months. Owing to variability regarding how these 
medications were prescribed in the clinic, we do not report on changes in 
BMI.  In other words, many patients were started on either phentermine or 
topiramate monotherapy followed by the addition of the other medication 
at a later time-point.  Table 3 summarizes: 1) the incidence of the most 

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Adolescents with Severe Obesity 
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commonly-reported adverse events; 2) the percent of patients experiencing 
resolution of the adverse event(s) while remaining on treatment; and 3) the 
percent of patients that discontinued treatment as a result of the adverse 
event(s).  Overall, results demonstrated a low incidence of adverse events 
with a relatively high rate of resolution.  Importantly, only a small percentage 
of the patients discontinued therapy as a result of adverse events.  
Therefore, these results provide preliminary evidence supporting the safety 
of these medications and demonstrate a reasonably high level of 
acceptability and tolerability in the adolescent population. 
 
Table 3. Adverse Events, Resolution, and Acceptability of Phentermine/Topiramate 
Treatment 
Adverse Event 
Description 
Overall Percent 
Affected 
Percent Resolution (of 
those affected) 
Overall Percent Discontinued 
Owing to Adverse Event 
Jittery/Shaky 
3.6% 
100% 
0% 
Moody/Irritable 
10.9% 
83% 
1.8% 
Difficulty Sleeping 
1.8% 
100% 
0% 
Dizziness 
1.8% 
100% 
0% 
Headache 
3.6% 
50% 
1.8% 
Paresthesia 
10.9% 
100% 
0% 
Cognitive Dulling 
5.4% 
66.7% 
1.8% 
Tachycardia 
1.8% 
0% 
1.8% 
 
Preliminary Safety and Efficacy of Phentermine/Topiramate in Adolescents 
with Obesity (unpublished data) 
The manufacturer of phentermine/topiramate recently completed a 
pharmacokinetic trial among adolescents (12-17 years old) with obesity (BMI 
≥95th percentile) and shared the results with our group.  Here we report on 
participants that were randomized to either placebo (N=14; 9 females) or 
high-dose phentermine/topiramate (15 mg/92 mg) (N=13; 9 females) and 
received treatment for 56-days.  In brief, pharmacokinetic results were 
similar to adults.  In aggregate, adverse events were experienced by 50% of 
the placebo group and 77% of the phentermine/topiramate group.  Details 
of the adverse events are shown in Table 4. 
 
 

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Table 4. Adverse Events of Phentermine/Topiramate Treatment in Adolescents with 
Obesity 
Adverse Event Description 
Placebo Group (%) 
Phentermine/Topiramate Group (%) 
Dry Mouth 
0% 
8% 
Abdominal Pain 
0% 
0% 
Constipation 
0% 
0% 
Diarrhea 
0% 
0% 
Ear Infection 
0% 
0% 
Nasopharyngitis 
7% 
0% 
Pharyngitis 
0% 
0% 
Procedural Pain 
7.1% 
0% 
Urine Osmolarity Increase 
0% 
0% 
Back Pain 
0% 
0% 
Headache 
21% 
15% 
Paresthesia 
7% 
31% 
Dizziness 
7% 
0% 
Insomnia 
7% 
0% 
Oropharyngeal Pain 
7% 
0% 
 
At 56 days, the percent change in body weight was +1.1±2.8% in the placebo 
group and -5.0±3.4% in the phentermine/topiramate group (placebo-
subtracted weight loss of 6.1%).  Owing to the relatively small sample size 
and the fact that weight reduction was a secondary outcome variable, the 
manufacturer did not perform a statistical analysis on these results.  
However, the preliminary results further support our estimated treatment 
effect, particularly considering the treatment period was only two months 
(56 days).  Indeed, the degree of placebo-subtracted weight loss was slightly 
better than what was observed in the adult trials at the two-month time-
point, suggesting that the effects are at least additive when these two 
medications are used together. 
 
In summary, this portfolio of preliminary work: 1) demonstrates our Center’s 
leadership role in, and commitment to, the field of pediatric obesity 
medicine; 2) highlights the benefits (short-term weight loss and 
cardiometabolic risk factor improvement) and limitations (long-term weight 
regain) of meal replacement therapy as well as our experience with this 
intervention; 3) provides preliminary evidence of the safety/efficacy of 
phentermine and topiramate monotherapy in the target population; 4) 
demonstrates the clinically-meaningful weight loss efficacy and safety 
profile of phentermine/topiramate combination therapy in adults; 5) 
provides preliminary evidence supporting the safety, efficacy, and 
acceptability 
of 
phentermine/topiramate 
combination 
therapy 
in 
adolescents with severe obesity; and 6) sets the stage for taking this next 
important step.  
 
 

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2.3 Primary Endpoint/Event/Outcome:  
• To evaluate the effects of phentermine/topiramate on weight loss 
maintenance and cardiometabolic risk factor improvements in 
adolescents (12 to <18 years old) with severe obesity.  We 
hypothesize that following initial BMI reduction with meal 
replacement 
therapy, 
52 
weeks 
of 
treatment 
with 
phentermine/topiramate vs. placebo will not only sustain, but 
further enhance reductions in BMI (primary endpoint), total body- 
and visceral-fat, cardiometabolic risk factors, inflammation, and 
oxidative stress. 
 
2.4 Secondary Endpoint(s)/Event(s)/Outcome(s):  
• Perform a comprehensive panel of in-depth physiological 
assessments to characterize the safety of phentermine/topiramate.  
Phentermine/topiramate will have an acceptable safety profile, 
demonstrating no statistically significant or clinically-meaningful 
differences from placebo in heart rate, blood pressure, cognition, 
mental health, or bone health. 
• Investigate mechanisms of action of phentermine/topiramate in 
counteracting biological forces favoring weight gain.  Compared to 
placebo, phentermine/topiramate will reduce appetite, enhance 
satiety, and increase resting and total energy expenditure. 
 
3.0 
Study Intervention(s)/Investigational Agent(s) 
3.1 Description:  
Lifestyle Modification/Behavioral Therapy and Counseling 
All participants, regardless of drug/placebo assignment, will receive the 
same lifestyle/behavioral modification counseling monthly throughout the 
entire study: delivered at each in-person study visit and on the phone for 
months when there is no study visit.  The lifestyle/behavioral modification 
curriculum has been adapted from the NIDDK-sponsored TODAY study 
lifestyle modification program materials59 and is based on principles detailed 
in U.S. Preventive Services Task Force screening recommendation statement 
and utilized by our group in a previous60 and ongoing trials.  Trained study 
coordinators will deliver the lifestyle/behavioral modification counseling, 
which will focus on small, successive changes in dietary physical activity 
behaviors through the use of evidence-based behavior change strategies 
such as self-monitoring, goal setting, reinforcement for goal achievement, 
stimulus control, social support, problem solving, and motivational 
techniques.  Selected sections of the educational materials will be reviewed 
and discussed at each face-to-face and phone-based lifestyle modification 

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counseling session.  We have demonstrated the effectiveness of this lifestyle 
modification protocol in a randomized, placebo-controlled trial among 
adolescents with severe obesity.60 To maximize generalizability and the 
interpretability of the findings, the frequency and intensity is intentionally 
designed to be practical, feasible and mimic the type and frequency of 
lifestyle counseling common to the clinic setting in pediatric weight 
management programs in the U.S.   
 
Meal Replacement Induction Period 
All participants will engage in a meal replacement induction period for six 
weeks with a goal of reducing individual BMI by at least 5%.  Our group has 
experience successfully utilizing a similar meal replacement protocol in the 
target population as evidenced by over 70% of the adolescents with severe 
obesity in an unpublished study having achieved ≥5% BMI reduction in up to 
two months (as detailed in the preliminary data section).  Berkowitz et al. 
have also demonstrated the utility of meal replacement therapy in 
adolescents with severe obesity.50 Participants will be asked to strictly follow 
the eating regimen, which will include a total of approximately 1,200 kcals 
per day of commercially-available liquid shakes, pre-packaged frozen entrée 
meals, two servings of fruit, and three servings of vegetables.  Shakes/meals 
will be provided free of charge – fruits/vegetables will be purchased by the 
participants.  Guidance will be provided regarding the use of the meal 
replacement shakes or frozen entrees at school, and participants will be 
encouraged to engage in family meal sessions despite eating different foods.  
Participants who attend a school that does not have a microwave available 
for student use will be offered a letter to provide to the school so that they 
can make use of a microwave. 
 
Medication and Placebo Administration, Dosing, and Compliance 
Participants will be randomized (1:1) to phentermine/topiramate or placebo 
immediately following the meal replacement induction period (if successful 
in achieving ≥5% BMI reduction within the allotted six weeks).  Participants 
randomized to phentermine/topiramate will initiate treatment at 3.75 
mg/23 mg orally once daily in the morning for 14 days, which will then be 
increased to 7.5 mg/46 mg orally once daily in the morning for 14 days, 
which will then be increased to 11.25 mg/69 mg orally once daily in the 
morning for 14 days, which will then be increased to 15 mg/92 mg orally 
once daily in the morning for the remainder of the trial.  Participants unable 
to tolerate the dosing regimen will be maintained at the maximally tolerated 
dose.  All participants will undergo the same dose escalation process 
(although actual doses will vary by assignment) to maintain the blind nature 
of the design.  Following the final study visit, all participants (including those 

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Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
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assigned to placebo) will be down-titrated gradually by taking medication 
every other day for seven days before stopping treatment altogether.  Vivus 
Pharmaceuticals will donate phentermine/topiramate and placebo.  Trial 
product will be managed by the University of Minnesota Investigational Drug 
Service Pharmacy.  Participants will be instructed to take the medication 
under the supervision of a parent/guardian and pill counts of returned 
product will serve as a proxy of treatment compliance.   
 
 
 
Study drug supply chain issues were identified in December of 2021.  The 
impact of this at our site is that we do not have enough of the full dose of 
Qsymia (15 mg/92 mg) at this time and we have limited supply of the ¾ 
dose (11.25 mg/69 mg).  The manufacturer believes that supply chain 
issues will be resolved in March-June of 2022 and they are working to be 
able to provide us with smaller shipments over the next 3-6 months.  We 
have temporarily slowed recruiting for the project as a result of this issue.  
We have a commitment of the manufacturer to provide us with sufficient 
study drug/placebo supply if we enroll at a rate of approximately 3-4 
participants per month.  Participants who are currently at ½ dose will 
continue to titrate up according to the protocol, but when they get to the 
full dose, we will ask them to take two pills per day of the ½ dose tablets 
(to achieve full dose).  We believe we have adequate supply of the ½ dose 
at our site to accommodate participants until supply of the full dose 
becomes available.   
 
Should the study drug supply chain issues not be resolved in 3-6 months 
and we are depleting our supply of the study drug, we would ask that 
participants taper off the study medication.  This will be accomplished by 
asking participants to take a dose every other day for one week before 
stopping the study medication.  We have ample supply for a down-
titration, should study drug supply chain issues persist. 
 
3.2 Drug/Device Handling:  
The phentermine/topiramate that will be used for this study will be stored 
with Investigational Drug Services (IDS).  The IDS office specializes in storing 
and dispensing investigational drugs for clinical trials.  Study physicians will 
write a prescription in order for IDS to dispense the 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 this 
study will maintain stability.  IDS will keep detailed records on the receipt of 
investigational product (including lot numbers) and detailed records on the 
dispensing of product to each subject enrolled in the study.  IDS is also 

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equipped to destroy any medication that is returned at the end of the study 
when all drug accountability has been completed. 
 
3.3 Biosafety:  
Not applicable 
 
3.4 Stem Cells:  
Not applicable 
 
4.0 
Procedures Involved 
4.1 Study Design: 
This will be a randomized, double-blind, placebo-controlled clinical trial 
specifically designed to evaluate the ability of phentermine/topiramate to 
improve weight loss maintenance following a short-term (six weeks) meal 
replacement induction period among approximately 100 adolescents with 
severe obesity.  Because the trial is designed to evaluate weight loss 
maintenance, participants must achieve at least 5% BMI reduction at week 
six of the meal replacement period in order to be randomized.  Participants 
who do not achieve 5% BMI reduction will not continue in the trial.  After 
achieving the 5% BMI reduction goal, participants will be randomized (1:1) 
to phentermine/topiramate or placebo for an additional 52 weeks while 
engaging in lifestyle modification therapy.   
 
The goal of 5% BMI reduction over a period of six weeks is realistically-
achievable based on our experience using a similar protocol in the target 
population, in which over 70% were able to lose the required amount of 
weight, and based on data reported by Berkowitz et al.,50 which utilized meal 
replacement therapy.  Estimating that 70% will meet the 5% BMI reduction 
benchmark during the induction period and considering a dropout rate of up 
to 20% after randomization (conservative estimate from our experience; 
note that one of the advantages of the meal replacement run-in period is 
that it will “weed out” individuals most likely to withdraw early in the trial, 
prior to randomization), we will enroll approximately 100 participants with 
the expectation that we will randomize approximately 60 participants. 
 
The schedule of events section (below) shows the data that will be collected 
at each study visit.  Following randomization, phone calls will be made 
monthly to assess adverse events and compliance and deliver lifestyle 
modification therapy.  All participants will receive reimbursement for 
completing study visit assessments. 
 

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Schedule of Events 
 
Screening 
Baseline 
Randomization 
(six weeks from 
baseline) 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 26 
Week 30 
Week 34 
Week 39 
Week 43 
Week 47 
Week 52 
 
Allowable window# 
 
 
±3 d 
± 3 d  
± 7d 
± 7d 
± 7d 
± 7d 
± 7d 
± 7d 
± 7d 
± 7d 
± 7d 
± 7d 
± 7d 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Environmental assessment1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review inclusion/exclusion 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Tanner staging 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Comprehensive Metabolic Panel 
X 
X2 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Pregnancy test 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Hemoglobin A1c 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Thyroid Stimulating Hormone (TSH) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Follicle Stimulating Hormone (FSH) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Luteinizing Hormone (LH) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Testosterone 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Estradiol 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Dehydroepiandrosterone (DHEAS) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Lipid Panel (total cholesterol, DHL, LDL and triglycerides) 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Glucose 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Insulin 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
C-Reactive Protein 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Oxidized LDL 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
At home monthly urine pregnancy test9 
 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
BMI/anthropometrics4 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
iDXA 5 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neuropsychological Function Testing6 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Physical Activity and Eating Behavior Questionnaires7 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Bone age 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Resting metabolic rate 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Total energy expenditure (N=60) 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 

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400-meter walk test 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Blood pressure and heart rate 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Depression and Suicide Screening8 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
AE assessment10 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Compliance assessment10 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lifestyle counseling11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contraceptive counseling12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Review of concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensing 
 
 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
# 
Allowable window is ± 3d for the Randomization visit (from baseline), ± 3d for the Week 4 visit and± 7d from the Randomization visit for the visits at Weeks 8,12, 16, 20, 26, 30, 34, 39, 43, 47, 
and 52. 
1 
Demographics to include age, sex, race, ethnicity, home address, total combined family income, parents’ level of education, parents’ employment status.  Environmental assessment to include 
Food Security Screen, Social Support for Eating Habits, Social Support for Exercise, ACE-Q Teen (Adverse Childhood Event) 
2 
Comprehensive metabolic panel does not need to be repeated at Baseline if it occurs within 30 days of screening.. 
4 
Height, weight, waist measurement, BMI, hip circumference.  Heart rate will be collected at Screening. 
5 
iDXA to include total/regional body fat and BMC 
6 
Neuropsychological Functioning to include NIH Toolbox (cognition battery), PROMIS-Anxiety, Impact of Weight on Quality of Life-Kids (IWQOL-Kids) 
7 
Physical Activity and Eating Behavior Questionnaires to include Visual Analog Scale of Self-Reported Appetite and Satiety, Questionnaire of Eating and Weight Patterns, Adult Eating Behavior 
Questionnaire (AEBQ), Reward Based Eating Drive Scale X5 (RED-5, hedonic eating), Dutch Eating Behavior Questionnaire (DEBQ) and the Physical Activity Questionnaire for Adolescents (PAQ-A) 
8 
Depression and Suicide Screening to include the PHQ-9 and the Columbia-Suicide Severity Rating Scale (C-SSRS) 
9 
Females of childbearing potential will be asked to conduct at home urine pregnancy tests every month where there is not an in-person visit.  Urine pregnancy tests will be provided to the 
participant.  
10. Adverse events and compliance assessments will be done over the phone at Weeks 16, 20, 30, 34, 43 and 47. 
11. Lifestyle counseling will be done over the phone at Weeks 16, 20, 30, 34, 43 and 47 
12. Contraceptive counseling including the two methods of contraception being utilized will be completed at all visits, including telephone visits. 
 

MEDICAL PROTOCOL WLM-001 
PROTOCOL TITLE:  Role of Pharmacotherapy in Counteracting Weight Regain in 
Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
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4.2 Study Procedures:  
Anthropometric Measurements and Quantification of Total Body- and 
Regional-Fat Depots  
Height and weight will be measured using a calibrated, wall-mounted 
stadiometer and an electronic scale, respectively.  Measurements will be 
obtained with participants in light clothing, without shoes.  Two consecutive 
height and weight measurements will be obtained and averaged.  If the first 
two values differ by more than 0.5 cm for height and/or 0.3 kg for weight, a 
third measurement will be obtained and the average of three measurements 
will be calculated.  BMI will be calculated as the weight in kilograms divided 
by the height in meters, squared.  Waist circumference will be measured at 
end-expiration midway between the base of the rib cage and the superior 
iliac crest.  Hip circumference will be measured at the maximal protuberance 
of the buttocks.  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.6   
 
Pubertal Development, Blood Pressure, and Blood Analyses 
All Tanner staging will be conducted by individuals trained in assessing 
Tanner stage.  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.61 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.  Fasting 
(≥12 hours) blood will be collected for the measurement of lipids (total-, LDL-
, HDL-cholesterol, and triglycerides), glucose, insulin, hemoglobin A1c, and 
pubertal hormones (assayed in Fairview Diagnostics Laboratories, 
Minneapolis, MN - a Center for Disease Control and Prevention certified 
laboratory).  Additional blood for C-reactive protein and oxidized LDL 
cholesterol will be processed and stored at -80 degrees C for a batched 
analysis in the University of Minnesota Cytokine Reference Laboratory (CLIA 
licensed). 
 
Measurement of Resting Metabolic Rate and Total Energy Expenditure 
Resting metabolic rate will be measured by indirect calorimetry after 
participants have been fasting for ≥12 hours.  Metabolic data will be 

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Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
Page 29 of 63 
 
collected using a ventilated hood (Parvo Medics; Sandy UT).  Previous 
investigations have shown the ventilated hood method to be more accurate 
and reliable when compared to the other techniques.62, 63 This method has 
been shown to be more comfortable in tests that last more than 5-10 
minutes.63 Participants will be instructed to not engage in exercise on the 
day prior to testing.  Resting gas exchange measurements will be collected 
using a Parvo Medics TrueOne 2400 Metabolic Cart, (Sandy, UT).  The cart 
will be calibrated for gas analyses and volume at least twice prior to each 
test session.  Room air (25°C) will be drawn through the hood at a rate of 40 
L/min.  Resting metabolic rates will be collected over the initial 30-minute 
reclining period with the last 10-minutes averaged into an estimate of 
resting metabolic rate.   
 
Total daily energy expenditure will be measured in a subset of participants 
(N = 60) during a one-week period by the doubly-labeled water method, 
which employs the stable isotopes deuterium (2H) and oxygen-18 (18O).  This 
method provides the most accurate assessment of free-living daily energy 
expenditure.  It is based upon the principle that the doubly labeled water is 
rapidly distributed into body water.  Oxygen atoms are eliminated from the 
body as both H2O and exhaled CO2, whereas hydrogen atoms are eliminated 
as H2O only.  Therefore, the rate of disappearance of deuterium reflects 
water turnover and the rate of disappearance of 18O represents water 
turnover as well as CO2 production.  The difference between the elimination 
rates of oxygen and hydrogen from body water represent a measure of CO2 
flux, which is proportional to total energy expenditure.  Each sample will be 
analyzed for H218O and 
2H2O abundances by isotope ratio mass 
spectrometry. 
 
400-Meter Walk Test 
• Limitation in ability to walk is an important outcome of severe 
obesity.  Walking ability and endurance can be directly assessed by 
performance testing.  The 400-meter walk test has been shown to 
be related to VO2 max (the maximum volume of oxygen consumed 
by the body each minute during exercise, while breathing air at sea 
level); thus, the walk not only tests ability to walk but physical 
fitness.  To eliminate the effect of different footwear on test 
performance, the test should be performed in tennis shoes or 
comfortable walking shoes with minimal or no heels.  Participants 
will be instructed prior to the visit that they should wear or bring 
appropriate shoes to the clinic.  Participants wearing footwear that 
impedes their walking should be excluded from the test. 
Participants with the following issues/conditions will not 

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Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
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participate in the 400-meter walk test: those who use a walking 
aid; participants whose systolic blood pressure (SBP) is > 180 
mmHg or whose diastolic blood pressure (DBP is > 100 mmHg); 
whose ECG at screening shows atrial fibrillation or atrial flutter; 
Wolff-Parkinson-White or ventricular pre-excitation, idioventricular 
rhythm, ventricular tachycardia, third degree or complete A-V 
block, any evidence of acute injury or acute ischemia or marked T-
wave abnormality. 
 
Visual Analog Scales and Standardized Questionnaires 
We will obtain self-report ratings (average over the preceding week) on 15-
cm visual analog scales anchored with “not at all” to “extremely” for appetite 
and satiety.  This method has been validated for use in appetite research64 
and was utilized by Sysko et al. in a study of adolescents with severe 
obesity.65  Self-reported appetite and satiety will also be measured using the 
Adult Eating Behavior Questionnaire (AEBQ); note: in our experience, the 
self-report version (AEBQ) is more appropriate for adolescents vs. the child 
version (CEBQ).  Binge eating behaviors/features will be measured with the 
Reward Based Eating Drive Scale X5 (RED-5)  Additional relevant eating 
behavior domains are addressed in the AEBQ including emotional overeating 
and enjoyment of food (hedonic eating) and will be captured in 
supplemental questionnaires: Dutch Eating Behavior Questionnaire,  and 
Questionnaire of Eating and Weight Patterns – Adolescent Questionnaires 
will allow us to examine the impact of eating behaviors in relation to weight 
loss response; results will be considered hypothesis-generating.  Quality of 
life will be assessed via the IWQOL-kids (weight-related quality of life).  
Physical activity of participants will be measured with the PAQ-A. 
 
Safety-Related Assessments 
Comprehensive metabolic panels will be performed at regular intervals 
throughout the study and may be performed more often if a participant has 
values that warrant closer monitoring.  Pregnancy test (for girls) will be 
performed at all in-person study visits.  Urine pregnancy tests will be 
provided to females of childbearing potential to be taken at home with 
results reported to the study team monthly when there is not a scheduled 
in-person visit.  We will require all female participants to confirm use of two 
forms of contraception if sexually active with males.  Effective contraception 
is defined as double barrier methods, stable hormonal contraception plus 
single barrier method, tubal ligation, or abstinence.  We will instruct all 
females who miss a menstrual period or when pregnancy is otherwise 
suspected to perform a pregnancy test.  We will monitor for potential 
changes in heart rate and arrhythmias (ECG), depression, suicidal behavior 

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Adolescents with Severe Obesity 
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and ideation, acute myopia and secondary angle closure glaucoma, mood 
and sleep disorders, cognitive impairment, metabolic acidosis, and elevated 
creatinine.  Sexual maturation (Tanner stage) and stature will be measured 
at baseline and 52 weeks for those less than Tanner 5 at baseline.  A panel 
of related biomarkers (TSH, FSH, LH, testosterone, estradiol, and DHEAS) will 
be measured at randomization and 52 weeks.  Changes in neurocognitive 
function will be evaluated with questionnaires and computer-based 
assessments including the NIH Toolbox.  Bone mineral content will be 
measured by iDXA.  Bone age will be measured at baseline and 52 weeks for 
those who have not reached complete bone maturation at baseline.   
 
Subjects will be assessed for depression and suicide with the Patient Health 
Questionnaire-9 [PHQ-9] and the Columbia-Suicide Severity Rating Scale [C-
SSRS] at each in person visit and the results will be reviewed by a staff 
member while the participant is still present at the visit.  Participants (and 
their parents, if the participant is a minor) will be referred to a mental health 
professional (MHP) or to their primary care provider if the subject has a PHQ-
9 score of >15, any suicidal behavior, or any suicidal ideation of type 4 or 5 
on the C-SSRS.  They will also be provided with the contact information for 
the nationwide Suicide and Crisis Lifeline (telephone 988 or 988lifeline.org).  
If the participant endorses current (in that moment), active suicidal ideation 
with plan and intent, they will also be referred to the emergency 
department.  Participants (and their parent) will be asked if they feel safe 
enough to leave the research clinic and with the established plan.  The 
decision as to whether the participant will be allowed to continue in the trial 
will be made by the local medical monitor in consultation with the MHP or 
primary care provider after the referral clinical visit.   
 
4.3 Study Duration:  
Fifty-eight weeks (six weeks of meal replacement therapy followed by 52 
weeks of medication/placebo treatment) 
4.4 Individually Identifiable Health Information:  
Please see PHI Section 16.0 
 
4.5 Use of radiation:  
This study will consist of up to two bone age (wrist) x-rays and iDXA scans, 
both of which utilize ionizing radiation.  None of the tests done for this study 
are considered part of standard medical care.  There will be up to two bone 
age (wrist) x-rays for the study.  Each x-ray consists of exposure to 0.001 mSv.  
There will be a total of 4 iDXA scans for the study.  Each iDXA consists of 
exposure to 0.01 mSv.  The anticipated total amount of radiation that an 

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Adolescents with Severe Obesity 
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individual would receive from participating in this study is estimated to be 
0.044 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.   
 
4.6 Use of Center for Magnetic Resonance Research:  
Not applicable 
 
5.0 
Data and Specimen Banking 
5.1 Storage and Access:  
Blood samples for lipids (total-, HDL-, and LDL-cholesterol and triglycerides), 
glucose, insulin, hemoglobin A1c and pubertal hormones will be sent to the 
Fairview Diagnostics Laboratory (which is CLIA licensed) after collection of 
the sample.  Blood samples for C-reactive protein and oxidized LDL 
cholesterol will be stored in a -80 C freezer and analyzed en masse for 
analysis at the University of Minnesota Cytokine Reference Laboratory, 
which is CLIA licensed. 
 
5.2 Data:  
Results from the Fairview Diagnostics Laboratories will be posted to chart 
and will also be logged into REDCap.  The results for the samples analyzed by 
the University of Minnesota Cytokine Reference Laboratory will be logged 
into REDCap. 
 
5.3 Release/Sharing: 
Access to the study’s data in REDCap will be restricted to the members of 
the study team by username and password. 
 
6.0 
Sharing of Results with Participants 
6.1 Sharing Results: 
Results from laboratory tests analyzed by the Fairview lab will be posted to 
the participant’s medical record.  Results of the testing conducted by the 
University of Minnesota Cytokine Reference Laboratory will not be shared 
and will be analyzed en masse at the end of the study. 
 
6.2 Sharing Genetic Results: 
Not applicable 
7.0 
Study Population 
7.1 Inclusion Criteria:  
• Severe obesity (BMI >/= 120% of the 95th percentile or BMI >/= 35 
kg/m2 

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• Age 12 to < 18 years of age at enrollment (screening) and Tanner 
stage >/=2 
• Female participants who are sexually active with males and who are 
able to get pregnant must agree to use two forms of contraception 
throughout the trial 
 
Exclusion Criteria:  
• Diabetes (type 1 or 2) 
• Current or recent (< six months prior to enrollment) use of anti-
obesity medication(s) defined as orlistat, phentermine, topiramate, 
combination phentermine/topiramate, liraglutide, and/or 
combination naltrexone/bupropion (monotherapy use of 
naltrexone or bupropion is not an exclusion) 
• Previous metabolic/bariatric surgery 
• Current use of a stimulant medication 
• History of glaucoma 
• Current or recent (<14 days) use of monoamine oxidase inhibitor 
• Known hypersensitivity to sympathomimetic amines 
• Any history of treatment with growth hormone 
• Any history of bulimia nervosa 
• Major psychiatric disorder as determined by the local medical 
monitor 
• Unstable and clinically-diagnosed (defined as documented in the 
medical record, if available) depression 
• Any history of active suicide attempt 
• History of suicidal ideation or self-harm within the previous 30 
days of screening 
• PHQ-9 score >15 at screening 
• Current pregnancy or plans to become pregnant during study 
participation 
• Current tobacco use 
• ALT or AST >/= 3 times the upper limit of normal 
• Bicarbonate <18 mmol/L 
• Creatinine > 1.2 mg/dL 
• Any history of seizures (with the exception of febrile seizures) 
• Uncontrolled hypertension as determined by the local medical 
monitor 
• History of structural heart defect or clinically significant arrhythmia 
• Diagnosed monogenic obesity 
• Any history of cholelithiasis 
• Any history of nephrolithiasis 

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• Clinically diagnosed hyperthyroidism 
• Untreated thyroid disorder 
• Any disorder, unwillingness, or inability, not covered by any other 
exclusion criteria, which in the investigator’s opinion, might 
jeopardize the subject’s safety or compliance with the protocol 
 
7.2 Screening Visit 
At this visit, the subject’s parent/legal guardian will be taken through and 
the consent process and sign the parental consent form and the subject 
will be asked to sign the assent form after they have had the opportunity to 
learn about the study and ask any questions that they may have. The 
subject will undergo the following: 
• BMI and Anthropometrics: height, weight, waist measurement, BMI, 
hip circumference. 
• Blood pressure and heart rate. 
• Physical examination and Tanner staging by a physician. 
• Blood draw for comprehensive metabolic panel, hemoglobin A1c.  
Pregnancy test for females 
• Electrocardiogram. 
• Demographics/Environmental assessment. 
• Depression and Suicide Screening with PHQ-9 and C-SSRS 
• Contraceptive counseling 
• Review of medications 
 
Baseline Visit (within 30 days of screening) 
Subjects will be asked to present at this visit after having fasted for at least 
12 hours.  Their medical and medication history will be reviewed against the 
study inclusion/exclusion criteria.  The subject will undergo the following: 
• Blood draw for comprehensive metabolic panel (if this visit is more 
than 30 days after the Screening visit), fasting lipid panel, glucose and 
insulin.  A pregnancy test for females 
• Blood will be drawn and banked for biomarker testing (C-reactive 
protein and oxidized LDL) which will be analyzed in masse at the 
conclusion of the study.  
• BMI and Anthropometrics: height, weight, waist measurement, BMI, 
hip circumference 
• iDXA to include total/regional body fat and BMC. 
• Neurocognitive testing (NIH Toolbox, PROMIS-Anxiety, Impact of 
Weight on Quality of Life-Kids (IWQOL-Kids)) 
• Bone age x-ray 
• Resting metabolic rate 

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• Total energy expenditure in subset (N=60) including drop-off of urine 
samples 
• 400-meter walk test 
• Blood pressure and heart rate 
• Questionnaires (Visual Analog Scale of Patient Reported Appetite 
and Satiety, Questionnaire of Eating and Weight Patterns-Adolescent 
(QEWP-A), Adult Eating Behavior Questionnaire (AEBQ), Reward 
Based Eating Drive Scale (RED-5, hedonic eating scale), Dutch Eating 
Behavior Questionnaire (DEBQ) and Physical Activity Questionnaire 
for Adolescents (PAQ-A) 
•  Depression and Suicide Screening with PHQ-9 and C-SSRS 
• Lifestyle counseling 
• Contraceptive counseling 
• Review of concomitant medications 
• Review of adverse events 
 
 
Randomization (six weeks±3 days from baseline) 
After six weeks of meal replacement therapy, subjects achieving the BMI 
reduction goal will be randomized (1:1 ratio) to either 
phentermine+topiramate or to placebo.  The following items will happen at 
the visit: 
• Blood draw for comprehensive metabolic panel, hemoglobin A1c, 
TSH, FSH, LH, testosterone, estradiol, DHEAS, lipid panel, glucose and 
insulin.  A pregnancy test for females. 
• Blood will be drawn and banked for biomarker testing (C-reactive 
protein and oxidized LDL) which will be analyzed en masse at the 
conclusion of the study.  
• BMI and Anthropometrics: height, weight, waist measurement, BMI, 
hip circumference 
• iDXA to include total/regional body fat and BMC. 
• Neurocognitive testing (NIH Toolbox, PROMIS-Anxiety, Impact of 
Weight on Quality of Life-Kids (IWQOL-Kids)) 
• Resting metabolic rate 
• Total energy expenditure in a subset (N=60), including drop-off of 
urine samples 
• 400-meter walk test 
• Blood pressure 
• Questionnaires (Visual Analog Scale of Patient Reported Appetite 
and Satiety, Questionnaire of Eating and Weight Patterns-Adolescent 
(QEWP-A), Adult Eating Behavior Questionnaire (AEBQ), Reward 
Based Eating Drive Scale (RED-5, hedonic eating scale), Dutch Eating 
Behavior Questionnaire (DEBQ) 

MEDICAL PROTOCOL WLM-001 
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• AE assessment 
• Compliance assessment 
• Depression and Suicide Screening with PHQ-9 and C-SSRS 
• Lifestyle counseling 
• Contraceptive counseling 
• Review of concomitant medications 
• Study drug dispensing with instructions on the up-titration schedule 
 
 
Week 4 (±3 days from Randomization) 
• Blood draw for a comprehensive metabolic panel.  A pregnancy test 
for females. 
• BMI and Anthropometrics: height, weight, waist measurement, BMI, 
hip circumference 
• Blood pressure 
• AE assessment 
• Compliance assessment 
• Depression and Suicide Screening with PHQ-9 and C-SSRS 
• Lifestyle counseling 
• Contraceptive counseling 
• Review of concomitant medications 
• Study drug dispensing with instructions on the up-titration schedule 
 
Week 8 (± 7days from Randomization) 
• BMI and Anthropometrics: height, weight, waist measurement, BMI, 
hip circumference 
• Blood pressure 
• AE Assessment 
• Compliance Assessment 
• Depression and Suicide Screening with PHQ-9 and C-SSRS 
• Lifestyle Counseling 
• Contraceptive counseling 
• Review of concomitant medications 
• At home pregnancy test (for females of childbearing potential) 
• Study drug dispensing with instructions on the up-titration schedule 
 
 
Week 12 (± 7days from Randomization) 
• Blood draw for a comprehensive metabolic panel.  A pregnancy test 
for females. 
• BMI and Anthropometrics: height, weight, waist measurement, BMI, 
hip circumference 
• Blood pressure 

MEDICAL PROTOCOL WLM-001 
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• AE assessment 
• Compliance assessment 
• Depression and Suicide Screening with PHQ-9 and C-SSRS 
• Lifestyle counseling 
• Contraceptive counseling 
• Review of concomitant medications 
• Study drug dispensing with instructions on the up-titration schedule 
 
Telephone Visit Week 16 (± 7days from Randomization) 
• AE Assessment 
• Compliance Assessment 
• Lifestyle Counseling 
• Contraceptive counseling 
• Review of concomitant medications 
• At home pregnancy test (for females of childbearing potential) 
 
Telephone Visit Week 20 (± 7days from Randomization) 
• AE Assessment 
• Compliance Assessment 
• Lifestyle Counseling 
• Contraceptive counseling 
• Review of concomitant medications 
• At home pregnancy test (for females of childbearing potential) 
 
 
Week 26 (± 7days from Randomization) 
• Blood draw for a comprehensive metabolic panel, hemoglobin A1c, 
lipid panel, glucose, and insulin. A pregnancy test for females. 
• Blood will be drawn and banked for biomarker testing (C-reactive 
protein and oxidized LDL) which will be analyzed en masse at the 
conclusion of the study.  
• BMI and Anthropometrics: height, weight, waist measurement, BMI, 
hip circumference 
• iDXA to include total/regional body fat and BMC. 
• Neurocognitive testing (NIH Toolbox, PROMIS-Anxiety, Impact of 
Weight on Quality of Life-Kids (IWQOL-Kids)) 
• Resting metabolic rate 
• Total energy expenditure in a subset (N=60), including drop-off of 
urine samples 
• Blood pressure 
• 400-meter walk test 

MEDICAL PROTOCOL WLM-001 
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• Questionnaires (Visual Analog Scale of Patient Reported Appetite 
and Satiety, Questionnaire of Eating and Weight Patterns-Adolescent 
(QEWP-A), Adult Eating Behavior Questionnaire (AEBQ), Reward 
Based Eating Drive Scale (RED-5, hedonic eating scale), Dutch Eating 
Behavior Questionnaire (DEBQ), and PAQ-A 
• AE assessment 
• Compliance assessment 
• Depression and Suicide Screening with PHQ-9 and C-SSRS 
• Lifestyle counseling 
• Contraceptive counseling 
• Review of concomitant medications 
• Study drug dispensing with instructions on the up-titration schedule 
 
Telephone Visit Week 30 (± 7days from Randomization) 
• AE Assessment 
• Compliance Assessment 
• Lifestyle Counseling 
• Contraceptive counseling 
• Review of concomitant medications 
• At home pregnancy test (for females of childbearing potential) 
 
Telephone Visit Week 34 (± 7days from Randomization) 
• AE Assessment 
• Compliance Assessment 
• Lifestyle Counseling 
• Contraceptive counseling 
• Review of concomitant medications 
• At home pregnancy test (for females of childbearing potential) 
 
 
Week 39 (± 7days from Randomization) 
• Blood draw for a comprehensive metabolic panel.  A pregnancy test 
for females. 
• BMI and Anthropometrics: height, weight, waist measurement, BMI, 
hip circumference 
• Blood pressure 
• AE assessment 
• Compliance assessment 
• Depression and Suicide Screening with PHQ-9 and C-SSRS 
• Lifestyle counseling 
• Contraceptive counseling 
• Review of concomitant medications 

MEDICAL PROTOCOL WLM-001 
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Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
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• Study drug dispensing with instructions on the up-titration schedule 
 
Telephone Visit Week 43 (± 7days from Randomization) 
• AE Assessment 
• Compliance Assessment 
• Lifestyle Counseling 
• Contraceptive counseling 
• Review of concomitant medications 
• At home pregnancy test (for females of childbearing potential) 
 
Telephone Visit Week 47 (± 7days from Randomization) 
• AE Assessment 
• Compliance Assessment 
• Lifestyle Counseling 
• Contraceptive counseling 
• Review of concomitant medications 
• At home pregnancy test (for females of childbearing potential) 
 
 
Week 52 (± 7days from Randomization) 
• Physical examination and Tanner staging (if necessary) 
• Blood draw for comprehensive metabolic panel, hemoglobin A1c, 
TSH, FSH, LH, testosterone, estradiol, DHEAS, lipid panel, glucose, 
and insulin.  A pregnancy test for females. 
• Blood will be drawn and banked for biomarker testing (C-reactive 
protein and oxidized LDL) which will be analyzed en masse at the 
conclusion of the study.  
• BMI and Anthropometrics: height, weight, waist measurement, BMI, 
hip circumference 
• iDXA to include total/regional body fat and BMC. 
• Neurocognitive testing (NIH Toolbox, PROMIS-Anxiety, Impact of 
Weight on Quality of Life-Kids (IWQOL-Kids)) 
• Bone age x-ray, if necessary 
• Resting metabolic rate 
• Total energy expenditure in a subset (N=60), including drop-off of 
urine samples 
• Blood pressure 
• 400-meter walk test 
• Questionnaires (Visual Analog Scale of Patient Reported Appetite 
and Satiety, Questionnaire of Eating and Weight Patterns-Adolescent 
(QEWP-A), Adult Eating Behavior Questionnaire (AEBQ), Reward 

MEDICAL PROTOCOL WLM-001 
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Based Eating Drive Scale (RED-5, hedonic eating scale), Dutch Eating 
Behavior Questionnaire (DEBQ) and PAQ-A 
• AE assessment 
• Compliance assessment 
• Depression and Suicide Screening with PHQ-9 and C-SSRS 
• Lifestyle counseling 
• Review of concomitant medications 
• Instructions on dose down-titration and stopping the study 
medication 
 
8.0 
Vulnerable Populations 
8.1 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 
not limited to, those with acute 
medical conditions, psychiatric 
disorders, neurologic disorders, 
developmental disorders, and 
behavioral disorders 
Excluded from Participation 
Non-English speakers 
Excluded from Participation 
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 

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PROTOCOL TITLE:  Role of Pharmacotherapy in Counteracting Weight Regain in 
Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
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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). 
Included/Allowed to Participate 
Any other circumstance/dynamic 
that could increase vulnerability to 
coercion or exploitation that might 
influence consent to research or 
decision to continue in research. 
Excluded from Participation 
 
8.2 Additional Safeguards:  
Not applicable 
 
9.0 
Local Number of Participants 
9.1 Local Number of Participants to be Consented:  
More than 120 – we anticipate needing to consent/assent approximately 
200 owing to potential screen failures.   
 
10.0 Local Recruitment Methods 
10.1 Recruitment Process  

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Our recruitment process will be four-fold: we will leverage the MN-POC for 
recruitment.  Member institutions include the University of Minnesota, 
Mayo Clinic, Children’s Hospitals and Clinics of Minnesota, and Park 
Nicollet/HealthPartners, which represent a large portion of the pediatric 
medical care provided in Minnesota.  We plan on reaching out to physicians 
in these member institutions and letting them know about the study so that 
they could refer patients who come into their clinics.  We may also work with 
these and other local health systems to have them send recruitment letters 
on our behalf to potentially eligible participants.  The second method will be 
to have BPIC run queries and get an eligible patient list and mail out letters, 
making certain to not put on the mailing list the patients who have opted 
out of being contacted about potential research projects.  We will also ask 
BPIC to run queries of patients who are waiting for appointments to be seen 
in the Pediatric Weight Management Clinic for the first time and who are on 
the waitlist to have an appointment scheduled in the Pediatric Weight 
Management Clinic.  Interested participants will be asked to contact the 
study team and up to three follow-up phone calls will be made by study staff 
if no initial response is received.  The follow-up phone call limit does not 
apply to situations of “phone-tag.”  Identification of Potential Participants:  
Both the referrals from MN-POC and the recruitment mailings will request 
that interested parties contact the research staff for additional information.  
If the interested party and the research staff do not connect on the first try, 
the research staff will attempt to contact the interested parties with up to 
three follow-up phone calls.  The follow-up phone call limit does not apply 
to situations of “phone-tag.”  The fourth method will be to partner with the 
Minneapolis YWCA to add information to their ‘Mission in Action e-
newsletter.  The newsletter reaches people involved with the YWCA 
Minneapolis through program participants, fitness members, donors, event 
attendees, and supporters. 
 
10.2 Recruitment Materials:  
A recruitment letter and recruitment flyers will be created for this study and 
approved by the IRB before use.  A small paragraph to be included in the 
‘Mission in Action e-newsletter’ will be created for this study and approved 
by the IRB before use. 
 
10.3 Payment:  
We would like to recognize that participation in this study is time intensive 
for the subject and their family members.  Participants will earn up to $960 
for their time and effort.  Payment will be made via the Greenphire 
ClinCard on the following schedule: 
• Screening visit: $100 

MEDICAL PROTOCOL WLM-001 
PROTOCOL TITLE:  Role of Pharmacotherapy in Counteracting Weight Regain in 
Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
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• Baseline visit: $100 
• Randomization visit: $100 (including participants who do not make 
the BMI goal) 
• Week 4 visit: $100 
• Week 8 visit: $100 
• Week 12 visit: $100 
• Week 26 visit: $100 
• Week 39 visit $100 
• Week 52 visit: $100 
• Phone visits: $10 per visit, if all 6 visits are completed, a total of $60 
will be provided 
 
Participants will also receive incentive payment for the number of lifestyle 
visits conducted by telephone that they complete.  This payment will be 
made after the Week 52 visit or earlier if the participant leaves the study 
early.  This brings the total an individual can earn up to $1060.  The 
payment will be applied to the ClinCard. 
• 3 or more therapy visits: $25 bonus 
• 6 or more therapy visits plus the Week 52 visit: $75 bonus 
 
Participants who are selected to be part of the calorie expenditure testing 
using doubly labeled water will receive additional payments for the time 
and effort that it takes to collect urine and drop it off 7 days after the 
following visits.  Participants selected for the calorie expenditure testing 
can receive an additional $80, bringing the maximum they can earn up to 
$1140: 
• Baseline + 7 days: $20 
• Randomization + 7 days: $20 
• Week 26 + 7 days: $20 
• Week 52 + 7 days: $20 
 
 
Parents/guardians attending the baseline, randomization, 26-week, and 52-week 
visits will be offered a meal voucher or Greenphire ClinCard for a meal ($10 
value) since these visits are long in duration. 
 
11.0 Withdrawal of Participants 
11.1 Withdrawal Circumstances:  
Subjects will be allowed to withdraw from the study at any time.  Subjects 
will be asked to taper the study medication as outlined by the medical safety 
officer in order to be safely removed from the study medication.  This is 
typically done by taking one dose every other day for at least one week prior 

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Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
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to stopping, but this may be tailored for each individual based on the medical 
safety officer’s assessment.  After the taper is complete, will be asked to 
return for one final visit and to return any study medication.  Subjects may 
be withdrawn from the study at any time based upon investigator 
judgement and subjects may be asked to taper the study medication if they 
are removed from the study in order to ensure subject safety.  Subjects who 
are not compliant with taking the study medication may be removed from 
the study.   
 
In the event that a participant has a serious adverse event that is deemed 
related to the study medication and/or procedures by the lead investigator 
for medical safety (medical safety officer), the participant will be required to 
immediately discontinue the intervention.   
 
11.2 Withdrawal Procedures:  
Any subject who is removed from the study will be asked to return for one 
final visit to assess adverse events and to collect any unused study 
medication and do a final study medication compliance. 
 
11.3 Termination Procedures:  
It will be noted in the subject enrollment log that the subject has been 
discontinued from the study and the date of the last study related visit.  No 
additional data will be collected after that time.  Data that has already been 
collected can be used in the study analysis. 
 
12.0 Risks to Participants 
12.1 Foreseeable Risks:  
Risks of blood sampling 
There is minimal risk of bruising, fainting and infection associated with 
blood draws and IV placement. 
 
 

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Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
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Meal Replacement Therapy 
All participants will engage in a meal replacement induction period with a 
goal of reducing individual BMI by at least 5%.  Our group has experience 
successfully utilizing a similar meal replacement protocol in the target 
population.  Meal replacements are commonly used in the clinical setting 
and this treatment approach is generally considered to be low-risk.   
 
DXA, Bone Age, and Doubly-Labeled Water 
The iDXA and bone age scans involve exposure to a very low dose of ionizing 
radiation.  The average amount of radiation that the average person would 
receive from the iDXA and bone age scan is less than 1% (3 mrem) of that 
received from natural sources of radiation by a Minnesota resident in one 
year (300 mrem).  The doubly labeled water test measures total energy 
expenditure over a 7-day period through the collection of urine samples.  
Participants will be asked to drink a glass of water that is enriched with two 
atoms which are called stable isotopes (non-radioactive) and provide 
periodic urine samples.  The extra neutron in the doubly labeled water is not 
radioactive and therefore poses no risk.  Previous studies have widely 
utilized this technique in both children and pregnant women. 
 
Expected Adverse Events – Qsymia 
Adverse events will be reviewed and documented at each study visit and 
phone call (monitored monthly throughout the study).  Participants will be 
instructed to contact study staff immediately if any adverse event is 
experienced.  Overall, the safety profile of Qsymia has been demonstrated 
to be acceptable in adults, with paresthesia (mild tingling in the extremities), 
dysgeusia (altered taste), insomnia, constipation, and dry mouth as the most 
commonly reported (incidence ≥5%).  On rare occasions (less than 2%) 
Qsymia may cause a severe rash with blisters and peeling skin, especially 
around the mouth, nose, eyes and genitals.  Qsymia should be discontinued 
at the first sign of a rash unless the rash is clearly not drug related.  Of note, 
topiramate use during the first trimester of pregnancy is associated with an 
increased risk of oral clefts in the fetus.  Comprehensive metabolic panels 
will be performed at routine intervals and more frequently while 
participants are starting the study medication.  Pregnancy tests (for girls) will 
be performed at all in-person study visits.  Female participants who are 
capable of getting pregnant will be provided with urine pregnancy tests to 
take at home on a monthly basis when there is no visit and they will be asked 
to report the results to the study team. We will require all female 
participants who are sexually active with males to confirm use of at least two 
forms of effective contraception.  Effective contraception is defined as 
double barrier methods, stable hormonal contraception plus single barrier 
method, tubal ligation, or abstinence.  We will instruct all females who miss 

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Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
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a menstrual period or when pregnancy is otherwise suspected to perform a 
pregnancy test. In addition, we will monitor for potential changes in 
depression, anxiety, suicidal behavior and ideation, acute myopia and 
secondary angle closure glaucoma, mood and sleep disorders, cognitive 
impairment, metabolic acidosis, and elevated creatinine.  Sexual maturation 
(Tanner stage), stature, and a panel of related biomarkers will be measured 
including TSH, FSH, LH, testosterone, estradiol, and DHEAS.  Individuals who 
abruptly stop taking phentermine/topiramate may be at risk of seizures.  For 
this reason, it is recommended that individuals do not stop taking 
phentermine/topiramate abruptly and take a dose every other day for one 
week to help avoid this issue. 
 
Changes in neurocognitive function will be evaluated with questionnaires 
and computer-based assessments including the NIH Toolbox, PROMIS-
Anxiety anxiety and IWQOL-Kids.  Bone mineral content will be measured by 
iDXA.  Bone age will be measured during the trial.  Our group has experience 
utilizing these tests within the context of previous clinical trials in 
adolescents with severe obesity. 
 
12.2 Reproduction Risks:  
All female participants who are sexually active with males must agree to 
use two forms of birth control during their time in the study.  Effective 
contraception is defined as double barrier methods, stable hormonal 
contraception plus single barrier method, tubal ligation, or abstinence.  We 
will instruct all females who miss a menstrual period or when pregnancy is 
otherwise suspected to perform a pregnancy test.  Females of childbearing 
potential will have urine pregnancy at each in-person visit and will be asked 
to perform urine pregnancy tests at home monthly (kit provided). 
 
12.3 Risks to Others: 
Not applicable 
12.4 Definition of Adverse Events: 
An adverse event is any untoward medical occurrence in a clinical trial 
subject that is temporally associated with the use of a medicinal product, 
whether or not 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 
associate with the use of a medical product.  
 
12.5 Definition of Adverse Events: 
An SAE is an AE that fulfills at least one of the following criteria: 
• Results in death 

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Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
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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 
12.6 Classification of an Adverse Event: 
Severity of Event.  The severity of all AEs will be assessed by the study 
clinician 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 trial, the study product must always be suspect. 
• Not Related: 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 study clinician 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.  
 
12.7 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 study product (assessed 
only by those with the training and authority to make a diagnosis), and time 

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Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
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of resolution/stabilization of the event.  All AEs occurring while on study 
must be documented appropriately regardless of relationship.  All AEs will 
be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is 
screened will be considered as baseline and not reported as an AE.  However, 
if the study participant’s condition deteriorates at any time during the study, 
it will be recorded as an AE. 
 
The study staff will record all reportable events with start dates occurring 
any time after informed consent is obtained until 7 days (for non-serious 
AEs) and 30 days (for SAEs) after the last day of study participation.  At each 
study visit, the study staff will inquire about the occurrence of AEs/SAEs 
since the last visit.  Events will be followed for outcome information until 
resolution or stabilization. 
 
The PI will notify the IRB 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 PI will be responsible for 
notifying the FDA of any unexpected fatal or life-threatening suspected SAE 
as soon as possible, but in no case later than 7 calendar days after the PI’s 
initial receipt of the information.  Non-fatal or non-life-threatening SAEs will 
be reported to the FDA no later than 15 calendar days after the PI’s initial 
receipt of the information.   
 
The DSMB will be provided with AE and SAE information prior to their review 
of the study, at least every six months. 
 
13.0 Potential Benefits to Participants 
13.1 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 cardiometabolic risk factor improvements during 
the meal replacement period.  Furthermore, participants randomized to 
receive phentermine+topiramate may benefit further.  Since data from 
clinical trials in adults have demonstrated reduction in BMI and 
improvements in cardiometabolic risk factors with phentermine+topiramate 
treatment, it is reasonable to expect similar results in the proposed clinical 
trial.  The side effect profile of phentermine+topiramate has been 
demonstrated to be acceptable in adults and the proposed tests are not 
more than minimal risk. The alternative treatment approach is standard-of-
care lifestyle/behavior modification therapy and/or treatment with orlistat 
or “off-label” obesity medications.  All participants in this study will receive 

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Adolescents with Severe Obesity 
VERSION DATE: 2025Mar27 
 
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lifestyle/behavioral modification therapy.  Based upon data in adults, it is 
possible that the benefits of phentermine+topiramate will be additive to the 
lifestyle/behavioral modification therapy. 
 
14.0 Statistical Considerations 
14.1 Data Analysis Plan:  
There are three analysis populations planned.  Intent-to-treat (ITT) will 
include any participant randomized according to their treatment 
assignment.  Per-protocol (PP) will include those without major protocol 
violations.  A detailed list of the protocol violations warranting exclusion 
from the PP analysis will be determined prior to trial commencement.  The 
safety population will include all who receive treatment, according to 
treatment received. 
14.2 Power Analysis: 
Based on our preliminary results using a similar meal replacement protocol in 
adolescents with severe obesity, results of the Berkowitz et al. trial 50 and an 
adult trial by Wadden et al. (in which 90% achieved ≥5% weight loss during 
the induction period),32 we anticipate that at least 70% will achieve the 5% 
BMI reduction goal and would be randomized.  Therefore, we will enroll 
approximately 100 participants who will start meal replacement therapy, 
anticipating that 60 (76%) will achieve 5% BMI reduction and be eligible for 
randomization.  Considering a dropout rate after randomization as high as 
20% (our previous experience with this population has been 10-15%),60,66 we 
expect to have complete follow-up data at 12 months post-randomization on 
≥67 participants.   
 
Regarding attrition, our group has had strong success in retaining 
participants.  In an unpublished trial with a similar design including a meal 
replacement run-in period (mentioned in the Research Strategy section), our 
retention rate following randomization was 85%.  We believe the primary 
reason for the high degree of retention relates to the meal replacement 
induction phase, which “weeds out” many of the participants most likely to 
subsequently withdraw.  Therefore, based on our track-record and the nature 
of our trial design, we anticipate having a dropout rate no higher than 20% 
following randomization (after the meal replacement phase).  
 
The table below presents the power associated with placebo-subtracted BMI 
reductions ranging from 7-10% between randomization and 12 months based 
on an overall sample size of 84 (those meeting the BMI reduction goal and 
ultimately randomized: 42 phentermine/topiramate and 42 placebo).  In 
arriving at these numbers, we considered variability estimates from our pilot 

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Adolescents with Severe Obesity 
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trials60,66 and the study of Berkowitz et al.,50 suggesting a conservative 
standard deviation of approximately 8.9, and a conservative correlation 
between baseline and follow-up scores of 0.6.  We provide the power for a 
wide range of scenarios including conservative estimates of the potential 
treatment effect (as low as 7%) and liberal estimates of potential attrition 
after randomization (as high as 20%).   
 
Power; N=60 (30 per 2 arms) rho=0.6 
  
  
  
  
  
  
Difference in change from baseline 
7% 
8% 
9% 
10% 
Two-sided 
96.9% 99.2% 
99.8% 
100.0% 
Two-sided with 10% attrition 
95.2% 98.5% 
99.7% 
99.9% 
Two-sided with 20% attrition 
92.8% 97.4% 
99.3% 
99.8% 
 
 
14.3 Statistical Analysis: 
Descriptive analyses of baseline characteristics and outcomes will include 
means and standard deviations for continuous variables and frequencies for 
categorical variables.  Treatment compliance will also be evaluated. Safety 
analyses will use the Safety analysis population and will be primarily 
descriptive reporting the number and percentage of adverse events.  All 
safety outcomes will be evaluated and monitored throughout the trial. 
 
Specific Aim #1: The primary analysis will be conducted using the ITT 
population to compare the mean BMI percent change from randomization to 
52 weeks of follow-up (after the meal replacement period) between the 
groups, adjusted for BMI at randomization.  Confidence intervals (CIs) and P-
values will be based on robust variance estimation.  Statistical significance will 
be considered as p<0.05.  Supportive analyses using the PP population will 
also be conducted along with consideration of adjustment for residual 
imbalances between treatment groups after randomization (e.g., in sex).  We 
will also evaluate differences in total body- and visceral-fat, cardiometabolic 
risk factors, inflammation, oxidative stress, and indices of vascular health 
over the full length of follow-up for each time point they are measured.  The 
evaluation will be in a similar fashion as the primary outcome wherein 
analyses will be adjusted for values at randomization.  Longitudinal analyses 
will also be conducted, incorporating the multiple time points these features 
are measured.  Supportive analyses using the PP population will also be 
conducted.  To address the issue of clinical responsiveness, we will describe 
the proportion of participants with ≥5% BMI reduction and ≥10% BMI 
reduction (from baseline, pre-meal replacement therapy) at 52 weeks with 
CIs and P-values based on the Chi-squared test. 
 

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Adolescents with Severe Obesity 
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Specific Aim #2: The safety analysis will include all participants who receive 
treatment, according to treatment received.  It should be noted that many of 
these measurements do not have established cut-points indicating a specific 
safety signal.  Therefore, we will evaluate the change from randomization to 
52 weeks of follow-up (after the meal replacement period) for heart rate, 
blood pressure, depression/suicidal ideation, and bone age between the 
phentermine/topiramate group vs. placebo group, adjusted for each value at 
randomization.  Confidence intervals (CIs) and P-values will be based on 
robust variance estimation.  
 
Exploratory Aim #3 (Hypothesis-Generating): Metrics of appetite, satiety, and 
resting/total energy expenditure at 26- and 52 weeks will each be evaluated 
in a similar fashion as other secondary endpoints wherein analyses will be 
adjusted for values at randomization and CIs and P-values will use robust 
variance estimation. 
14.4 Data Integrity: 
Despite best efforts, it is possible that some data will be missing, which could 
limit the interpretation and generalizability of results. If the data are missing 
at random, conditioned on measured covariates, then supplementary 
analyses adjusting for these covariates will produce unbiased results.  For 
potential missing data mechanisms beyond measured covariates, we will 
examine the extent to which results may be affected.  Imputation techniques 
will be considered for missing data issues (e.g., multiple imputation).  In 
particular, for the primary analysis we will use multiple imputation 
techniques 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.  Secondary endpoints will be handled 
similarly. 
 
15.0 Health Information and Privacy Compliance 
15.1 Select which of the following is applicable to your research: 
☐ My research does not require access to individual health information.   
☒ 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. 
Appropriate Use for Research:  

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15.2 
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:  
15.3 
Explain how you will ensure that only records of patients who have 
agreed to have their information used for research will be reviewed. 
We will work with Fairview Research Administration to pull a pool of 
individuals who have agreed, in their electronic medical record, to learn 
about potential research studies.  The data will be placed in the data 
shelter so that recruitment letters can be generated and sent to potential 
participants.  Individuals who have indicated that they do not want to be 
contacted about research will not be approached. 
15.4 Approximate number of records required for review: >10,000 
15.5 
Please describe how you will communicate with research participants 
during the course of this research.  Check all applicable boxes 
☐ This research involves record review only. There will be no 
communication with research participants. 
☐ Communication with research participants will take place in the course 
of treatment, through MyChart, or other similar forms of 
communication used with patients receiving treatment.  
☒ 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.  
Subjects will receive telephone calls and emails regarding the study.  
The detail of telephone calls that this study requires is outlined in the 

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consent form.  Emails that contain PHI will be sent to the 
subject/parent via a secure, encrypted manner. 
15.6 Explain how the research team has legitimate access to 
patients/potential participants: This has been explained in other sections of the 
protocol. 
15.7 
Location(s) of storage, sharing and analysis of research data, including 
any links to research data (check all that apply).   
☒ 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: 
Indicate if data will be collected, downloaded, accessed, shared or stored 
using a server, desktop, laptop, external drive or mobile device (including a 
tablet computer such as an iPad or a smartform (iPhone or Android 
devices) that you have not already identified in the preceding questions 
☐I will use a server not previously listed to collect/download research data 

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☐I will use a desktop or laptop not previously listed 
☐I will use an external hard drive or USB drive (“flash” or “thumb” drives) 
not previously listed  
☐I will use a mobile device such as a tablet or smartphone not previously 
listed 
 
15.8 Consultants. Vendors. Third Parties: 
15.9 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 other laboratories will be identified only by study 
identification number, never by name.  Data to be used in scientific 
presentations or publications will not contain participant identifiers. 
 
15.10 Sharing of Data with Research Team Members: 
Study team members will have access to Box and to RedCAP. 
 
15.11 Storage and Disposal of Paper Documents:  
All data will be stored in locked offices and will not be released without 
consent of participants.   
16.0 Confidentiality 
16.1 Data Security: 
Absolute confidentiality will be maintained.  All data will be stored in locked 
offices and will not be released without consent of participant.  Data that is 
collected will be entered into REDCap which is only accessible by the study 
team.  Blood samples that are sent to a Fairview laboratory for analysis will 
be identified by name and MR number and the results will be posted to the 
medical record and available to the study participant/parent via MyChart.  
The samples that are sent to the University of Minnesota Cytokine Reference 
Laboratory will be identified only by study identification number, and never 
by name and the results will not be shared with study participants.  Data to 
be used in scientific presentations or publications will not contain participant 
identifiers. 
 
17.0 Provisions to Monitor the Data to Ensure the Safety of Participants 
17.1 Data Integrity Monitoring.  
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 

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regulatory compliance for clinical trials associated with the Food and Drug 
Administration.  This service provides regular monitoring of all research-
related activities and is offered free of charge through the University of 
Minnesota 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. 
17.2 Data Safety Monitoring 
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 every six months, beginning six months after enrollment of 
the first participant, during the trial 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 trial.  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.  
An important charge of the DSMB will be to closely monitor fidelity to the 
protocol (e.g. regularly review the number and types of protocol deviations) 
as well as monitor the integrity of the data. 
17.3 Suicidal Behavior and Suicidal Ideation 
Participants (and their parents, if the participant is a minor) will be referred 
to a mental health professional (MHP) or to their primary care provider if 
the subject has a PHQ-9 score of >15, any suicidal behavior, or any suicidal 
ideation of type 4 or 5 on the C-SSRS.  They will also be provided with the 
contact information for the nationwide Suicide and Crisis Lifeline 
(telephone 988 or 988lifeline.org).  If the participant endorses current (in 
that moment), active suicidal ideation with plan and intent, they will also 
be referred to the emergency department.  Participants (and their parent) 
will be asked if they feel safe enough to leave the research clinic.  If a 
participant (and their parent) do not feel safe we can help to guide them to 
the emergency department.   
18.0 Provisions to Protect the Privacy Interests of Participants 
18.1 Protecting Privacy: see HIPCO ancillary review 

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18.2 Access to Participants: Please refer to the recruitment section 
19.0 Compensation for Research-Related Injury 
19.1 Compensation for Research-Related Injury:  
Treatment for injuries that result from participating in the research activity 
will be available.  Those treatments include first aid, emergency treatment 
and follow-up care as needed.  Care for such injuries will be billed in the 
ordinary manner, to the subject or to their insurance company.  Subjects will 
be encouraged to contact the study team if they think that they have 
suffered a research related injury. 
19.2 Contract Language:  
Not applicable. 
 
20.0 Consent Process 
20.1 Consent Process (when consent will be obtained):  
Assent and parental consent will be obtained by a study investigator or the 
study coordinator after explaining the entire study in detail, asking the 
participant and the parent(s)/guardian(s) to explain the purpose, risk and 
benefits, and other details of the study, and giving the participant and 
parent(s)/guardian(s) an opportunity to ask questions.  A copy of the assent 
and parental consent form will be given to the participants and 
parent(s)/guardian(s). 
20.2 Waiver or Alteration of Consent Process (when consent will not be 
obtained):  
There is no plan to request a waiver or alteration of the consent process. 
20.3 Waiver of Written/Signed Documentation of Consent (when written/signed 
consent will not be obtained): 
There is no plan to request a waiver of written/signed documentation of 
consent. 
20.4 Non-English Speaking Participants:  
We do not plan on enrolling non-English speaking participants at this time.  
If we elect to do so at a later time, a revised protocol and translated 
consents would be sent to the IRB for review and approval. 
20.5 Participants Who Are Not Yet Adults (infants, children, teenagers under 18 
years of age): 

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This study will enroll subjects who are under the age of 18 and they will be 
asked to sign an IRB-approved assent form.  Their parent(s)/guardian(s) 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 to indicate that they are still 
willing to participate in the study.  A copy of the consent form will be given 
to the participant. 
20.6 Cognitively Impaired Adults, or adults with fluctuating or diminished 
capacity to consent: 
Not applicable 
20.7 Adults Unable to Consent: 
• 
Permission:  
Not applicable 
• 
Assent: 
Not applicable 
• 
Dissent:  
Not applicable 
 
21.0 Setting 
21.1 Research Sites:  
• Center for Pediatric Obesity Medicine 
• Delaware Clinical Research Unit 
• MHealth Clinics and Surgery Center 
21.2 International Research:  
Not applicable 
 
22.0 Multi-Site Research 
Not applicable 
 
23.0 Coordinating Center Research 
Not applicable 
 
24.0 Resources Available 
The YWCA Minneapolis is a nonprofit organization founded in 1891 to 
promote health, education, and gender and racial equity throughout the 
Twin Cities.  YWCA Minneapolis has been cultivating an inclusive and 
healthy community through a range of programs, classes and workshops.  
They provide high-quality Racial Justice, Early Childhood Education, Girls & 
Youth, Health & Wellness and Workforce Development programs that 

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help build a vibrant, healthy community for all.  The YWCA Minneapolis is 
willing to collaborate with us to include information about research 
opportunities to 30,000 people who subscribe to their ‘Mission in Action 
e-newsletter.  The e-newsletter reaches people involved with the YWCA 
Minneapolis through their program participants, fitness members, 
volunteers, donor event attendees and supporters.  
 
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