Phentermine/Topiramate in Adolescents With Type 2 Diabetes and Obesity
Phase: EARLY_PHASE1
Conditions: Pediatric Obesity
Sponsor: University of Minnesota

O"icial Title:  Phentermine/Topiramate in Adolescents with Type 2 Diabetes and Obesity 
NCT#: NCT04881799 
Date of the Protocol:  2024Dec10 

MEDICAL PROTOCOL PEDS-2021-29785 
PROTOCOL TITLE: Phentermine/Topiramate in Adolescents with Type 2 Diabetes and 
Obesity 
 
VERSION DATE: 10Dec2024 
 
Page 1 of 45 
 
 
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  
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☐ 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 
☐ 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: 

MEDICAL PROTOCOL PEDS-2021-29785 
PROTOCOL TITLE: Phentermine/Topiramate in Adolescents with Type 2 Diabetes and 
Obesity 
 
VERSION DATE: 10Dec2024 
 
Page 2 of 45 
 
☐ Yes 
☒ No 
Include the use of human fetal 
tissue, human embryos, or 
embryonic stem cells? 
Contact OBAO for submission 
instructions and guidance 
application 
process.  
☒ 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 PEDS-2021-29785 
PROTOCOL TITLE: Phentermine/Topiramate in Adolescents with Type 2 Diabetes and 
Obesity 
 
VERSION DATE: 10Dec2024 
 
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PROTOCOL COVER PAGE 
 
 
 
 
Protocol Title 
Phentermine/topiramate in Adolescents with Type 2 Diabetes 
and Obesity 
Principal 
Investigator/Faculty 
Advisor 
Name: Megan Bensignor, MD 
Department: Pediatrics 
Telephone Number: (612) 626-2809 
Email Address: moberle@umn.edu 
Student 
Investigator 
Name: N/A 
Current Academic Status (Student, Fellow, Resident): 
  
Department: 
Telephone Number: 
Institutional Email Address: 
Scientific 
Assessment 
Nationally-based, federal funding organizations 
IND/IDE # (if 
applicable) 
158959 
IND/IDE Holder 
Megan Bensignor, MD 
Investigational Drug 
Services # (if 
applicable) 
5826 
Version 
Number/Date: 
Version 17.0, Dated 10Dec2024 
 

MEDICAL PROTOCOL PEDS-2021-29785 
PROTOCOL TITLE: Phentermine/Topiramate in Adolescents with Type 2 Diabetes and 
Obesity 
 
VERSION DATE: 10Dec2024 
 
Page 4 of 45 
 
 
REVISION HISTORY 
Revision # 
Version Date 
Summary of Changes 
Consent Change? 
1 
2.0 
Change in the medication to be used 
in this study and update to the known 
risks of the new study medication. 
Health-related Pediatric-Quality of 
Life  measures will also be added at 
baseline, 6 and 12 months.  
Yes 
2 
3.0 
Changes dictated by FDA letter; 
addition of lifestyle modification; 
assessment of TSH at baseline and 
lipid profile, basic metabolic panel 
and vitamin D at baseline, 6 and 12 
months; PHQ-9 modified for teens will 
be used for participants from 12 to 
<18; addition of several exclusion 
criteria per FDA recommendations 
Yes 
3 
4.0 
• Adds a $20 payment at Week 20 
for the upload of CGM data. 
• Revises the visits at Week 12 and 
36 to be conducted in person 
with addition of anthropometrics, 
vital signs, and A1c to be done at 
CRU. 
• Removes screening labs. 
• Collects weight measurements 
monthly. 
• Updates the schedule of events to 
note when additional CGM 
sensors will be dispensed 
• Allows flexibility of in-person 
monthly visits after week 24 visit 
• Added instructions of CGM 
upload, water bottle and bags to 
patient facing materials 
Yes 
 
 

MEDICAL PROTOCOL PEDS-2021-29785 
PROTOCOL TITLE: Phentermine/Topiramate in Adolescents with Type 2 Diabetes and 
Obesity 
 
VERSION DATE: 10Dec2024 
 
Page 5 of 45 
 
4 
5.0 
Modifies section 9 of the protocol to 
indicate that the study will secure 
consent from parents who are non-
English speakers and submits a 
Spanish language parental consent 
form. 
Yes, creates a 
Spanish language 
parental consent 
form 
5 
6.0 
Modifies section 10.2 to note that 
endocrinologists at Park Nicollet and 
Children’s may provide flyers to their 
patients who appear to qualify for the 
study. 
 
Revises the exclusion criteria for 
medications that we anticipate may 
become FDA-approved for pediatrics 
during the course of the project. 
Yes, to make 
clarifications to the 
scales. 
6 
7.0 
Modification of exclusion criteria to 
now include those treated with 
liraglutide at its 1.8 mg dose and  
exenatide ER.  
Yes 
7 
8.0 
Splits the screening visit into two 
parts: a screening and a baseline visit 
with the addition of $75 in 
compensation for the screening visit. 
 
Modifies recruitment to allow Dr. 
Bensignor to directly reach out to 
primary care providers or primary 
endocrinologists of eligible patients 
identified through BPIC data pull. 
 
Corrects the numbering of the 
references for the study. 
 
Yes 
8 
9.0 
Corrects discrepancies between the 
schedule of events and description of 
study activities 
Yes 
9 
10.0 
Updates the IND holder on the cover 
page of the protocol, revises section 
4.2 of the protocol which discusses 
how IDS holds the randomization key 
and can break the blind for a 
participant if an emergency arises, 
and how they will destroy the 
medication returned by subjects. 
No 

MEDICAL PROTOCOL PEDS-2021-29785 
PROTOCOL TITLE: Phentermine/Topiramate in Adolescents with Type 2 Diabetes and 
Obesity 
 
VERSION DATE: 10Dec2024 
 
Page 6 of 45 
 
10 
11.0 
Clarifies section 4.2 of the protocol 
with regard to medication dispensing 
for the open label portion of the 
study.  Revises section 10.1 to add 
that the study coordinator may 
initiate telephone contact after 
recruitment letters are sent. 
 
11 
12.0 
Revises sections 10.1 and 10.3 to note 
that Children’s of Minnesota will send 
out recruitment letters 
No 
12 
13.0 
Revises the protocol to note that the 
Dexcom G7 will be phased in as the 
CGM to be used for the study. The 
Dexcom G7 does not require swiping 
so compensation plan has been 
reworded.    
Yes 
13 
14.0 
Revises the exclusion criteria to allow 
individuals with febrile seizures to 
enroll in the study 
No 
14 
15.0 
Corrects the schedule of events and 
protocol language to be consistent 
with the study consent forms.  Revises 
the parental consent and adult 
consent forms to note that study 
medication should be returned at 
Weeks 12, 24, 36 and 52 for 
compliance.  Adds into the assent 
form the risks of physical exams and 
Tanner staging. 
Yes 
15 
16.0 
Revises the study so that if a 
participant arrives without having 
withheld insulin for the hours 
required for the OGTT testing ,the 
visit will proceed without the OGTT 
but the participant will be asked to 
return within one week to complete 
the OGTT testing. 
No 
16 
17.0 
Modifies section 4.1 of the protocol to 
note when participants will be taken 
off of basal insulin.  Updates the risks 
section to note that kidney stones are 
a known risk of topiramate, one of the 
components of Qsymia. 
Yes 
 
 
 

MEDICAL PROTOCOL PEDS-2021-29785 
PROTOCOL TITLE: Phentermine/Topiramate in Adolescents with Type 2 Diabetes and 
Obesity 
 
VERSION DATE: 10Dec2024 
 
Page 7 of 45 
 
 
Table of Contents 
 
1.0 
Objectives 
9 
2.0 
Background 
9 
3.0 
Study Endpoints/Events/Outcomes 
14 
4.0 
Study Intervention(s)/Investigational Agent(s) 
14 
5.0 
Procedures Involved 
16 
6.0 
Data and Specimen Banking: Not applicable 
21 
7.0 
Sharing of Results with Participants 
21 
8.0 
Study Population 
21 
10.0 
Local Recruitment Methods 
26 
11.0 
Withdrawal of Participants 
28 
12.0 
Risks to Participants 
28 
13.0 
Potential Benefits to Participants 
32 
14.0 
Statistical Considerations 
33 
15.0 
Health Information and Privacy Compliance 
35 
16.0 
Confidentiality 
38 
17.0 
Provisions to Monitor the Data to Ensure the Safety of Participants 
38 
18.0 
Provisions to Protect the Privacy Interests of Participants 
40 
19.0 
Compensation for Research-Related Injury 
40 
20.0 
Consent Process 
41 
21.0 
Setting 
42 
22.0 
Multi-Site Research 
42 
23.0 
Coordinating Center Research 
42 
24.0 
Resources Available 
42 
25.0 
References 
43 
 
 
 

MEDICAL PROTOCOL PEDS-2021-29785 
PROTOCOL TITLE: Phentermine/Topiramate in Adolescents with Type 2 Diabetes and 
Obesity 
 
VERSION DATE: 10Dec2024 
 
Page 8 of 45 
 
 
ABBREVIATIONS/DEFINITIONS 
A1c 
Glycated hemoglobin 
AE 
Adverse event 
BG 
Blood glucose 
BMI 
Body mass index 
BP 
Blood pressure 
CCRC 
Certified Clinical Research Coordinator 
CFR 
U.S. Code of Federal Regulations 
CGM 
Continuous glucose monitor 
CI 
Confidence interval 
CRF 
Case report form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTSI 
Clinical and Translational Science Institute 
DPP-IVi 
Dipeptidyl peptidase-4 inhibitors 
DSMB 
Data and Safety Monitoring Board 
EDE-Q 
Eating Disorder Examination Questionnaire 
EKG 
Electrocardiogram 
FDA 
U.S. Food and Drug Administration 
FPG 
Fasting plasma glucose 
HbA1c 
Hemoglobin A1c, glycated hemoglobin 
HIPAA 
Health Information Portability and Accountability Act 
HR 
Heart rate 
ICH GCP 
International Code of Harmonisation-Good Clinical Practice 
ICS 
Informatics consulting service 
IDS 
Investigational drug service 
iDXA 
Dual energy x-ray absorptiometry 
IE 
Information exchange 
ITT 
Intent-to-Treat 
IRB 
Institutional Review Board 
MCMC 
Markov Chain Monte Carlo 
MEN-1 
Multiple Endocrine Neoplasia-1 
oDI 
Oral deposition index 
OGTT 
Oral glucose tolerance test 
PHN/TPM 
Phentermine/Topiramate 
PHQ-9 
Patient Health Questionnaire 
PI 
Principal investigator 
PP 
Per-protocol 
QoL 
Quality of life 
RISE Study 
Restoring Insulin Secretion Pediatric Medication Study 
SAE 
Serious adverse event 
T2D 
Type 2 diabetes 
Teen LABS 
Teen-Longitudinal Assessment of Bariatric Surgery Study 
TODAY Study 
Treatment Options for T2DM for Adolescents and Youth Study 
U.S. 
United States 
 
 
 
 
 

MEDICAL PROTOCOL PEDS-2021-29785 
PROTOCOL TITLE: Phentermine/Topiramate in Adolescents with Type 2 Diabetes and 
Obesity 
 
VERSION DATE: 10Dec2024 
 
Page 9 of 45 
 
 
1.0 
Objectives 
1.1 Purpose:  
We will conduct a pilot, pragmatic, randomized trial with a 6-month placebo-
controlled period followed by a 6-month open-label extension, investigating the 
effects of phentermine/topiramate (PHN/TPM) on BMI, insulin sensitivity, and 
glycemic control compared to placebo plus standard treatment (metformin 
+insulin) in adolescents with T2D. The purpose of this study is to 1) evaluate the 
effects of PHN/TPM vs. placebo+ standard treatment on BMI in adolescents with 
T2D and obesity and 2) evaluate the effects of PHN/TPM vs. placebo + standard 
treatment on insulin sensitivity and B-cell function in adolescents with T2D and 
obesity. 
 
2.0 
Background 
2.1 Significance of Research Question/Purpose:  
             As the prevalence of obesity rises in the U.S., so does the incidence of pediatric 
type 2 diabetes (T2D), which is associated with more aggressive disease 
progression than in adults.  From 2002-2012, the incidence of T2D in youth 
increased by 7% annually in the U.S.1 Compared to adults, T2D in adolescents is a 
much more progressive and recalcitrant disease, characterized by more rapid 
deterioration of β-cell function and earlier incidence of exogenous insulin 
dependence and diabetes-related comorbidities.2 A potential factor that drives 
the rapid progression of adolescent T2D is obesity (body mass index [BMI] >95th 
percentile.3,4 Lifestyle interventions focused on weight reduction is an essential 
part of initial and long-term treatment for pediatric T2D. A body mass index (BMI) 
reduction of about 8% has been found to decrease insulin resistance in 
adolescents with T2D.5 A 7-10% decrease in excess weight is also recommended 
by the ADA for pediatric T2DM.38 However, current treatment guidelines for T2D 
recommend lifestyle management and metformin as first-line therapy, which 
rarely achieve such a BMI reduction in adolescents.6, 7, 8  
There are limited medical therapies that effectively and concurrently improve 
glycemic control, reduce obesity, and beneficially impact β-cell function and 
insulin sensitivity in adolescents with T2D.  Current treatment guidelines for 
pediatric T2D recommend lifestyle management and metformin as first-line 
therapies,6-8 which rarely achieve meaningful BMI reduction in adolescents.2, 9-13  
The Treatment Options for T2DM for Adolescents and Youth (TODAY) study 
showed that metformin monotherapy and metformin plus lifestyle management 
were less effective in adolescents than adults, resulting in increased BMI and 
visceral body fat.2,13-14 About half of participants (52%) on metformin 

MEDICAL PROTOCOL PEDS-2021-29785 
PROTOCOL TITLE: Phentermine/Topiramate in Adolescents with Type 2 Diabetes and 
Obesity 
 
VERSION DATE: 10Dec2024 
 
Page 10 of 45 
 
monotherapy and 47% on metformin and intensive lifestyle therapies progressed 
to exogenous insulin dependence within four years.2 Furthermore, the Restoring 
Insulin Secretion (RISE) Pediatric Medication Study demonstrated that metformin 
+ insulin did not slow the progression of β-cell deterioration in adolescents with 
T2D or impaired glucose tolerance.12 Making matters worse, insulin-associated 
weight gain can increase BMI and body fat, and exacerbate insulin resistance, 
requiring the use of additional insulin therapy.15Conversely, tight glycemic control 
is imperative as adolescents with T2D are also more likely to have diabetes-
related comorbidities such as hypertension, atherosclerosis, and kidney disease 
(albuminuria) earlier compared to adults.2 
Even the two-newly FDA-approved glucagon-like peptide receptor agonists (GLP-
1RAs) for youth > 10 years with T2DM (liraglutide 1.8 mg and exenatide ER) did 
not result in the weight reduction recommended for pediatric patients by the 
ADA.39-41 For example, liraglutide at doses up to 1.8 mg/day did not significantly 
reduce BMI in 134 adolescents, aged 10-17 years with T2DM and 
overweight/obesity (mean BMI of 33.90 + 9.25 kg/m2) after a 26-week double-
blind randomized, control trial (RCT).40  At the end of the 26-week open-label 
extension of this trial, a minimal estimated treatment difference in BMI of -0.89 
kg/m2 or a 2.73% decrease between liraglutide and placebo groups was 
found.39,40 Although the BMI reduction with liraglutide 1.8mg/day is statistically 
significant, it remains unclear the clinical significance of this finding. Exenatide ER 
also did not significantly reduce weight compared to placebo after a 24-week 
randomized controlled trial (-0.59 + 0.665 kg vs + 0.63 + 0.882. kg, respectively, 
p=0.307) and the 28 open-label extension (0.04+ 6.09 kg versus -0.04 + 4.69 kg, 
respectively) of 84 In the randomized control trial of adolescents with obesity 
(mean BMI: 36.36 +8.57 kg/m2) and T2DM, previously treated with diet and 
exercise alone or with metformin + a sulfonylurea and/or insulin.41 
Only bariatric surgery has been shown to be a long-term effective treatment for 
T2D, improving both BMI and glycemic control (A1c), more significantly than 
insulin and metformin therapy in adolescents.16-17A secondary analysis comparing 
adolescents with T2D treated with bariatric surgery (Teen-Longitudinal 
Assessment of Bariatric Surgery [LABS] Study) and adolescents with T2D treated 
with medication (TODAY Study) found that mean A1c decreased from 6.8% to 
5.5% in adolescents who underwent bariatric surgery compared to a mean A1c 
increase from 6.4% to 7.8% in TODAY participants.16 Additionally, the mean BMI 
in the Teen-LABS cohort decreased by 29.0% from baseline compared with a 3.7% 
increase in TODAY participants during the 2-year follow-up.16 However, bariatric 
surgery is not a feasible therapy for all patients.  Scalable, non-surgical strategies 
for the management of T2D in adolescence which lead to meaningful clinical BMI 
reduction and decrease in insulin resistance are needed. 

MEDICAL PROTOCOL PEDS-2021-29785 
PROTOCOL TITLE: Phentermine/Topiramate in Adolescents with Type 2 Diabetes and 
Obesity 
 
VERSION DATE: 10Dec2024 
 
Page 11 of 45 
 
A combination of two oral anti-obesity pharmacotherapies, phentermine and 
topiramate (PHN/TPM), is now FDA-approved to treat obesity in the pediatric 
population for patients > 12 years of age with obesity. About 31% of adolescent 
participants without diabetes with a BMI of  37.8 + 7.1 kg/2 receiving mid-dose 
PHN/TPM and 42.5 % receiving top dose compared to 0% receiving placebo 
achieved at least a 10% weight reduction over 1 year in a recent randomized 
control trial. In this trial, triglycerides significantly decreased by 12% with both 
mid-dose and top-dose compared to an 8% increase with placebo. This finding is 
of particular interest as excess circulating triglycerides accumulate in muscle, 
liver, and pancreatic cells, leading to insulin resistance and β-cell dysfunction 
during the pathogenesis of T2DM. Although, weight reduction can decrease intra-
pancreatic lipid content, normalize pancreatic morphology, and restore first-
phase insulin secretion in adults with T2DM, it is not known if reduction in serum 
triglycerides will improve β-cell function, particularly in youth with rapidly 
progressing diabetes. 
 
The rationale for specifically focusing on PHN/TPM (vs. other medications, 
including GLP-1RAs) to reduce BMI is supported by feasibility of attainment of 
study drug for a pilot study as well as ease of administration as it is a daily oral 
medication.  PHN/TPM also have multiple mechanisms of action, which are 
thought to target many of the counter-regulatory biological adaptation, which 
prevent weight loss. 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 PHN/TPM); and 3) increasing energy expenditure (both 
phentermine and topiramate independently).24-30 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, or are 
injectable medications, which may decrease treatment adherence.31  PHN/TPM 
offers the potential to achieve greater BMI reduction than standard diabetes 
treatment of metformin + insulin. 
2.2 Existing Literature:  
To our knowledge, no PHN/TPM trials have been conducted in adolescents with 
T2D with a primary focus on BMI reduction, and improvement in β-cell function.  
Therefore, our focus will be novel for the field of pediatric T2D research. Based on 
adult outcomes with PHN/TPM, we anticipate a mean placebo-subtracted BMI 
reduction of 8-10% at 52 weeks, a level considered clinically-meaningful in 
adolescents and will help improve insulin resistance.5, 19, 31-33    
 
 

MEDICAL PROTOCOL PEDS-2021-29785 
PROTOCOL TITLE: Phentermine/Topiramate in Adolescents with Type 2 Diabetes and 
Obesity 
 
VERSION DATE: 10Dec2024 
 
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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 one of the most effective obesity 
medications 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.35   
Results from a large phase III clinical trial demonstrated placebo-subtracted 
weight loss of >9% with treatment for one year at the top dose.36  Importantly, a 
separate trial demonstrated that the treatment effect is durable out to at least 
two years.437The 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. 
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 1 
summarizes: 1) the incidence of the most 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 

MEDICAL PROTOCOL PEDS-2021-29785 
PROTOCOL TITLE: Phentermine/Topiramate in Adolescents with Type 2 Diabetes and 
Obesity 
 
VERSION DATE: 10Dec2024 
 
Page 13 of 45 
 
the safety of these medications and demonstrate a reasonably high level of 
acceptability and tolerability in the adolescent population.  
 
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 2. 
 
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 PHN/TPM 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 

MEDICAL PROTOCOL PEDS-2021-29785 
PROTOCOL TITLE: Phentermine/Topiramate in Adolescents with Type 2 Diabetes and 
Obesity 
 
VERSION DATE: 10Dec2024 
 
Page 14 of 45 
 
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 (weight loss and cardiometabolic risk factor improvement) 
as well as our experience with this intervention; 3) provides preliminary evidence 
supporting the safety, efficacy, and acceptability of  combination therapy in 
adolescents with severe obesity; and 4) sets the stage for taking this next 
important step.   
3.0 
Study Endpoints/Events/Outcomes 
3.1 Primary Endpoint/Event/Outcome:  
• To evaluate the effects of PHN/TPM  vs. placebo + standard treatment 
(metformin + insulin + liraglutide 1.8 mg or exenatide ER) on BMI in 
adolescents with T2D and obesity. 
3.2 Secondary Endpoints/Events/Outcomes:  
• To evaluate the effects of PHN/TPM  vs. placebo + standard treatment on 
insulin sensitivity and β-cell function in adolescents with T2D and obesity. 
3.3 Exploratory Endpoints/Events/Outcomes 
● To evaluate the effects of PHN/TPM on total and visceral body fat 
● To evaluate the effects of PHN/TPM  vs. placebo + standard treatment 
on cardiometabolic measures (lipid panel [TC, LDL-C, TG, HDL-C], blood 
pressure and heart rate). 
 
4.0 
Study Intervention(s)/Investigational Agent(s) 
4.1 Description:  
Phentermine/topiramate Therapy 
Participants randomized to PHN/TPM 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. There will not be a pause in dose titration between weeks 
4 and 12 as indicated by the medication labeling as this pause is indicated to 
clinically assess weight loss response on mid-dose PHN/TPM before up-titrating to 
high-dose PHN/TPM. However, the goal of this proposed study is to assess BMI 
reduction on the maximum tolerated dose of PHN/TPM in a clinical research 
setting. Therefore, an assessment of weight loss on the moderate dose of 

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PHN/TPM between weeks 4 and 12 is not warranted. Participants unable to 
tolerate the dosing regimen will be maintained at the maximally tolerated dose.   
Following the final study visit, all participants will be down-titrated gradually by 
taking medication every other day for seven days before stopping treatment 
altogether. PHN/TPM will be purchased from an independent vendor by the 
University of Minnesota Investigational Drug Service Pharmacy (IDS).  Placebo will 
be manufactured by IDS.  The placebo capsules manufactured by IDS will not be 
able to be matched to the commercial product. The PI and research coordinator 
will not be involved in pill counting to evaluate adherence for this trial in order to 
preserve the blinding of investigators.  Participants will not be told which 
treatment arm they are in to preserve the blinding of participants. 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 adherence.  If the average fasting plasma glucose (FPG), measured by 
CGM, is >185 mg/dL after titration to PHN/TPM 15mg/92mg or maximum 
tolerated dose, metformin therapy or basal insulin therapy will be started or 
titrated for a goal average FPG <110 mg/dL.   
 
Metformin Therapy 
Participants who are on metformin therapy prior to enrollment will remain on 
metformin, if tolerated.  Titration and maximum tolerated dose will be at the 
discretion of the principal investigator and a dose of 2000 mg daily will be 
targeted if CGM is > 185 mg/dL after titration to PHN/TPM 15mg/92or maximum 
tolerated dose.   
 
Insulin Therapy  
Insulin will be started per the American Diabetes Association guidelines on any 
participants whose A1c is >8.5%. For those treated with insulin prior to 
enrollment, basal insulin dose will be reduced by 20% at start of PHN/TPM 
therapy and then by 20% every 4 weeks if average FPG is <110 ml/dL. Basal 
insulin dose will continue to be reduced every four weeks until basal insulin dose 
is below 0.2 units/kg/day and then basal insulin will be stopped.  If the FPG value 
is >185 mg/dL after titration to maximum tolerated dose of PHN/TPM and 
metformin, basal insulin therapy will be started or titrated up by 20% until for a 
goal average FPG <110 mg/dL.  If participants are on rapid-acting insulin meal 
dosing (carbohydrate coverage), this will be discontinued at the start of the 
PHN/TPM therapy and only restarted if two-hour post-prandial plasma glucose 
>200 md/dL.  Rapid-acting insulin will be used as a rescue medication for BG >200 
mg/dL per PI discretion. 
 
 

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4.2 Drug/Device Handling:  
The PHN/TPM that will be used for this study will be stored with the IDS 
pharmacy. Placebo will be manufactured by IDS. The IDS pharmacy specializes in 
storing and dispensing investigational drugs for clinical trials.  Study physicians 
will write a prescription in order for IDS to dispense the study medication.  IDS is a 
secure facility (behind two locked doors) and maintains refrigerators and freezers 
with temperature tracking to assure that the drugs utilized in this study will 
maintain stability.  IDS will keep detailed records on the receipt of investigational 
product (including lot numbers) and detailed records on the dispensing of 
product to each subject enrolled in the study.  IDS is also equipped to destroy any 
medication that remains at the end of the study or any product that is returned 
by the study participants.  IDS will also be hold the randomization key for the 
study, which was developed by the study biostatistician, and will follow their 
internal standard operating procedures for breaking the blind in the event of an 
emergency.   
When an individual participant transitions from the placebo-controlled portion of 
the study to the open-label portion of the study, the study physician will put in 
orders for the open label study for IDS to dispense medication and the IDS staff 
will review the patient randomization and will either continue to fill the 
prescription with the maintenance dose or fill the prescription to have the 
participant titrate up on the study medication in order to help keep the study 
team blinded. 
 
4.3 
Biosafety: 
Not applicable. 
  
4.4 
Stem Cells:  
Not applicable. 
 
4.5 
Fetal Tissue:  
Not applicable 
 
5.0 
Procedures Involved 
5.1 Study Design:  
This is a pilot, pragmatic, randomized trial with 6-month placebo-controlled 
period followed by a 6-month open label extension.  Thirty pubertal or post-
pubertal adolescents will be randomized into one of two arms: 
• PHN/TPM  
• Placebo 

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Participants will engage in typical T2D clinical care and lifestyle management, with 
the addition of PHN/TPM or placebo therapy for 6 months followed by a 6-month 
open label extension during which all participants will be given PHN/TPM in an 
unblinded fashion.   
The schedule of events (below) shows the data that will be collected at each 
study visit. 
 
 

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Schedule of Events 
 
Screening 
Baseline 
Placebo-Controlled 
 
Week 
-4% 
0% 
4 
8 
12% 
16 
20 
24% 
28 
32 
36% 
40 
44 
48 
52% 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam  
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Tanner staging 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Anthropometricsa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (Blood pressure and 
heart rate) 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
EKG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Contraceptive counseling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hemoglobin A1c 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Eating Disorder Examination 
Questionnaire (EDE-Q) 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Peds-QOL (general and 
diabetes modules) 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Patient Health Questionnaire 
(PHQ-9) 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Total daily insulin dose 
assessment 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Oral Glucose Tolerance Test 
(OGTT) 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
ALT, AST, INR, TSH, bilirubin, 
albumin, basic metabolic panel 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Lipid profile, vitamin D 1,25b 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma glucose levelb 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
c-peptide levelb 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Insulin levelb 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
iDXA (visceral and total body fat 
and bone mineral density) 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Review of CGM datac 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Insulin titration per CGM 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense new CGM sensor 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense study medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Review of medication 
adherence 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Review of co-administered 
drugs 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Lifestyle and behavior 
counseling 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Highlighted “X” will be done in the Clinical Research Unit. Non-highlighted X will be done in the Delaware Clinical Research Center 
a 
Including height and weight at Weeks 0, 12, 24, 36 and 52. Weight only will be done at Weeks 4, 8, 16, 20, 28, 32, 40, 44, 48. Weight done remotely via Bluetooth monthly if  there are no in-
person visit scheduled for weeks28, 32, 40, 44, and 48. 
b 
Blood will be drawn during the OGTT at baseline, 30-, 60-, 90- and 120-minutes following glucose ingestion 
c 
Continuous glucose monitoring with CGM data will be reviewed with participant via telephone after upload by PI or Marrissa Ludwig, Clinical Diabetes Educator. 
d 
Urine pregnancy tests will be done on all females of childbearing potential.  Tests will be done at in-person or at home. 
$ 
Visit windows for Weeks 4-52 are +/-7 days from the baseline visit 
% 
In-person visits 

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5.2 Study Procedures:  
Physical exam: A study physician will conduct a physical examination to ensure 
the participant is healthy enough to enroll in the study.  A pubertal status will also 
be undertaken by the study physician (Dr. Bensignor) who is a trained pediatric 
endocrinologist. She has been trained in the proper technique to assess pubertal 
stages and will be the same study physician conducting all assessments 
throughout the trial. 
Vital signs:  Blood pressure (BP) and heart rate (HR) will be collected. 
Hemoglobin A1c: Blood will be collected for a hemoglobin A1c level. 
EKG: Electrocardiogram will be performed at screening/baseline visit and per PI 
discretion.  
Eating Disorder Examination Questionnaire (EDE-Q): The EDE-Q identifies 
disordered eating behaviors and unhealthy attitudes about weight, such as 
purging, unhealthy obsession with dieting and/or body weight, prolonged 
fasting/starvation, use of laxatives to control weight and excessive exercise. 
Patient Health Questionnaire-9 (PHQ-9): The PHQ-9 measures depression and 
suicidality. The PHQ-9 Modified for Teens will be administered to participants < 
18 years of age. A participant will be referred to a mental health professional or 
primary care provider if s/he has a PHQ-9 score of > 10 or reports any suicidal 
behavior. A PHQ-9 score > 15 at the screening vision is an exclusion criteria.  
Columbia-Suicide Severity Rating Scale (C-SSRS): The C-SSRS measures depression 
and suicidality.  A participant will be referred to a mental health professional or 
primary care provider if s/he has any suicidal behavior or any suicidal ideation of 
type 4 or 5 on the C-SSRS. Please see Exclusion Criteria for cut-off scores related 
to the C-SSRS.  
Pediatric Quality of Life Inventory (PedsQLTM): The PedsQL measures general and 
disease-specific quality of life. We will be using the participant-reported measures 
for the PedsQLTM Generic Core Scales and Diabetes Module Version 3.2 for young 
adults (aged 18-25 years) and Teens (12-18 years).  
Oral Glucose Tolerance Test (OGTT): Insulin sensitivity and β-cell function will be 
measured via a 2-hour, 75 mg oral glucose tolerance test.  OGTT has been widely 
used in the evaluation of β-cell dysfunction and T2D, including in the TODAY and 
RISE studies.2,12 The OGTT will be performed following a 10-12 hour overnight 
fast.  Participants will take their last dose of metformin (if applicable) the evening 
before testing.  Participants on basal or bolus insulin will be asked to withhold 
insulin dose either 36 hours or 6 hours, respectively, prior to testing.  Plasma 
glucose levels, C-peptide, and insulin levels will be measured at baseline, 30, 60, 
90 and 120 minutes following standard glucose ingestion.  If a participant comes 
to a visit and has not withheld insulin for the required number of hours, the visit 

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VERSION DATE: 10Dec2024 
 
Page 20 of 45 
 
will proceed without the OGTT and the participant will be asked to return to 
perform the OGTT within one week of the originally scheduled visit. 
Glycemic Control: Time in range (BG of 70-180 mg/dL) and hypoglycemic events 
will be measured using Continuous Glucose Monitors, either Freestyle Libre 14 
day or Dexcom G7. The Freestyle Libre 14 day is no longer being produced so we 
will phase in the use of Dexcom G7 CGM. Worn on the skin, the disposable, single 
use sensor will continually measure glucose levels from the interstitium, every 
minute for 14 days (Libre) or 10 days (Dexcom G7) and will upload the data for 
review, and the participant will be asked to share this data with the study team.   
Participants will be taught how to place and replace the CGM.  Participants who 
have a Libre CGM will be instructed to swipe the sensor at least twice daily 
(fasting and at bedtime) and to upload their CGM data monthly.  Participants who 
have the Dexcom CGM will not need to swipe, but will be instructed to upload 
their CGM data monthly. CGM data will also be used to titrate insulin and 
metformin dosing.  Percent time of CGM use will be used to assess adherence.   
Total daily insulin dose: For participants on insulin therapy, total daily insulin dose 
(units/kg/day) will be averaged over the previous month at each study visits.  
Participants will log their insulin doses and return pens to study visits.   
Body composition: Total body and visceral fat (% and kg) and measures of bone 
mineral density will be measured by dual energy x-ray absorptiometry (iDXA).  
iDXA measurements, using standard positioning techniques, will be conducted 
and analyzed by trained staff.   
Anthropometrics: Height and weight will be collected by trained research staff at 
weeks 0, 12, 24, 36 and 52.  Weight only will be collected at Weeks 4, 8, 16, 20, 
28, 32, 40, 44, and 48. Weight will be collected via a scale provided to the 
participants and reported directly to the research coordinator at Week 28, 32, 40, 
44, and 48 if there no monthly visits and per the PI’s discretion. 
Lifestyle and behavior management: 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 and virtual 
study visit (screening/baseline visit prior to randomization and weeks 12, 24, 36, 
and 52).  The lifestyle/behavioral modification curriculum has been adapted from 
the NIDDK-sponsored TODAY study lifestyle modification program materials and 
is based on principles detailed in U.S. Preventive Services Task Force screening 
recommendation statement and utilized by our group in a previous 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.  

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This will include guidance on a hypocaloric diet (500 calorie per day deficit) and 
increasing physical activity. 
 
5.3 
Study Duration:  
This pilot study will enroll approximately 30 participants.  Participation will last 
for approximately 52 weeks. 
 
We anticipate that it will take 36 months to enroll and have all 30 participants 
complete 52 weeks of treatment. 
5.4 Use of Radiation:  
The iDXA used in this study uses radiation to generate its picture.  The average 
iDXA is equal to a few hours of ionizing radiation exposure in Minnesota.  The 
AURPAC will be asked to review the consent form language and dosimetry 
calculations to ensure that they are correct. 
6.0 
Data and Specimen Banking: Not applicable 
7.0 
Sharing of Results with Participants 
7.1 The results of tests done during the study will be shared with participants upon 
request. 
7.2 Sharing of genetic testing: Not applicable 
8.0 
Study Population 
8.1 Inclusion Criteria:  
• Ages 12 to < 20 years at study entry 
• Obesity (BMI > the 95th percentile for age and sex) 
• HgbA1c > 6.5% at type 2 diabetes diagnosis 
• Negative diabetes auto-antibodies 
• English-speaking  
• For participants of child-bearing potential: when sexually active, agreement to 
use two forms highly effective contraception (oral contraceptive pill, IUD, 
implant, and/or condoms) during study participation 
8.2 Exclusion Criteria:  
• Pregnancy or lactation 
• Newly-initiated or change in dose of weight altering medication within past 6 
months, including SGLT-2 inhibitors,  DPP-IV inhibitors, liraglutide 1.8 mg and 
exenatide ER 
• Current or recent (< six months prior to enrollment) use of anti-obesity 
medication(s) defined as orlistat, phentermine, topiramate, combination 

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PHN/TPM, semaglutide, and/or combination naltrexone/bupropion 
(monotherapy use of naltrexone or bupropion is not an exclusion) 
• Current use of sulfonylureas 
• Previous metabolic/bariatric surgery 
• Current use of a stimulant medication 
• History of glaucoma 
• Current or recent (<14 days) use of monoamine oxidase inhibitor or carbonic 
anhydrase inhibitors 
• 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 or PHQ-9 score > 15 
• Any history of active suicide attempt,  a  “yes” answer to Question 4 (Active 
Suicidal Ideation with Some Intent to Act, Without Specific Plan) on the 
“Suicidal Ideation” portion of the C-SSR, or a “yes” to answer to Question 5 
(Active Suicidal Ideation with Specific Plan and Intent) on the “Suicidal 
Ideation” portion of the C-SSRS 
• History of suicidal ideation or self-harm within the previous 30 days or a “yes” 
answer to any of the suicide-related behaviors (actual attempt, interrupted 
attempt, aborted attempt, preparatory act, or behavior) on the “Suicidal 
Behavior” portion of the C-SSRS and the ideation or behavior occurred within 
the past month. 
• Current pregnancy or plans to become pregnant during study participation 
• Current tobacco use 
• ALT or AST >/= 3 times the upper limit of normal 
• Moderate (Child-Pugh score 7-9) or severe (Child-Pugh score 10-15) 
• Bicarbonate <18 mmol/L 
• Moderate (creatinine clearance [CrCl] greater than or equal to 30 and less 
than 50 mL/min) or severe (CrCl less than 30 mL/min) renal impairment 
• History of seizures (with the exception of febrile seizures) 
• BP for ages 13 and older of > 130/80 on 3 separate measurements and for age 
12 > 95th percentile on 3 separate measurements 
• HR ≥120 bpm on 3 separate measurements 
• History of structural heart defect or clinically significant arrhythmia 
• Diagnosed monogenic obesity 
• Any history of cholelithiasis 
• Any history of nephrolithiasis 
• Clinically diagnosed hyperthyroidism 
• Untreated thyroid disorder or TSH below the lower laboratory limit of normal 

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• Any disorder, unwillingness, or inability, not covered by any other exclusion 
criteria, which in the investigator’s opinion may put the participant at risk. 
 
8.3 Visit Detail:  
Screening Visit:  After explaining the study in detail, written parental consent and 
assent will be obtained.  If the participant is >18 years of age, the participant 
consent will be obtained.  Potential participants will then undergo screening for 
inclusion and exclusion criteria (physical exam with height and weight for BMI 
calculation, Tanner staging for pubertal status.  Screening lab  [AST, ALT, INR, TSH, 
bilirubin, albumin, basic metabolic panel will be drawn at this visit and reviewed 
before setting up the baseline visit.  INR, bilirubin, and albumin will be used to 
determine a Child-Pugh score for hepatic impairment for eligibility. Urine 
pregnancy test for participants of child-bearing potential will be obtained. BP and 
HR will be taken. Contraceptive counseling will be provided. The PHQ-9 and C-
SSRS will then be completed. All other co-administered medications will be 
assessed.  Participants will then have their medical and medication history 
collected and demographics collected.  
 
Baseline Visit:  Participants who meet eligibility criteria will return for a baseline 
visit within 4 weeks of the screening visit.  Participants will have a physical 
examination, their height and weight will be measured and their blood pressure 
and heart rate will be taken.  An EKG will be done, and contraceptive counseling 
will be given.  Participants will complete the EDE-Q,  and PedsQL.  Their daily 
insulin and metformin doses will be reviewed if applicable.  Participants will be 
instructed how to place and replace a CGM as well as swipe and upload data.  The 
participant will have the OGTT testing and the plasma glucose levels, c-peptide 
levels and insulin levels taken at outlined timepoints as well as baseline lipid 
profile, and vitamin D level be drawn at time 0.  Approximately 2 tablespoons of 
blood will be drawn at the visit. The participant will also have an iDXA for total 
body fat, visceral fat and bone mineral density calculations. Lifestyle management 
counseling will be given. The participant will then be randomized to receive either 
PHN/TPM or placebo and will be instructed on how to take the study medication.  
The participant will be provided with a Bluetooth scale for use at home and to 
transmit weights to the study team, with a water bottle to encourage water 
intake and with a drawstring bag to carry the study items.   
Weeks 4, 8, 16, 20, 28, 32, 40, 44 and 48: At these timepoints the study staff will 
review the CGM data, and the participant may be contacted via telephone about 
adjusting their insulin or metformin dose.  Participant will also present to the 
DCRU to collect study medication as well as upload CGM data if they are unable 
to do so from home and they will be given new CGM sensors. Monthly urine 

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pregnancy test results and contraceptive counseling if applicable will also done 
when the patient collects their study medication. If participants are able to 
upload CGM at home, then after week 24, a 2-month supply of study drug and 
CGM sensors and 2 urine pregnancy tests will be given to participants at visit 24 
and a 3-month supply of study mediation and CGM sensors and 3 pregnancy tests 
will be given at visit 36. Study coordinator will then only do a telephone visit for 
weeks 28, 32, 40, 44, and 48 to review adverse events, home weight, and results 
of urine pregnancy test.  
Week 12 and Week 36: Visits at these timepoints will be conducted at the CRU.  
Vital signs and weight will be collected.  Participants will be asked about any 
adverse events they have experienced. Contraceptive and lifestyle management 
counseling will again be given and a pregnancy test will be performed.  
Participants will have a physical examination and pubertal assessment.  
Approximately one teaspoon of blood will be drawn for a hemoglobin A1c. 
Patients will also complete the EDE-Q, PHQ-9, and C-SSRS. Participants will be 
provided with new CGM sensors and study Medication bottles will be collected 
and pills counted by the study team to assess compliance.  At the Week 12 visit, 
the pill count will be conducted by a team member not involved in the study so 
that the study blind is not broken. 
Week 24 and Week 52: Participants will present for an in-person visit for a 
physical examination. Tanner staging, height and weight measurements will be 
collected.  Vital signs (BP and HR) will also be collected.  Contraceptive counseling 
and lifestyle management will again be given. Participants will be asked about 
adverse events that they have experienced.  Blood will be drawn for a 
hemoglobin A1c, basic metabolic panel, lipid profile, and a Vitamin D 25.  A 
review of the participants’ daily insulin doses will be reviewed. Any co-
administered medications will be discussed. Participants will have the OGTT 
testing and blood will be collected at the outlined timepoints for plasma glucose 
levels, c-peptide levels and insulin levels.  Approximately two tablespoons of 
blood will be drawn at the visit. Participants will be asked to complete the EDE-Q, 
PedsQL, PHQ-9 and C-SSRS evaluations.  Urine pregnancy test will be done and 
reviewed if applicable. An iDXA for total body fat,  visceral fat and bone mineral 
density will be conducted.  The participant will have their CGM data reviewed and 
new CGM sensors will be provided at week 24. The participant’s insulin dose will 
be reviewed and their adherence to the study medication will be assessed. Study 
medication will be distributed for week 24. Instructions on how to down-titrate 
off the study medication will be done on week 52.  Participants who elect to 
upload their CGM data remotely before the visit may elect to receive study 
medication, home urine pregnancy tests, and sensors to last them for the 
remainder of the study.  
 
 

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9.0 
Vulnerable Populations 
9.1 Vulnerable Populations:  
Population / Group 
Identify whether any of the 
following populations will be 
targeted, included (not necessarily 
targeted) or excluded from 
participation in the study.  
Children 
Targeted Population 
Pregnant women/fetuses/neonates 
Excluded from Participation 
Prisoners 
Excluded from Participation 
Adults lacking capacity to consent 
and/or adults with diminished 
capacity to consent, including, but 
not limited to, those with acute 
medical conditions, psychiatric 
disorders, neurologic disorders, 
developmental disorders, and 
behavioral disorders 
Excluded from Participation 
Non-English speakers 
Included/Allowed to Participate 
Those unable to read (illiterate) 
Excluded from Participation 
Employees of the researcher 
Excluded from Participation 
Students of the researcher 
Excluded from Participation 
Undervalued or disenfranchised 
social group 
Included/Allowed to Participate 
Active members of the military 
(service members), DoD personnel 
(including civilian employees) 
Excluded from Participation 
Individual or group that is 
approached for participation in 
research during a stressful situation 
Excluded from Participation 

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such as emergency room setting, 
childbirth (labor), etc. 
Individual or group that is 
disadvantaged in the distribution of 
social goods and services such as 
income, housing, or healthcare. 
Included/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. 
Included/Allowed to Participate 
 
9.2 Additional Safeguards:  
Minor children will be enrolled in this study and will be asked to sign an assent 
form after their parents or legal guardian(s) sign a parental consent form.  Legal 
guardians will be asked to provide proof of their status.  If a minor child turns 18 
while they are participating in the project, they will be asked to sign an adult 
consent form and HIPAA authorization at their next scheduled visit to indicate 
their willingness to stay in the study.  
A parental consent form in Spanish has been created as a number of our 
participant children may be bilingual, but their parent may not be as comfortable 
with speaking English.  
9.2 Local Number of Participants to be Consented:  
We plan to enroll 30 participants into this pilot study.  
10.0 Local Recruitment Methods 
10.1 Recruitment Process:  
We will work with Fairview Research Administration to identify potential 
participants who have not opted out of hearing about research projects and send 

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them a letter.  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.  We will also reach out directly to the patient’s primary care provider 
or primary diabetes provider to inform the provider that their patient is possibly 
eligible for this study and provide them with a flyer for the patient.  The patient 
can then contact the research coordinator directly or give verbal permission to be 
contacted. 
 
Children’s Minnesota will also send out recruitment letters to their patients. 
  
10.2 Identification of Potential Participants:  
Potential participants may self-identify by calling the study coordinator after 
receiving a recruitment letter (described above).  Additionally, Dr. Bensignor may 
approach potential participants that she sees as part of standard care who may 
qualify for the project and inquire about their willingness to learn more.   
10.3 Recruitment Materials:  
A recruitment letter will be used to recruit potential participants. A recruitment 
flyer with study information will be given to patients in T2D clinic.   
Endocrinologists within Park Nicollet and Children’s will also be provided with a 
flyer to provide to interested patients who are seen in their clinic and will send 
out recruitment letters. 
10.4 Payment:  
Participants will be compensated for the study items that they complete.  
Participants can earn a total of $2265.  The amount to be earned is broken down 
as follows: 
• Screening visit $75 
• Baseline visit: $100 
• Week 4: $20 for review of CGM data 
• Week 8: $20 for review of CGM data 
• Week 12: $115 ($95 for the visit and blood draw, $20 for CGM review) 
• Week 16: $20 for review of CGM data 
• Week 20: $20 for review of CGM data  
• Week 24: $120 ($100 for in-person visit and $20 for review of CGM data) 
• Week 28: $20 for review of CGM data  
• Week 32: $20 for review of CGM data 
• Week 36: $115 ($95for the visit and blood draw, $20 for CGM review) 
• Week 40: $20 for review of CGM data  
• Week 44: $20 for review of CGM data  
• Week 48: $20 for review of CGM data  

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• Week 52: $120 ($100 for in-person visit and $20 for review of CGM data) 
• Swiping of the Libre CGM: $2/swipe (participants will be asked to swipe 
twice per day ($4 maximum per day, or $120 for a full month of swiping 
twice per day).  For participants on the Dexcom G7, the data retrieval is 
automatic (swiping is not required) and participants will receive $4/day 
for each day the CGM is worn (maximum of $120 for each month). 
 
The Greenphire ClinCard will be used for all compensation.  
11.0 Withdrawal of Participants 
11.1 Withdrawal Circumstances:  
Participants who ask to be withdrawn from the project will have their request 
honored.  Participants may be asked to come to one final study visit for a physical 
examination and hemoglobin A1c measurement for safety, if the PI thinks that 
this is required, and discuss how their insulin should be adjusted after taking 
PHN/TPM or placebo is stopped. 
Participants who are not uploading their CGM data may be withdrawn from the 
study at the PI’s discretion. 
11.2 Withdrawal Procedures:  
Participants who wish to withdraw from the study will be allowed to do so.  They 
will also be offered to stop taking the study medication/placebo but continue 
with the visits.  
11.3 Termination Procedures:  
Participants who withdraw from the study will not have additional study 
information collected.  Data that had been collected prior to their withdraw will 
still be reviewed and utilized. 
12.0 Risks to Participants 
12.1 Foreseeable Risks:  
Expected Adverse Events  
PHN/TPM: 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 PHN/TPM 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%).  Of note, topiramate use during the first trimester of pregnancy 
is associated with an increased risk of oral clefts in the fetus.  A basic metabolic 
panel at weeks 0, 24, and 52,  and urine pregnancy test (for persons of child-

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bearing potential) will be performed monthly.  We will require all sexually active 
participants who are of child-bearing potential to confirm use of at least two 
forms of effective contraception. 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, kidney stones, and elevated creatinine.  
Participants will be asked to increase their fluid intake in order to help decrease 
the concentration of substances involved in kidney formation.  Topiramate can 
increase the risk of suicidal ideation and behavior. Participants will be screened 
for depression with the PHQ-9 and suicidal ideation and behavior with the C-SSRS. 
If any questionnaire reveals suicidal behavior or ideation with some intent to act 
on it, then test results will be confirmed by the PI prior to discharging the subject 
from the study. Study medications will be weaned off if there is suicidal behavior 
or ideation with some intent to act on it.  
Insulin: Participants may already be on insulin therapy upon enrollment in the 
study or it may be used to treat hyperglycemia.  There is a risk of bruising, 
bleeding and infection associated with insulin injection.  Hypoglycemia may also 
occur with insulin use, and this risk increases with weight loss.  Participants who 
are on insulin will be trained on the signs of low blood sugar and how to treat an 
episode of hypoglycemia.  Hypoglycemic episodes will be documented by CGM 
and reviewed monthly, or sooner if needed.  Doses of metformin and insulin (if 
applicable) will be down titrated to help prevent further hypoglycemia. 
Metformin: Participants may already be on metformin therapy upon enrollment 
into the study or the metformin dose may be titrated during the course of the 
study.  Side effects of metformin include diarrhea, bloating, nausea and vomiting, 
which are usually self-resolving.  Side effects will be reviewed at each study visit 
and metformin can be down titrated or discontinued if warranted by the PI.  
Participants can be on either immediate-release or extended-release 
formulations of metformin. 
OGTT: There is a minimal risk of bruising, bleeding and infection associated with 
the blood draw and peripheral IV placement for the OGTT.  There is also a risk of 
temporary hyperglycemia during the testing. 
Continuous Glucose Monitoring: There is a minimal risk of bruising, bleeding, and 
infection associated with placement of the CGM device.  Participants will be 
trained how to apply the device at baseline.  In general, CGM is well tolerated and 
accepted.  A diabetes clinical nurse will be available to participants to help 
address any issues with CGM placement and maintenance remotely. 
Screening and monitoring labs: The risks of drawing blood for this test include 
bruising, bleeding and infection at the site where the needle enters the skin.  On 
rare occasions, fainting may occur. 

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Dual Energy X-ray Absorptiometry (iDXA): The iDXA scans involve exposure to a 
very low dose of ionizing radiation to generate their picture.  The average amount 
of radiation that the average person would receive from the iDXA scans in this 
study is less than 1% (3 mrem) of that received from natural sources of radiation 
by a Minnesota resident in one year (300 mrem). 
Risks of Questionnaires, EDE-Q, PHQ-9, C-SSRS, PedsQL: Individuals may feel self- 
conscious or nervous about answering these questions.  However, the risk of 
being able to provide an intervention if an individual develops unhealthy eating 
habits or suicidal ideations is felt to outweigh the risks. 
There is always a risk of a breach in confidentiality associated with the use of data 
that can be linked back to individuals.  The study team will utilize password 
protected programs in which to enter data and study data in paper form will be 
kept in offices that are locked when unattended.   
12.2 Reproduction Risks:  
All participants of child-bearing potential who are sexually active must agree to 
use two forms of birth control during their time in the study.  Participants of 
childbearing potential will have urine pregnancy monthly, during a study visit or 
medication pick-up. Participants of childbearing potential who are sexually active 
will be instructed to use a highly effective birth control method.  Participants of 
childbearing potential who think that they may be pregnant will be asked to stop 
taking the study medication and call the study doctor as soon as possible. 
12.3 Risks to Others:  
Not applicable. 
12.4 
Definition of Adverse Events (AE): 
An adverse event is any untoward medical occurrence in a clinical trial subject 
that is temporally associated with the use of the 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 associated with the use of 
a medical product. 
12.5 
Definition of Serious Adverse Events (SAE): 
A SAE is an AE that fulfills at least one of the following criteria: 
• Results in death 
• Is life-threatening 
• Requires impatient hospitalization or prolongation of existing 
hospitalization 
• Results in persistent disability/incapacity 
• Is a congenital anomaly/birth defect 
12.6 
Classification of an Adverse Event 

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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. 
• Unrelated: clearly not related to the investigational agent(s) 
• Unlikely: doubtfully related to the investigational agent(s) 
• Possible: may be related to the investigational agent(s) 
• Probable: likely related to the investigational agent(s) 
• Definite: clearly related to the investigational agent(s) 
 
Expectedness: The study clinician will be responsible for determining whether 
an AE is expected or unexpected.  An AE will be considered unexpected if the 
mature, 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 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. 
 

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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 in person 
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 
unexpected (in terms of nature, severity or frequency), that is related or 
possibly related to participation in the research and places the subject or others 
at increased risk of harm per current IRB policy 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 seven calendar days after the PI’s initial receipt of the information in 
compliance with the FDCA  (21 U.S.C. §§ 301 et. seq.) as well as the 
implementing regulations [Title 21 of the Code of Federal Regulations (CFR)].  
Non-fatal or non-life-threatening SAEs will be reported to the FDA no later than 
15 days after the PI’s initial receipt of the information.  The PI will report any (1) 
serious, unexpected suspected adverse reactions, (2) findings from other 
clinical, animal, or in-vitro studies that suggest significant human risk, and (3) a 
clinically important increase in the rate of a serious suspected adverse reaction 
to the FDA no later than 15 calendar days after determining that the 
information qualifies for reporting [21 CFR 312.32(c)(1)]. The PI will also submit 
annual progress reports within 60 days of the anniversary of the date that the 
IND becomes active.  
 
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:  
The interventions and outcome measures in the proposed study, with the 
exception of PHN/TPM, presents experiences to participants that are reasonably 
commensurate with those inherent in their actual or expected medical situations 
and typical clinical care. Since data from clinical trials in adults and adolescents 
with obesity have demonstrated reduction in BMI with PHN/TPM treatment, it is 
anticipated that PHN/TPM will provide greater BMI reduction and therefore 
improved insulin sensitivity and glycemic control than standard T2D care.  
 
 

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14.0 Statistical Considerations 
14.1 Data Analysis Plan:  
There are 3 analysis populations planned, Intention-to-treat (ITT) will include any 
participant randomized according to their treatment assignment.  Per-protocol 
(PP) will include those without protocol violations and who were compliant 
(>80%) with their treatment assignment measured by medication log and 
medication collection.  The safety population will include all who receive 
treatment, according to treatment received.  
14.2 Power Analysis:  
Percent change in BMI from baseline (randomization) and 6 months will serve as 
the primary outcome for which the sample size determination is based.  Sample 
size was based on feasibility. We consider variability estimates from our previous 
experience with anti-obesity medication trials in the adolescent population, 
suggesting a standard deviation of approximately 8.9 and a conservative 
correlation between baseline and follow-up of 0.75.  Based on an overall sample 
size of 30 (15 in each of two treatment arms) and type I error of 0.05, we will 
have 80% power to detect treatment difference of 6%.  This percent change in 
BMI is clinically significant and similar to other results found in the previous 
PHN/TPM trials.6,35 We also appreciate degree of attrition may be unavoidable.  In 
the event of 10% attrition (recent experience for our study group in a trial 
involving a similar adolescent population with severe obesity), we will have 80% 
power for a treatment difference of 6.3%. 
14.3 Statistical Analysis:  
Descriptive analyses of baseline characteristics and outcomes will include means 
and standard deviations, median and range for continuous variables and 
frequencies for categorical variables.  Treatment adherence will also be evaluated 
by the methods described above.  Safety analyses will be primarily descriptive 
reporting the number and percentage of adverse events.  All safety outcomes will 
be evaluated and monitored throughout the trial.  Confidence intervals (CIs) and 
p-values will be based on robust variance estimation.  Statistical significance will 
be considered as p<0.05. 
Aim 1: The primary analysis will be conducted using the ITT population to 
compare the mean BMI percent change (primary outcome measure) from 
randomization to 6 months of follow-up between the groups, adjusted for BMI at 
randomization for added precision.38-39 We hypothesize that with participants 
treated with PHN/TPM will demonstrate greater BMI percent change compared 
to controls at 6 months.  Supportive analyses using the PP population will also be 
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between treatment groups after randomization (e.g., in sex as a biological 
variable).  Longitudinal analyses will also be conducted, incorporating the multiple 
time points through the open-label extension (6 months to 12 months follow-up) 
during which these BMI measurements will be obtained.  This will examine 
durability of changes observed over the masked portion of follow-up, as well as 
provide additional safety information.  Supportive analyses using the PP 
population will also be conducted. 
Aim 2: Secondary outcomes will be analyzed in the same fashion as the primary 
endpoint wherein analyses will be adjusted for values at randomization.  
Outcome measures for Aim 2 are c-peptide index (∆C30/∆G30), insulin sensitivity 
(1/fasting insulin), β-cell function relative to insulin sensitivity (oral deposition 
index [oDI]), A1c (%), and total daily insulin dose (units/kg/day).  We hypothesize 
that participants treated with PHN/TPM will demonstrated improved insulin 
sensitivity and β-cell function compared to those assigned to placebo as 
measured by OGTT, A1c and total daily insulin doses.  Complementary secondary 
analyses will also be conducted for each secondary outcome as described for the 
primary outcome. 
Exploratory Aim: In an exploratory fashion, we will compare the mean change in 
total body- and visceral fat (expressed as percent and absolute) and 
cardiometabolic measures from randomization to 6 months of follow-up between 
the groups, adjusted for randomization values for added precision.  
 
14.4 Data Integrity:  
Despite 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 a last observation carried forward approach for participants on whom we 
do not have a final measurement.  Additional complementary analyses will 
incorporate Markov Chain Monte Carlo (MCMC) multiple imputation to handle 
missing data.   The imputation model will be stratified by treatment group and 
include baseline values at randomization.  Additional variables for possible 
inclusion in the model include age, race, sex, and Tanner stage, though unlikely to 
be more than one in any single model due to sample size limitations.  MCMC 
imputation will be used to estimate treatment group differences, 95% confidence 
intervals and P values; observed data will be used to estimate within treatment 
group changes.  If the analyses with ad without multiple imputed values differ 

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substantially, then exploratory analyses will be performed to evaluated factors 
that may have contributed to the differences.  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 and 
therefore assert HIPAA does not apply.   
 
☒ I am requesting that all research participants sign a HIPCO approved HIPAA 
Disclosure Authorization to participate in the research (either the standalone 
form or the combined consent and HIPAA Authorization). 
☐ I am requesting the IRB to approve a Waiver or an alteration of research 
participant authorization to participate in the research. 
Appropriate Use for Research:  
☐ An external IRB (e.g. Advarra) is reviewing and we are requesting use of the 
authorization language embedded in the template consent form in lieu of the 
U of M stand-alone HIPAA Authorization.  Note: External IRB must be serving 
as the privacy board for this option. 
 
15.2 
Identify the source of Private Health Information you will be using for your 
research (Check all that apply)   
☒ 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.    
 

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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, virtual visits through the AmWell 
Platform, and emails regarding the study.  The detail of telephone calls that 
this study requires is outlined in the consent form.  Emails that contain PHI 
will be sent to the subject/parent in 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 

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☐ In Qualtrics (qualtrics.umn.edu) 
 ☐ Store 
☐ Analyze 
☐ Share 
☐ In OnCore (oncore.umn.edu) OnCore will serve as the EDC for the project 
 ☐ Store 
☐ Analyze 
☐ Share 
☒ In the University’s Box Secure Storage (box.umn.edu) 
 ☒ Store 
☐ Analyze 
☒ Share 
☐ In an AHC-IS supported server. Provide folder path, location of server and IT 
Support Contact: 
 ☐ Store 
☐ Analyze 
☐ Share 
☒ In an AHC-IS supported desktop or laptop.  
Provide UMN device numbers of all devices:  
 ☒ Store 
☐ Analyze 
☒ Share 
☐ Other. Describe:  
Indicate if data will be collected, downloaded, accessed, shared or stored using a 
server, desktop, laptop, external drive or mobile device (including a tablet 
computer such as an iPad or a smartform (iPhone or Android devices) that you 
have not already identified in the preceding questions 
☐I will use a server not previously listed to collect/download research data 
☐I will use a desktop or laptop not previously listed 
☐I will use an external hard drive or USB drive (“flash” or “thumb” drives) not 
previously listed  
☐I will use a mobile device such as a tablet or smartphone not previously listed 
 
15.8 Consultants. Vendors. Third Parties. The CGM that is provided to the participant 
in the Discovery Clinic can collect and transmit data.  The participant can choose, 
via the app, to share the data with the study team.    
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.  Data to be used 
in scientific presentations or publications will not contain participant identifiers.  
 
15.10 Sharing of Data with Research Team Members.  

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Study team members will have access to the data shelter, REDCap, Box and to 
OnCore. 
 
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 outside of the study team without consent of the 
participant.  Data that is collected will be entered into OnCore, REDCap, and Box 
which are accessible only by the study team.  Data to be used in scientific 
presentations or publications will not contain participant identifiers.  As this study 
is funded by the National Institutes of Health, a Certificate of Confidentiality will 
be in place to help protect the research data from disclosure to outside entities. 
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 at the University of 
Minnesota’s Clinical Trial Monitoring Service, which specializes in regulatory 
compliance for clinical trials associated with the Food and Drug Administration.  
This service provides regular monitoring of all research-related activities and is 
offered free of charge through the University of Minnesota 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.  
Responsible Individual: Dr. Bensignor will be responsible for data and safety 
monitoring and will review all adverse events and serious adverse events 
regularly throughout the trial.  A data and safety monitoring board (DSMB) has 
been established and includes one adult endocrinologist, one pediatric 
endocrinologist and one biostatistician.  DSMB members are not to be affiliated 
with the study.  The DSMB will meet regularly (frequency to be determined by the 
DSMB) during the trial to review data and evaluate participant safety.  A charter 
for the DSMB to outline the responsibilities and procedures for the conduct of the 
monitoring board has been developed and approved by its members along with a 

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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 (co-mentor). A report from each meeting will be 
sent to the PI and her mentorship team 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 University of Minnesota Institutional 
Review Board (IRB). An important charge of the DSMB will be to closely monitor 
progress and timelines related to recruitment goals, fidelity to the protocol (e.g. 
regularly review the number and types of protocol deviations), as well as monitor 
the quality and integrity of the data. The DSMB will communicate any concerns 
relevant to these issues of trial conduct to the PI and her mentorship team and 
note specific recommendations for improvement in the meeting report. 
Overall Framework:  There will be a specific and comprehensive plan for 
monitoring the safety of participants and the integrity of the study data, which 
will include careful assessment and appropriate reporting of adverse events and 
use of a DSMB as described above. Adverse events will be monitored closely, and 
participants will be provided with information about the risks/side effects of the 
study medication (PHN/TPM) and study procedures. Participant safety is the 
study team’s utmost priority. Accordingly, Dr. Bensignor will involve a team of 
experienced clinical investigators who will adhere to the standards of the 
International Conference on Harmonisation Good Clinical Practice (ICH GCP), 
applicable U.S. Code of Federal Regulations (CFR), and the protocol, which will be 
approved by the University of Minnesota IRB. Adverse events and protocol 
deviations will be reviewed by Dr. Bensignor, the clinical nurse, and research 
coordinator after each study visit. Additionally, Dr. Bensignor will receive 
guidance and regulatory support from her mentorship team and the Center for 
Pediatric Obesity Medicine’s Regulatory Specialist, Lisa Hostetler, CCRC. 
Participant Safety:  At the outset, participant risk will be minimized by study team 
adherence to exclusion and inclusion criteria during screening. The proposed 
research will expose the participants to a minor increase over minimal risk. The 
exclusion criteria include, but are not limited to, contraindications to PHN/TPM.  
Participant assessments will be done at study visits every three months. 
Participants and their parent/guardian (if < 18 years) will be provided with 
contact information for Dr. Bensignor (study PI), clinical nurse, and the research 
coordinator with explicit instructions to contact the study team in the event of 
emergencies. 
Participant Stopping Rules:  In the event that a participant has a serious adverse 
event that is deemed related to the study medication and/or procedures by the 
PI, the participant will be required to immediately discontinue the intervention. 
The overall study may be stopped at any time at the request of the PI and/or the 
DSMB. Participants will be removed from the study if suicidal ideation, excessive 

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weight loss, or disordered eating is present at any time during the trial or if any 
clinically significant changes (at the discretion of the PI) in mood and/or 
depression are observed. If the ratio of participants on medication vs. placebo 
developing a serious adverse event requiring withdrawal exceeds 4:1 (after ≥ 50% 
enrollment and a minimum of 5 total events, regardless of group assignment), the 
trial will be stopped. Patients will be instructed that they may withdraw from the 
study at any time and for any reason without impact on their typical clinical care. 
Study Integrity:  As stated above, the study will undergo annual monitoring of the 
facility, staff, and study documents by clinical research associates of the 
University of Minnesota Clinical Trials Monitoring Service. Monitoring staff will 
provide a summary report to Dr. Bensignor and her mentorship team after each 
site visit. If necessary, corrective action plans will be devised and implemented by 
Dr. Bensignor to address deficiencies.   
The PI and research coordinator will generate administrative reports describing the 
study progress, subject recruitment, subject demographic data, subject status, 
compliance with inclusion/exclusion criteria, and adverse events. The study 
statistician and co-mentor, Dr. Rudser, will review data on adverse events, and 
notify Dr. Bensignor if any events pose statistical concern or occur in 
disproportionate numbers throughout the intervention groups.  Further, the PI and 
research coordinator will regularly monitor data for accuracy. 
18.0 Provisions to Protect the Privacy Interests of Participants 
18.1 Protecting Privacy: see HIPCO ancillary review 
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 they have suffered a research related injury.   
19.2 Contract Language:  
Not applicable.  
 
 

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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 parents/guardians to explain the purpose, risk and benefits, and other details 
of the study, and giving the participant and parents/guardians an opportunity to 
ask questions.  A copy of the signed assent and parental consent forms will be 
given to the participants and parents/guardians.  For individuals who are 18 years 
of age or older at study entry, the same process as described above will happen, 
but the participant will sign a consent form.  
In an effort to minimize participant face-to-face time due to COVID-19 concerns, 
the consent discussion and process may be done virtually.  This will be offered to 
be conducted via Zoom for families with a computer and an internet connection 
and the Zoom connection will be encrypted so that it will be private.  The study 
coordinator will mail two copies of the parental consent, assent and HIPAA forms 
and will review the study, review the documents and address any concerns that 
the parent or participant may have.  If the participant and parent agree to enroll 
in the study, they will be asked to sign both copies of each of the forms and 
return one set of originals via mail to the study coordinator for placement in the 
participant file. We anticipate that there will be a date discrepancy between 
when the participant and parent sign the forms and the date the form is returned 
to the study coordinator and a notation will be made about the discrepancy. 
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):  
Not applicable.  
20.4 Non-English Speaking Participants:  
We do not plan on enrolling non-English speaking participants at this time.   
20.5 Participants Who Are Not Yet Adults (infants, children, teenagers under 18 years 
of age): 
This study will enroll participants who are under the age of 18 and they will be 
asked to sign an IRB-approved assent form.  Their parents/guardians will be asked 
to sign a parental consent form. 
Individuals who sign an assent form but turn 18 during the course of the study will 
be asked to sign a consent form and HIPAA to indicate that they are still willing to 

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participate in the study.  A copy of the signed 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:  
● 
Delaware Clinical Research Unit 
● 
Clinical Research Unit 
21.2 International Research:  
Not applicable.  
22.0 Multi-Site Research 
Not applicable.  
23.0 Coordinating Center Research 
Not applicable.  
 
24.0 Resources Available 
24.1 Resources Available:  
The Delaware Clinical Research Unit (DCRU) is a research unit at the University of 
Minnesota that includes a waiting room, playroom, exam rooms, laboratory 
processing facility, temporary freezer and refrigerator storage, physician dictation 
rooms, and an iDXA.  The staff who will be performing the phlebotomy for this 
project have CITI and HIPAA training, have been trained in proper phlebotomy 
techniques and have bloodborne pathogen training and hazardous sample 
shipping training.  The personnel who run the iDXA also have training certification 
on file. 
The Clinical Research Unit (CRU) is a joint venture of MHealth, Fairview, the 
University of Minnesota and UM Physicians.  The unit is equipped for research as 
well as standard medical care and is available for overnight stays, as needed.   
 
 

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