Adjunctive Anti-Obesity Pharmacotherapy in Adolescents and Young Adults After Bariatric Surgery: A Randomized Controlled Pilot Study
Phase: PHASE2
Conditions: Obesity, Morbid, Bariatric Surgery, Adolescent, Young Adult, Drug Therapy
Sponsor: University of Colorado, Denver

Title: Adjunctive Anti-Obesity Pharmacotherapy in Adolescents and Young Adults after 
Bariatric Surgery: A Randomized Controlled Pilot Study 
 
NCT#: NCT04095104 
 
Document Version Date: 07/21/2021 

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COMIRB Protocol 
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD 
CAMPUS BOX F-490    TELEPHONE:  303-724-1055  Fax:  303-724-0990 
 
Protocol #: 18-2793 
Project Title: Adjunctive Anti-Obesity Pharmacotherapy in Adolescents and Young Adults after 
Bariatric Surgery: A Randomized Controlled Pilot Study 
 
 
 
 
Principal Investigator: Jaime Moore, MD 
Co-Investigators: Megan Kelsey, MD; Thomas Inge, MD PhD; Richard Boles, PhD; Marc Cornier, MD 
Version Date: 7/21/21 
 
 
I. Hypotheses and Specific Aims:  
 
Primary Aim 1: Assess the feasibility (including protocol implementation and acceptability) of a 
randomized, placebo-controlled, double-blinded, adjunctive 12-week phentermine + topiramate 
intervention beginning 6-12 months after bariatric surgery, among adolescents and young adults (age 
12-24 years) who don’t achieve expected weight loss or who remain severely obese (n=14 total). 
Hypothesis 1: Protocol implementation, including recruitment and retention, will be feasible based on 
achievement of adequate enrollment and participant completion of at least 80% of study visits. The 
experimental group will report better acceptability compared to the control group based on satisfaction 
with the desired effects of the active drugs.  
 
Secondary Aim 2: Test the initial efficacy of standard of care plus 12 weeks of active drugs or placebo 
on percent weight loss beginning 6 to 12 months postoperatively. 
Hypothesis 2: The experimental group will experience a greater percent weight loss than the control 
group at the end of the 12 week intervention period.  
 
Secondary Aim 3: Evaluate the initial effects of standard of care plus 12 weeks of active drugs or 
placebo on cardiometabolic, eating behavior, and quality of life outcomes beginning 6 to 12 months 
postoperatively. 
Hypothesis 3: The experimental group will demonstrate greater improvements than the control group 
in blood pressure (BP), lipids, alanine aminotransferase (ALT), hemoglobin A1c (HbA1c), and fat mass 
reduction; and, will report less hunger, increased satiety, more cognitive restraint, decreased daily 
caloric intake, increased resting metabolic rate, and better quality of life at the end of the 12 week 
intervention period. 
 
II. Background and Significance:  
Severe obesity affects 4.5 million children and adolescents in the US and is rising across all age 
groups.1,2 Adolescent severe obesity is associated with significantly increased risks of cardiometabolic 
disease, decreased quality of life, and premature death.3–5 The most effective and durable treatment for 
severe obesity is bariatric surgery.6 However, large prospective trials among US adolescents 
demonstrate that even after bariatric surgery, more than 50% will remain severely obese at 3 or more 
years postoperatively,7,8 despite multidisciplinary lifestyle-based postoperative standard of care. To 
date, there have been very few pre- or postoperative factors identified among adolescents that predict 
long-term success after bariatric surgery.9,10 And, neither preoperative nor postoperative lifestyle-based 
interventions in adults have had a clinically meaningful impact on long-term weight outcomes.11,12  
Bariatric surgery is increasingly recognized as an effective and safe tool to treat adolescents with 
severe obesity.7,8,13 Current indications for bariatric surgery in adolescents are either 1) A BMI ≥35kg/m2 
or ≥120% of the 95th percentile + an obesity-related comorbidity or 2) BMI ≥40kg/m2 or ≥140% of the 

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95th percentile alone, and a demonstrated ability to adhere to pre- and postoperative 
recommendations.13 Maximal weight loss after bariatric surgery in adolescents is typically seen at 1 
year (with the most rapid loss within the first 6 months) followed by modest weight regain. In US 
adolescent cohorts, weight loss at 6 months after surgery closely approximates weight loss achieved at 
3 years.7 Notably, in two large observational trials of US adolescents with severe obesity undergoing 
bariatric surgery, 55-63% remained severely obese at long-term follow-up.7,8  
This represents a combination of individuals who did not achieve optimal post-surgical weight 
loss, who experienced significant weight regain, and/or whose preoperative BMI was so high that even 
after expected weight loss they remained severely obese. This suggests that bariatric surgery alone will 
not be the absolute treatment solution for a significant subset of adolescents. These individuals will 
continue to have unacceptably high personal health risks throughout adulthood, and will pose an 
ongoing economic and public health burden to society.14 Interventions that result in even a 1% 
decrease in obesity prevalence could save an estimated $4 billion/year in medical costs alone.15  
Numerous studies in adults have demonstrated that the amount of weight loss after bariatric 
surgery predicts long-term odds of remission for obesity comorbidities. Specifically, total postsurgical 
weight loss is a predictor of type 2 diabetes remission.16–18 Further, in the longest published outcomes 
from the Longitudinal Assessment of Bariatric Surgery Study (LABS-2) cohort 7 years after RYGB, 
individuals in the most favorable weight trajectory (greatest % weight loss) had significantly higher 
remission rates of type 2 diabetes, low HDL cholesterol, and hypertension (adjusted relative risk of 
remission: 2.44, 2.07, and 2.1, respectively) than those with the least favorable trajectory.19 Finally, 
degree of postoperative weight loss is associated with improvements in health-related quality of life up 
to 10 years after surgery.20 In contrast to adults, in whom specific postoperative behaviors (e.g. weekly 
self-weighing, not eating when feeling full, and not eating continuously) explain a significant amount of 
variability in weight loss at three years postoperatively,21 adolescent behaviors associated with post-
operative weight loss have not been identified.10 In addition, perioperative lifestyle-based interventions 
in adults have shown limited efficacy on postoperative outcomes. Anti-obesity medications represent 
an understudied tool that may augment or maintain weight loss, further increase the odds of 
comorbidity remission, and reduce risks of recurrent and incident comorbidities in the post-
bariatric setting.    
Phentermine as a monotherapy is FDA-approved for short-term treatment of obesity in 
adolescents ≥17 years. Topiramate has long been used in pediatrics for epilepsy and migraine 
prevention, and has been studied as an anti-obesity medication in adolescents.22 Among the 5 
medications FDA-approved for long-term treatment of obesity in adults, the combination of phentermine 
and extended release (ER) topiramate results in the most weight loss at 1 year in placebo-controlled 
clinical trials (~20lbs, 15mg/96mg dose; ~15lbs, 7.5mg/46mg dose).23 In two large RCTs of 
phentermine/topiramate in adults, the odds ratio (OR) for achieving ≥10% weight loss was 11.34, and 
the OR for discontinuation of drug due to adverse events was 2.32 vs. placebo.24 This drug combination 
has never been prospectively studied for obesity treatment in adolescents, despite its frequent empiric 
clinical use with good patient tolerance. Phentermine acts as a central nervous system stimulant 
through norepinephrine reuptake inhibition, resulting in appetite suppression and increased resting 
energy expenditure.25 Topiramate’s exact mechanistic effect on appetite is unclear, but is likely linked to 
central GABA and dopamine modulation.25 The only RCT of topiramate for weight loss among 
adolescents was a pilot study in a non-surgical setting that evaluated 24 weeks at 75mg/day and found 
no significant difference in mean percent change in BMI, but this may have been affected by the study’s 
4-week run in of meal replacement.22 A retrospective review of 15mg/day phentermine + SOC vs. SOC 
alone among adolescents with obesity/severe obesity demonstrated a greater percent decrease in BMI 
at 6 months in the phentermine + SOC group vs. matched controls, with no between-group differences 
in blood pressure.26 After bariatric surgery, several retrospective studies in adults have shown 
significant beneficial effects of anti-obesity medications (including phentermine, topiramate, and the 
combination) in halting weight regain and achieving additional weight loss after plateau.27–30  
Additionally, the first ever framework for the use of anti-obesity medications in adolescents 

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highlights the post-surgical period as one setting for which pharmacotherapy should be considered, but 
without a supporting evidence base.31 Thus, studies of anti-obesity pharmacotherapy in adolescents 
are needed.  
 
III. Preliminary Studies  
Unpublished latent class growth trajectory modeling data from our group of the Teen-LABS32 
participants 5 years after Roux-en-Y Gastric Bypass (RYGB) or Sleeve Gastrectomy (SG) demonstrate 
significant heterogeneity in surgical response. Where ³ 20% BMI loss is considered to be an adequate 
response, among adolescents who had RYGB, 16% achieved only a 5% BMI loss and another 21% 
achieved a 16% BMI loss at 5 years. Among those who had SG, 36% achieved only a 7% BMI loss at 5 
years postoperatively. Additionally, greater %BMI loss at 6 months postoperatively was associated with 
a more successful 5-year BMI trajectory. These data further underscore the need for adjunct treatment 
options for a sizeable subset of adolescents within the first year after bariatric surgery.        
The Bariatric Surgery Center at Children’s Hospital Colorado33, led by Drs. Thomas Inge 
(Surgical Director) and Megan Kelsey (Medical Director), began seeing patients in June 2017. Patients 
undergo either SG or RYGB. Over the last 25 months, patient volume has accelerated, and currently 
there are 103 patients in the program (Mean age: 17 [Range: 10-36]; Female: 73%; Race/Ethnicity: 
46% Hispanic, 27% Non-Hispanic White, 14% Black, 13% Other). Based on a chart review of current 
postoperative patients who have had surgery ≥6 months ago, we estimate that 2 patients per month will 
meet inclusion criteria for this study. Therefore, we anticipate that 14 patients will be eligible for 
enrollment during the proposed 7-month recruitment timeline (Table 2). This allows for a 29% reduction 
in eligible individuals from the combination of upfront decline and dropout to successfully meet the 
target sample size of 10. This does not account for projected increases in overall Bariatric Surgery 
Clinic patient volume over the proposed timeline.   
The patented combination pill phentermine/topiramate XR (trade name Qsymia) is generally not 
covered by Colorado insurance plans and costs ~$200/month out of pocket, which makes it 
inaccessible for the vast majority of our patient population. We, like other pediatric weight management 
programs, prescribe phentermine and immediate release topiramate as individual medications 
(~$30/month). This research proposal was designed to mimic this usual practice of prescribing 
individual phentermine and immediate release topiramate pills, which will allow for a more realistic 
assessment of feasibility and increases generalizability. 
Prior to study start, within the Bariatric Surgery Center, we had managed 13 patients 
perioperatively on phentermine, topiramate, or the combination for weight stabilization/loss. The PI and 
primary mentor continue to manage many additional patients on topiramate and phentermine in the 
broader Lifestyle Medicine weight management program at Children’s Colorado, and we have 
developed clinical guidelines for the use of these medications at CHCO. In our perioperative 
experience, these medications are generally very well-tolerated.  
Given the current Food and Drug Administration labeling for each of the proposed study drugs, 
the PI has successfully obtained an Investigational New Drug Application (IND 142590) for this 
pilot study. The IND is active for the use of phentermine and immediate release topiramate in 12-24 
year olds after bariatric surgery as defined in this research protocol. We will follow a data and safety 
monitoring plan (see page 12), which includes an appointed Safety Officer in conjunction with IRB 
approval and study launch. 
 
IV. Research Methods 
 
A.  Outcome Measure(s):   
       Primary Aim 1:  
Feasibility 
• 
Protocol Implementation: recruitment, enrollment, randomization, and dropout rates 

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• 
Acceptability: Adherence to medication: Self-report by questionnaire, pill counts and urine 
amphetamine testing | Tolerability to medication: Self-report by questionnaire assessing 
effects, side effects, barriers to adherence, and standardized assessment of possible 
adverse effects by study staff 
            Secondary Aim 2:  
• 
Weight, BMI  
            Secondary Aim 3:  
• 
Manual blood pressure 
• 
Fasting lipid panel: Total cholesterol, HDL, non-HDL, LDL, Triglycerides 
• 
Alanine aminotransferase (ALT) as a surrogate for non-alcoholic fatty liver disease 
improvement 
• 
Hemoglobin A1c (HbA1c)  
• 
Dietary intake 
• 
Resting metabolic rate 
• 
Body composition and Bone density 
• 
Eating behaviors 
• 
Physical activity 
• 
Quality of Life 
 
B. Description of Population to be Enrolled:   
Fourteen patients (7/arm) followed in the Children’s Hospital Colorado Bariatric Surgery Center 
who meet inclusion criteria: 12-24yo; s/p SG or RYGB; and at 6-12 months post bariatric surgerya, 
have either a) not achieved mean expected weight loss based on national standards and still have 
at least class 1 obesity or b) remain severely obese (≥120% of 95%ile or BMI ≥35kg/m2 for 12-
17yo; BMI ≥35kg/m2 for 18-24yo) will be randomized 1:1 to pharmacotherapy + SOCb or placebo + 
SOC in double-blind fashion. Expected weight loss at 6, 9, and 12 months postoperatively will be 
defined as a ≥26%, ≥28%, and ≥31% decrease in weight, respectively, from preoperative weight 
(within 1 week of surgery) as was observed in the Teen-LABS study.7  
Exclusion criteria: absolute contraindication to phentermine or topiramate (i.e. phentermine: 
history of coronary artery disease, stroke, arrhythmia, congestive heart failure, uncontrolled 
hypertension), hypersensitivity to sympathomimetic amines, current or recent (within 14 days) use 
of monoamine oxidase inhibitors, glaucoma, or hyperthyroidism; topiramate: hypersensitivity to 
topiramate, history of nephrolithiasis), concomitant use of phenytoin, carbamazepine, or carbonic 
anhydrase inhibitors (e.g. zonisamide, acetazolamide, or dichlorphenamide), use of anti-obesity 
medication within 6 months of screening, initiation of a new medication associated with weight loss 
or gain within 30 days of screening, hypothalamic obesity, unmanaged (e.g. without medications 
and/or psychotherapy) clinically significant (determined by a mental health professional using 
diagnostic instruments and/or clinical interview) depression or anxiety, history of any suicidal 
behavior within 30 days of screening or any suicidal ideation with either some intent to act or with 
intent and a specific plan within 30 days of screening, history of severe psychiatric disorders (i.e. 
schizophrenia), severe hepatic impairment (ALT >10x upper limit of normal or known synthetic liver 
dysfunction), moderate or severe renal impairment (GFR <30mL/min/1.73m2), inability to meet 
minimum nutrition requirements, current pregnancy/plans to become pregnant for 16 weeks from 
study drug start date, and any females without a long acting reversible contraceptive (LARC) who 
do not commit to using 2 forms of birth control. (Of note, the vast majority of female patients 
undergoing surgery have a LARC placed intra-operatively, significantly reducing pregnancy risk 
during the trial). Patients on medications for hypertension, dyslipidemia, depression, and anxiety 
should be on these at a stable dose for >4 weeks prior to study enrollment, and on contraception for 
>7 days prior to study enrollment.  
 

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• 
Maximum number of subjects (patients + parent/guardian/LAR counted separately) needed to 
consent at all sites: 60 
• 
Maximum number of local subjects (patients + parent/guardian/LAR counted separately) that 
will be consented, including screen failures and withdrawals: 60 
• 
Number of local subjects (patients + parent/guardian/LAR counted separately) necessary to 
collect sufficient data to answer the research question: 20 
 
Recruitment and Informed Consent/Assent Plan:  
 
The PI and/or professional research assistant (PRA) will review the charts of bariatric surgery 
patients prior to their projected Screening Visit (6, 9, or 12 months postoperatively) to assess the 
percent weight loss trajectory over the preceding postoperative visits to identify those who have not 
achieved expected weight loss and/or whose baseline BMI was so high that even if they were to 
achieve expected weight loss, they would continue to have severe obesity. Chart review for 
evidence of any exclusion criteria will also be performed. For patients who don't have any exclusion 
criteria by chart review and attend the postoperative clinical visit 3 months prior to their projected 
Screening Visit, the PI/PRA will present them the Recruitment Flyer either in person, via secure 
video call, via research MyChart message in the Epic electronic medical record, or by telephone 
with the Recruitment Flyer emailed. For those who express interest, the study team will at the same 
time complete the Pre-screening Consent Script requesting permission to contact the family within 
the week before their Screening Visit with a reminder to fast, if not already done clinically. On the 
day of the Screening Visit, the PI/PRA will review the measured weight/height to confirm whether or 
not weight/BMI inclusion criteria are met. If weight/BMI inclusion criteria are met, the PI/PRA will 
approach the individual and parent/guardian/LAR/proxy during that visit to discuss eligibility, 
complete the inclusion/exclusion criteria form, obtain consent/assent if the patient/parent qualify and 
are interested, and collect Enrollment Visit measures.     
 
When a participant chooses to take the consent home first to read it and/or to reduce in-person  
time on campus, the study team may use an eConsent process. In either situation, the eConsent 
process could be completed in advance of the Screening/Enrollment Visit, with enrollment 
contingent on results of the screening bloodwork and urine pregnancy test for females. A link to the 
eConsent will be emailed to the participant in advance of the informed consent discussion using 
REDCap's survey distribution tool. The eConsent form is designed to allow the participant to 
navigate forward and backward through the entire form and to access the form at a later time if 
desired. As this research is FDA-regulated study, an impartial witness will also participate in the 
informed consent discussion. This witness will either be a family member of the participant's 
choosing, or a clinician, researcher, or PRA who is not part of the study team. The discussion will 
begin with identification of who is participating. During the informed consent discussion, the 
potential participant's questions will be answered and at the end, the participant will verbally confirm 
they agree to be in the study. Because there can only be one signature ("certifier") for each 
REDCap eConsent form, there are separate REDCap eConsent forms for the 
parent/guardian/LAR/proxy, adolescent/young adult, witness, and researcher. The eConsent gives 
subjects the option to download a copy of the signed form. If a participant refuses or is unable to 
eConsent but is still interested in participating, a physical consent will be collected by the study 
team at the next in-person visit to the bariatric surgery center. 
 
Similarly, an eAssent process may be used when a participant (12 years old without intellectual 
disability OR those 12-24 years old with intellectual disability who have decisional capacity 
determined using the COMIRB-preferred method) chooses to take the assent home first to read it 
and/or to reduce in-person time on campus. In either situation, the eAssent process could be 
completed in advance of the Screening/Enrollment Visit, with enrollment contingent on results of the 
screening bloodwork and urine pregnancy test for females. A link to the eAssent will be emailed to 

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the participant in advance of the informed assent discussion using REDCap's survey distribution 
tool. The eAssent form is designed to allow the participant to navigate forward and backward 
through the entire form and to access the form at a later time if desired. During the informed assent 
discussion, the potential participant's questions will be answered and at the end, the participant will 
verbally confirm they agree to be in the study. Because there can only be one signature ("certifier") 
for each REDCap eAssent form, there are separate REDCap eAonsent forms for the 
adolescent/young adult and the researcher presenting the form. The eAssent gives subjects the 
option to download a copy of the signed form. If a participant refuses or is unable to eAssent but is 
still interested in participating, a physical assent will be collected by the study team at the next in-
person visit to the bariatric surgery center. 
 
 
C. Study Design and Research Methods   
 
Figure 1. Study Design  
 
 
 
The pharmacotherapy group will receive oral phentermine and immediate release topiramate in 
combination, up-titrated to goal doses of 16mg and 100mg, respectively over 4 weeks*, then 
maintained at this dose for 8 additional weeks. Topiramate is gradually down-titrated during weeks 
13 and 14 to prevent possible discontinuation symptoms.  
 
 
Dosing Schedule†,§ 
Uptitration: 
• Week 1: 4mg phentermine + 25mg immediate release topiramate 
• Week 2: 8mg phentermine + 50mg immediate release topiramate 
• Week 3: 12mg phentermine + 75mg immediate release topiramate 
Goal Dose:  
• Weeks 4-12: 16mg phentermine + 100mg immediate release topiramate 
Discontinuation (at study Visit 4): 
• Week 13: Discontinue Phentermine + Decrease topiramate to 50mg  
• Week 14: Decrease topiramate to 25mg for 7 days, then discontinue 
 
 (*) Participants who do not tolerate goal doses will be maintained at the highest tolerated dose. 
(§) Per existing literature34 and discussion with pharmacy, participants with moderate hepatic impairment 
(ALT >3x ULN but <10x ULN on two consecutive measures outside of acute illness, and no evidence of 
hepatic synthetic dysfunction), will follow the same dosing schedule, with doses reduced as needed 
based on side effects (See Procedure for Study Drug Dose Reduction/Discontinuation).       

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(†) All topiramate and phentermine doses will be taken once daily in the morning. Per detailed discussion 
with pharmacy, once daily dosing of 100mg per day immediate release topiramate is expected to be 
effective and safe in adolescents, and thus does not require BID dosing. 
 
 
 
We chose to intervene at 6-12 months postoperatively because the first year after surgery 
represents the most rapid phase of weight loss, and interventions that can prolong this most rapid 
phase may result in improved long-term weight loss outcomes. We are not intervening earlier 
because there is a gradual dietary progression followed through the first 3 months after surgery and 
we want participants to be following this stable “lifelong nutrition plan” for at least 3 months before 
introducing medications that can further alter hunger and satiety.  
 
Standard of care will be delivered throughout the study via the Children’s Colorado Bariatric 
Surgery Clinic’s multidisciplinary team, which targets nutrition, physical activity, and self-monitoring. 
This includes routine in-person clinic visits at 6, 9, and 12 months postoperatively.  
 
Concomitant Medications 
Background concomitant medications may be adjusted during the treatment period. Any 
modifications will be recorded at each study visit within the Concomitant Medication Form. Anti-
hypertensives may be adjusted during the treatment period by the study team. In our experience, 
some patients who have significant weight loss on phentermine/topiramate, may have a decrease in 
blood pressure, necessitating a reduction in anti-hypertensive medication dose. Psychiatric 
medications may be altered by the participant’s primary psychiatric prescriber.   
 
D. Description, Risks and Justification of Procedures and Data Collection  
Tools: 
 
1) Study medications  
 
Overall, we contend that for adolescents and young adults who have undergone the most 
effective and durable treatment available (bariatric surgery) for severe obesity, and remain at 
high risk for future obesity-related morbidity and premature mortality, the potential benefits of a 
12-week trial of phentermine + topiramate outweigh the potential risks. 
Phentermine and immediate release topiramate are already being empirically used off label 
in pediatric weight management programs as an adjunctive tool for weight loss when lifestyle-
based interventions +/- bariatric surgery have not resulted in acceptable weight loss or 
cardiometabolic risk reduction. We are proposing a systematic way to begin to study this empiric 
use among adolescents and young adults following bariatric surgery. In all existing trials 
registered on clinicaltrials.gov using phentermine, topiramate, or the combination of the two for 
the treatment of obesity in children and adolescents, individuals with prior bariatric surgery have 
been specifically excluded.  
The FDA recommends that obesity pharmacotherapy interventions last at least 1 year in 
duration. However, for a pilot study with a primary aim of feasibility and acceptability in a novel 
setting, 12 weeks may be considered reasonable.   
 
Phentermine (Justification/Rationale) 
1) Phentermine alone is FDA approved as an adjunct to behaviorally based interventions for 
the short-term treatment of obesity in patients 17 or older with a BMI ≥30kg/m2 or ≥27kg/m2 
plus an obesity-related comorbidity.  The present study proposes to use the lowest dose 
formulation commercially available (8mg scored tablet available as trade name Lomaira35) 
for maximal flexibility in uptitration and dose adjustment based on possible side effects.    

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2) Ryder et al.’s 2017 retrospective review of phentermine’s effectiveness and side effect 
profile in a cohort of 25 obese adolescents who had not undergone bariatric surgery at the 
University of Minnesota’s Pediatric Weight Management Clinic is the only contemporary 
published study of phentermine in obese adolescents.26 The authors compared adolescents 
who received phentermine (15mg/day) + SOC to adolescents who received SOC alone, 
matched on age and BMI. The phentermine + SOC group vs. SOC alone achieved a greater 
percent BMI reduction at 1, 3, and 6 months, with no difference in systolic or diastolic blood 
pressure between the groups. Heart rate was statistically significantly higher in the 
phentermine group at 3 months, but not at 1 or 6 months after phentermine initiation. 
3) Within pediatrics, there is a much larger body of literature examining the use of FDA-
approved stimulant medications for first-line treatment of attention deficit hyperactivity 
disorder (ADHD).36,37 Adderall is approved for use in children as young as 3 years of age 
and methylphenidate is approved in children 6 and older. Guidelines do not recommend any 
differential treatment for children/adolescents with overweight or obesity. We argue that the 
use of phentermine for weight loss poses no greater expected risk in the target population 
than that of an overweight/obese child or adolescent receiving stimulants for ADHD. And, 
that the same precautions applied to children and adolescents for whom an ADHD stimulant 
is considered (i.e. patient selection and monitoring) can be equally applied to those who 
receive phentermine for weight loss.  
4) The proposed period of drug exposure for this initial pilot study is limited, and consistent with 
the Pediatric Endocrine Society’s guidelines for an initial trial of weight loss medication.38 
5) While the target age range for the proposed study is somewhat broad (12-24 years old), the 
mean age of our bariatric surgery clinic population is 16 years. Phentermine is FDA-
approved for short-term use (12-weeks or fewer) in individuals 17 years or above.  
6) Obesity-associated cardiovascular risk can be reduced with even modest weight loss.39 This 
risk reduction is balanced with the possible increased cardiovascular risk associated with 
use of phentermine. 
7) Phentermine is contraindicated in pregnancy. All female bariatric surgery candidates 
routinely undergo contraceptive counseling preoperatively with a gynecologist. The vast 
majority of females have a long acting reversible contraceptive (LARC) placed prior to or at 
the time of surgery. Those who do not must be on two forms of birth control. Additionally, a 
urine pregnancy test will be obtained at enrollment and each study visit.  
8) The Children’s Colorado Bariatric Surgery Center is medically supervised by Drs. Matt 
Haemer (Nutrition), Megan Kelsey (Endocrinology), Shikha Sundaram 
(Gastroenterology/Liver), and Sonali Patel (Cardiology). The behavioral health specialist 
within the Bariatric Surgery Center is pediatric clinical psychologist Dr. Richard Boles. In the 
event of an adverse cardiovascular side effect associated with phentermine use as part of 
this study, we have the ability to obtain prompt clinical evaluation by a Lifestyle Medicine 
cardiologist. Similarly, in the event of an adverse side effect related to mood, we have the 
ability to arrange a prompt mental health evaluation with a Lifestyle Medicine clinical 
psychologist. The PI and primary mentor/bariatric clinic medical director Megan Kelsey will 
manage any other physical medical side effects that may arise. 
 
Phentermine Risk Mitigation Strategy (also see Table 2):  
Steps to mitigate potential risks related to phentermine in this study include exclusion of 
individuals with any absolute contraindication to phentermine (as defined by the FDA label), 
drug interaction check prior to initiation, review of baseline kidney function, ALT, urine 
pregnancy tests at enrollment and every study visit, baseline echocardiogram per standard of 
care in individuals with hypertension or severe obstructive sleep apnea + known poor 
adherence to positive pressure therapy who have not had one in the previous 6 months, 
documented commitment from female participants who don’t have a LARC, to use two forms of 

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birth control, phone calls at 1, 2, and 3 weeks after study pill initiation and weekly during any 
additional titration during the protocol to assess for adverse effects, and evaluation of heart rate, 
blood pressure, comprehensive review of systems and a physical exam performed by a study 
physician at enrollment and every study visit.    
 
Topiramate  
1)  The present study proposes to use generic immediate release topiramate  
tablets.  
2)  Topiramate alone is not FDA-approved to treat obesity at any age.  
3) In pediatrics, there is extensive experience using topiramate in children as young as 2 years 
old for seizure disorders with dosing frequently between 200-400mg/day, compared to the 
100mg per day maximal dose proposed in this study. Topiramate is also FDA-approved for 
migraine prophylaxis in adolescents 12 years and older at a recommended dose of 
100mg/day.  
4) Topiramate is a known teratogen. All female bariatric surgery candidates routinely undergo 
contraceptive counseling preoperatively with a gynecologist. The vast majority of females 
have a long acting reversible contraceptive (LARC) placed prior to or at the time of surgery.  
5) Potential adverse effects of topiramate include paresthesias, fatigue, dysgeusia, 
psychomotor slowing, nephrolithiasis, anhidrosis/hypohidrosis, trouble with 
memory/concentration/word finding, and change in mood.40 In the event of an adverse side 
effect related to mood, we have the ability to arrange a prompt mental health evaluation with 
clinical psychologist Dr. Boles. The PI and primary mentor/bariatric clinic medical director 
Megan Kelsey will manage any physical medical side effects that may arise. 
 
Topiramate Risk Mitigation Strategy (also see Table 2): 
Although the weight loss effect of topiramate is dose-dependent up to ~200mg/day,41 
adverse cognitive side effects are more commonly seen at doses over 100mg/day, and also 
when topiramate is not gradually uptitrated.42,43 Thus, the maximum dose chosen for this study 
is 100mg/day using a gradual up-titration of 25mg per week. Additional steps to mitigate 
potential risks related to topiramate include exclusion of individuals with any absolute 
contraindication to topiramate (as defined by the FDA label), drug interaction check prior to 
initiation, review of baseline bicarbonate, kidney function, ALT, documented commitment from 
female participants who don’t have a LARC to use two forms of birth control, urine pregnancy 
test at enrollment and every study visit, phone call at 1, 2, and 3 weeks after study pill initiation 
and weekly during any additional titration during the protocol to assess for adverse effects, and 
comprehensive review of systems and a physical exam performed by a physician at enrollment 
and every study visit.  
 
Phentermine + Topiramate  
1) Extended release topiramate in combination with phentermine (trade name Qsymia) is FDA 
approved for chronic weight management in adults 18 years and older with a BMI ≥30kg/m2 
or ≥27kg/m2 plus an obesity-related comorbidity. 
2) Phentermine and Topiramate were paired to theoretically reduce/neutralize the side effects 
seen with either medication alone, and additively or synergistically impact weight loss.  
3) The longest published (2 year) weight outcomes and safety data from phentermine + 
controlled release (CR) topiramate in adults demonstrate a -10.5%, -9.3%, and -1.8% 
change in weight from baseline in the phentermine 15mg/topiramate CR 92mg, phentermine 
7.5mg/topiramate CR 46mg, and placebo groups respectively.44 Subjects in both 
phentermine/topiramate CR groups demonstrated greater cardiometabolic benefits than the 
placebo group including greater reductions in triglycerides, greater increases in HDL 
cholesterol, greater improvements in insulin sensitivity, and the need for fewer 

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antihypertensive, lipid lowering, and diabetic medications. The 15mg/96mg group 
demonstrated the lowest risk of progression to type 2 diabetes (76% risk reduction vs. 54% 
for the 7.5mg/46mg group). Anxiety-related adverse events were lowest in the placebo 
group and highest in the 15mg/96mg group, but depression-related adverse events were 
similar between placebo and 15mg/96mg groups. There were no serious cardiac, metabolic, 
or mental health-related adverse events and no deaths in this extension study.  
4) There is no data to suggest that there are unique or increased risks associated with the 
combination of these two medications, compared to the individual risks of each medication 
alone.    
 
Table 2. Possible adverse reactions of medications and mitigation plan 
Phentermine 
Plan to Mitigate Risk 
(Details of the data and safety monitoring plan 
(DSMP) can be found in the next section of the 
protocol) 
Common35 
Restlessness, Irritability, Anxiety 
DSMP; Mood assessment preoperatively, at 
enrollment, and at every study visit; Prompt 
mental health evaluation/management available 
on site 
Dizziness 
DSMP 
Insomnia 
Will be taken in the morning to prevent disruption 
of sleep 
Dry mouth, dysgeusia, diarrhea, 
constipation 
DSMP 
Increased heart rate and/or blood 
pressure 
We are starting with the lowest possible dose 
available and increasing to a maximum dose 
comparable to the highest Qsymia dose (15mg) 
evaluated, and less than 50% of the highest 
available dose (37.5mg); DSMP (including blood 
pressure, heart rate, review of systems, and 
physical exams at every study visit). Individuals 
who meet inclusion criteria and have well-
controlled hypertension, must have a cardiac 
echocardiogram reviewed by Cardiology within 
the prior 6 months before the initiation of 
phentermine, consistent with the Children’s 
Colorado Lifestyle Medicine clinical protocol. 
Rare, but Serious 
Primary pulmonary hypertension, 
Regurgitant cardiac valvular 
disease 
DSMP (including blood pressure, heart rate, 
review of systems, and physical exams at every 
study visit). Individuals who meet inclusion 
criteria and have well-controlled hypertension, 
must have a cardiac echocardiogram reviewed 
by Cardiology within the prior 6 months before 
the initiation of phentermine, consistent with the 
Children’s Colorado Lifestyle Medicine clinical 
protocol. 
Tolerance, Diversion potential 
(without clear evidence of 
withdrawal)45  
Short duration of intervention may reduce risk of 
tolerance.  
Serotonin Syndrome 
Drug interaction check; DSMP 

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Hypoglycemia (in the presence of 
glucose lowering drugs) 
Patients with diabetes are being excluded from 
this study, so the chance that a participant is on 
a glucose-lowering agent is very low. Drug 
interaction check; DSMP; Availability of pediatric 
endocrinologist to adjust medications as needed 
to maintain normoglycemia 
Psychosis 
DSMP; Mood assessment preoperatively, at 
enrollment, and at every study visit. Prompt 
mental health evaluation/management available 
on site 
Pregnancy Risk Factor Category: X 
(Contraindicated in pregnancy) 
Pregnancy tests at every study visit 
Requirement for females to either have a LARC 
(majority) or documented commitment to use 2 
forms of birth control  
Topiramate 
Plan to Mitigate Risk 
(Details of the data and safety monitoring plan 
(DSMP) can be found in the next section of the 
protocol) 
Common (≥5% more frequent than placebo or low-dose Topamax as 
monotherapy) in controlled, epilepsy clinical trials40 
Paresthesia 
DSMP 
Anorexia, Weight Loss 
Desired effect 
Fatigue, Somnolence 
Pairing with a stimulant 
Dizziness 
DSMP 
Psychomotor slowing, Difficulty with 
memory, concentration, attention, 
other cognitive problems, Confusion 
Gradual (4-week) uptitration to 100mg max 
dose42,43; DSMP 
Mood problems 
DSMP; Mood assessment preoperatively, at 
enrollment, and at every study visit. Prompt 
mental health evaluation/management available 
on site 
Fever, Infection 
DSMP 
Flushing 
DSMP 
Common (≥5% more frequent than placebo) in controlled, migraine clinical trials40 
Paresthesia  
DSMP 
Taste perversion 
DSMP 
Common (≥5% more frequent than placebo) in the only RCT for weight loss in 
severely obese adolescents22 
Paresthesia 
DSMP 
Amenorrhea 
Monitoring plan (not unexpected for our females 
with LARCs) 
Concussion 
DSMP 
Dizziness 
DSMP 
Dysgeusia 
DSMP 
Tendon Injury 
DSMP 
Fever due to pharyngitis 
DSMP 
Nausea, Vomiting, Diarrhea 
DSMP 
Rare, but Serious40 

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Acute myopia, Secondary angle 
closure glaucoma 
DSMP 
Oligohidrosis, Hyperthermia 
DSMP (including temperature at every study 
visit) 
Metabolic acidosis 
Bicarbonate at enrollment, visit 2, and visit 4  
Suicidal ideation/attempt 
DSMP with assessment at every study visit 
Fetal toxicity  
(Pregnancy Risk Factor Category 
D- positive evidence of risk) 
Pregnancy tests at enrollment and every study 
visit 
Requirement for females to either have a LARC 
(majority) or documented commitment to use 2 
forms of birth control 
Withdrawal symptoms 
Gradual discontinuation at the end of the study 
Hyperammonemia and 
encephalopathy 
Drug interaction check; DSMP 
Kidney stones 
BMP at enrollment, visit 2, and visit 4; Drug 
interaction check; DSMP 
Topiramate-Ethanol interaction 
(potential to cause increased CNS 
depression) 
Counseling about alcohol avoidance, and 
specific language about this risk in the 
consent/assent 
 
Methods for systematically assessing changes in mood, suicidality, and cognition. 
Mood: 
Changes in mood will be systematically screened for using the Center for Epidemiologic 
Studies Depression Scale (CES-D). This is a 20-item self-report questionnaire that covers areas 
including depressed mood, feelings of guilt/worthlessness, helplessness, psychomotor 
retardation, loss of appetite and sleep disturbance over the previous week.46 This instrument 
has yielded adequate internal reliability that is robust to age, clinical vs. nonclinical setting, and 
risk of bias.47 The original version of the measure is appropriate for individuals 12 years of age 
and older. The CES-D is routinely administered to individuals receiving care at the Children’s 
Colorado Bariatric Surgery Center at every follow-up pre-operative and post-operative clinic 
appointment.  
The proposed study will additionally administer the CES-D at all study visits not aligned 
with a clinical visit and will be scored by the PI or professional research assistant. A CES-D 
score <20 indicates no to mild depressive symptoms. And a CES-D score >20 indicates 
elevated depressive symptoms. This is based on a metaregression that supported higher cut 
points having better diagnostic accuracy.47  
Any study participant who a) newly scores >20 at any time during the study or b) has a 
baseline score of >20 and who demonstrates any absolute increase in this score, compared to 
previous measures, will be discussed within 72 hours with the Bariatric Surgery Center’s 
pediatric clinical psychologist to consider a more comprehensive follow-up clinical interview. The 
clinical interview will guide additional management recommendations, which may include 
psychoeducation on depression, a referral to therapy, a referral to psychiatry, and/or a reduction 
of study medication.   
Weekly phone calls after study drug start also include a question about depressed mood 
over the previous week and if present, ask participants to rank this as mild, moderate, or severe. 
If depressed mood is present and moderate or severe, the PI will discuss follow-up steps with 
the participant and caregiver within 24 hours of identification after consulting with study 
psychologist Dr. Boles; If mild and new, the PI will discuss with study psychologist Dr. Boles 
within 1 week of identification. 
 
 
Suicidality:  

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Suicidal ideation and behavior will be assessed using the Columbia Suicide Severity 
Rating Scale (C-SSRS)48,49 at enrollment and each study visit. Any participant who reports 
suicidal behavior or suicidal ideation with some intent to act (Type 4) or with intent and a 
specific plan (Type 5) during the study will be discussed with the PI during that visit. The PI will 
determine whether the participant should be escorted to the Children’s Hospital Colorado 
Emergency Department for an emergent mental health evaluation or will be discussed within 72 
hours with the Bariatric Surgery Center’s pediatric clinical psychologist for additional 
assessment/treatment recommendations. 
 
For both mood and suicidality, if a participant’s psychiatric disorder can be adequately treated 
with psycho- and/or pharmacotherapy, then the patient, at the discretion of the mental health 
provider, should be continued in the trial on randomized therapy.       
 
Cognition: 
 
At 1, 2, and 3 weeks after study medication initiation, weekly during any additional 
titration during the protocol, and at each study visit, participants will be asked to complete a self-
report checklist of possible adverse effects that have reported associations with the active study 
drugs, which include changes in memory, attention/concentration, word-finding/language, and 
overall academic/job performance, along with the perceived severity of each (mild, moderate, or 
severe). 
Severe cognitive difficulty, which is a drug dose reduction/discontinuation criteria, will be 
defined as self-report of a “severe” change in memory, attention/concentration, or word 
finding/language that the participant believes is significantly impacting academic or job 
performance and that is not otherwise explained by non-study medication related factors.  
Of note, in the one randomized controlled trial of topiramate for weight loss among 
severely obese adolescents50 (24-week intervention of 75mg/day topiramate vs. placebo), Fox 
et al. found no significant differences between topiramate and placebo groups on subscales of 
the Cambridge Neuropsychological Test Automated Battery (CANTAB) or Behavioral Rating 
Inventory of Executive Function-Self Report (BRIEF-SR), and on the Connors Continuous 
Performance Test II (CPT II), the only significant finding was faster reaction time in the 
topiramate group compared to the placebo group.  
 
2) Data and Safety Monitoring Plan (DSMP):  
 
Definitions: The PI will use the FDA’s/Center for Drug Evaluation and Research’s “Guidance 
for Industry Investigators Safety Reporting Requirements for INDs and BA/BE Studies” 
document to define the terms: adverse event (AE), suspected adverse reaction, adverse 
reaction, unexpected, serious, and life-threatening.  
 
1. Describe who will monitor for unanticipated problems of subjects: The PI and the 
professional research assistant (who reports directly to the PI) will primarily monitor for 
unanticipated events (e.g. breach of confidentiality) and unexpected adverse events. 
Additionally, a Safety Officer will be appointed to this study to objectively oversee unanticipated 
problems. We define an unexpected AE (21 CFR 312.32(a)) as an adverse event or suspected 
adverse reaction that is not listed in the FDA-approved label or is not listed at the specificity or 
severity that has been observed. Unexpected also refers to AEs or suspected adverse reactions 
that are mentioned as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with phentermine or 

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immediate release topiramate. All unanticipated problems will be reported to COMIRB within 5 
days of the occurrence. 
 
2. Will the PI be responsible for ongoing review of local adverse events and serious 
adverse events? (physical or psychological harm to subjects): Yes. The PI will be 
responsible for ongoing review of local AEs and serious adverse events (SAE).  
 
 
We define an AE (21 CFR 312.32(a)) as any untoward medical occurrence associated with the 
use of the study drugs, whether or not considered drug related. This may be any unfavorable or 
unintended sign (e.g. abnormal lab), symptom, or disease temporally associated with the use of 
a drug, and does not imply any judgment about causality. 
 
We define an SAE (21 CFR 312.32(a)) as an adverse event or suspected adverse reaction that 
results in any of the following: death, life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. 
Other events could be considered serious if they may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the above listed outcomes (e.g. allergic 
bronchospasm requiring intensive treatment). 
 
Specifically, an AE form will be completed for any complaints/AEs that are participant-reported 
or elicited during the study. And an SAE report will be generated if criteria are met. AEs will be 
identified with the following procedures: 
-Comprehensive review of systems at every study visit (to capture possible AEs not 
reported previously)  
-Physical exam at every study visit (e.g. new murmurs, rubs, or gallops, new increased 
work of breathing, new pulmonary edema, new peripheral edema);   
-Vitals at every study visit (e.g. new fever, tachycardia, new elevated blood 
pressure/hypertension)  
-Phone call 1, 2, and 3 weeks after study drug initiation and in-person with a 
questionnaire at visits 2, 3, and 4 to review known possible side effects of phentermine 
and topiramate 
-Lab monitoring: basic metabolic panel (to assess for new metabolic acidosis: bicarb < 
18 mmol/L); urine pregnancy tests for all females at every visit. 
-Monitoring of mood, suicidality, and cognition per above with validated assessments at 
enrollment and every study visit (e.g. new or worsened depression, new suicidal 
ideation/behavior) 
-Between study visits, participants with questions about symptoms will also be 
encouraged to call the PI directly (voicemail messages are forwarded to the PI’s 
password-protected email) 
 
  
3. To what external entities will local adverse events be reported?: In addition to COMIRB, 
the PI will report local adverse events to the FDA, according to their safety reporting 
requirements: https://www.fda.gov/downloads/Drugs/Guidances/UCM227351.pdf). Specifically, 
the PI will report to the Division of Metabolism and Endocrinology within the FDA’s Center for 
Drug Evaluation and Research, which reviewed the IND application for this study. The PI will 
report to this Division: 1) Any unexpected fatal or life-threatening suspected adverse reactions 
no later than 7 calendar days after initial receipt of the information, and 2) Any a) serious, 
unexpected suspected adverse reactions, b) findings from other clinical/animal/in-vitro studies 

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that suggest significant human risk, and c) a clinically important increase in the rate of serious 
suspected adverse reactions no later than 15 calendar days after determining that this 
information qualifies for reporting. 
  
4. Will periodic global review of safety/adverse events (serious adverse events and adverse 
events) occur?: Yes, reviews will be performed by the PI, and a three-member data and safety 
monitoring board (DSMB), including a primary Safety Officer. 
 
Reviewer 
Expertise 
Review 
Frequency 
Written 
Reports 
Report 
Frequency 
PI 
Board Certified in 
Internal Medicine and 
Pediatrics; Assistant 
Professor in 
Pediatrics, Section of 
Nutrition with 
specialized training in 
pediatric anti-obesity 
pharmacotherapy; 
Primary author of 
Children’s Hospital 
Colorado’s Lifestyle 
Medicine clinical 
protocols for anti-
obesity 
pharmacotherapy. 
Monthly  
Yes 
Within 5 days of any 
SAE and monthly for 
all other AEs 
Medical/Safety 
Officer 
Endocrinology faculty 
member with 
expertise in pediatric 
clinical trials 
Every 3 months 
Yes 
Every 6 months 
Data and Safety 
Monitoring 
Board (DSMB) 
Safety Officer (above) 
+ 2 additional faculty 
with clinical and 
clinical trial expertise 
in using anti-obesity 
pharmacotherapy 
across the age range 
studied 
Every 6 months 
Yes 
Every 6 months 
 
 
A three-member Data and Safety Monitoring board, including a primary Safety Officer, who are 
independent of the study personnel, have been appointed to this study. Like the study staff, they 
will be blinded to participants’ randomized treatment assignments. 
 
The Safety Officer will:  
1) Approve criteria for modifying or discontinuing study drugs for individual participants 
2) Review data generated by the study, including study safety events (SAEs) every 3 months for 
the duration of the study.  
 
The three-member Data and Safety Monitoring Board will: 
1) Evaluate the progress of the trial, including periodic assessments of recruitment, screen 
failures, enrollment, and retention 
2) Report on the safety and progress of the study every 6 months 
3) Consider the impact of new or relevant information such as scientific or therapeutic 
developments (provided by the PI) that may have an impact on the safety or scientific integrity 
of the study. 
4) Determine whether the overall integrity and conduct of the study remain acceptable  

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5) Based on these responsibilities/functions, the DSMB will act in an advisory capacity and 
recommend one of the following actions to the PI (Dr. Moore) every 6 months: 
A) Continue the study according to the protocol and any related amendments. 
B) Modify the study protocol. Modifications may include, but are not limited to, changes in 
inclusion/exclusion criteria, frequency/mechanism of safety monitoring, alterations in 
study procedures, and changes in duration of observation and follow-up.  
C) Discontinue the study (with provisions for organized discontinuation in accordance with 
safe medical practice).    
 
 
5. Will any formal interim analysis be performed?: Interim assessments of feasibility, 
acceptability, and safety per above will be performed, but there will be no formal interim analysis 
for this 12-month study.  
 
6.   Are there defined participant discontinuation criteria?: There are no participant 
discontinuation criteria. However, there are defined drug discontinuation criteria as follows:  
a) Development of an anaphylactic allergic reaction, pulmonary hypertension, evidence of 
new valvular heart disease, uncontrolled systemic hypertension, new arrhythmia (including 
persistent tachycardia), severe anxiety unresponsive to dose decrease, psychiatric disorder 
that cannot be adequately treated with psycho- and/or pharmacotherapy at the discretion of 
the study’s clinical psychologist, serotonin syndrome, or pregnancy during the 
pharmacotherapy intervention will lead to discontinuation of phentermine. 
b) Development of an anaphylactic allergic reaction, nephrolithiasis, severe, persistent 
cognitive difficulties, psychiatric disorder that cannot be adequately treated with psycho- 
and/or pharmacotherapy at the discretion of the study’s clinical psychologist, new acute 
myopia or secondary angle closure glaucoma, severe metabolic acidosis, hyperammonemia 
with encephalopathy, or pregnancy during the pharmacotherapy intervention will lead to 
discontinuation of topiramate. 
c) If one medication is stopped secondary to the criteria above, the participant, if in 
agreement, will be continued on the other medication as monotherapy. 
d) With consent, participants for whom one or both medications are stopped will continue to 
be followed according to the proposed study timeline.  
 
7. How will the PI/research team determine if an adverse event (AE) is related to either of the 
study drugs?  
Relatedness will be defined according to the National Institutes of Health National Institute 
on Aging Data Safety and Monitoring Plan Toolkit template 
(https://www.nia.nih.gov/research/dgcg/clinical-research-study-investigators-toolbox/data-
and-safety-monitoring) as follows: 
• 
Definitely Related: The AE is clearly related to the study drug i.e. an event that follows 
a reasonable temporal sequence from administration, follows a known or expected 
response pattern to the drug (intervention), that is confirmed by improvement on 
stopping and reappearance of the event on repeated exposure and that could not be 
reasonably explained by the known characteristics of the subject’s clinical state.  
• 
Possibly Related: An AE that follows a reasonable temporal sequence from 
administration of the study drug (intervention), follows a known or expected response 
pattern to the intervention, but that could readily have been produced by a number of 
other factors.  
• 
Not Related: The AE is clearly not related to the drug i.e. another cause of the event is 
most plausible; and/or a clinically plausible temporal sequence is inconsistent with the 

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onset of the event and the study intervention and/or causal relationship is considered 
biologically implausible. 
 
8. Are there overall protocol/study stopping rules?: Any life-threatening adverse drug 
experience (other than an anaphylactic reaction), or death of any patient, determined to be 
associated with either study drug.  
 
2) Data collection tools 
• 
Primary Aim 1: Questionnaires. We believe these represent a minimal risk to participants. 
The only potential study-related burden for these tools is the time required to complete 
them, which we have factored into our determination for incentives. These are essential to 
adequately address Aim 1. 
• 
Secondary Aim 2: Weight. Measuring weight is a standardized part of every primary care 
and most specialty care medical visits throughout the lifespan. We believe this represents 
minimal risk to participants. In the perioperative setting for adolescent bariatric surgery, 
patients have the option to decline being informed of their weight if this increases stress, 
anxiety, or other emotional discomfort. Change in weight is the central physiologic measure 
of interest for this study to assess initial efficacy of the medication vs. placebo group.  
• 
Secondary Aim 3: Venipuncture for bloodwork, manual blood pressure, DEXA, indirect 
calorimetry, and questionnaires.  
 
o We believe the manual blood pressure and questionnaires (routine components of 
most medical visits) both represent minimal risk.   
o For routine clinical care, all bariatric surgery patients undergo venipuncture for lab 
monitoring at 6, 9, and 12 months postoperatively. Study-specific labs will be added 
to these routine blood draws. The additional study-specific blood tests are needed to 
detect any changes (between intervention and control groups) in lipids, ALT, and/or 
hemoglobin A1c as a result of the medication. A pediatric CTRC research nurse will 
be scheduled to obtain labs at study visit 2, and at Enrollment and study visit 4 if not 
obtained by the clinical lab. The risks of a venipuncture include pain at the puncture 
site, possible bruising and edema around the puncture site, less commonly 
dizziness/presycope/syncope, and rarely infection. 
o DEXA scans will be performed at Visits 1 and 4 (of the total body, hip, and spine). 
The cumulative radiation exposure from these tests is considered small and is not 
likely to adversely affect participants. The potential risks related to the additive effect 
of radiation over a lifetime is included in the assent/consent. 
o Indirect calorimetry will be performed at Visits 1 and 4, and uses a canopy method. 
Potential risks include a feeling of claustrophobia, which are included in the 
assent/consent. 
 
• 
Optional banking of specimens for future research: This is an optional procedure. For those 
who assent/consent, blood and urine samples will be collected at Enrollment, Visit 2, and 
Visit 4. DNA will be isolated from a portion of the whole blood collected at the Enrollment 
visit only in Dr. Christina Aquilante’s lab at the University of Colorado Skaggs School of 
Pharmacy after all samples are collected. Prior to DNA isolation, the samples will be stored 
at -80°C. The isolated DNA will be stored at -20°C. All other blood and urine specimen, will 
be processed, fractionated (as appropriate), aliquoted and stored at -80°C.   
 
3) Research-specific study visits  

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• 
Patients in the Bariatric Surgery program at Children’s Colorado have several standard 
postoperative visits in the first year after surgery including at 3, 6, 9, and 12 months. The 
screening/enrollment visit will take place concurrent with the 6, 9, or 12 month postop visit 
whenever possible. For those with a screening/enrollment visit at 6 or 9 months, Visit 4 will 
typically take place concurrent with the 9 or 12 month postop visit, respectively. For those 
with a screening/enrollment visit at 12 months, Visit 4 will typically not be concurrent with a 
regularly scheduled postop visit.  
• 
There will be a screening visit at 6, 9, or 12 months postoperatively. Eligible participants will 
be consented at this visit, and will be asked to come to campus ~1 week later for study visit 
1. Enrollment and Visit 1 cannot be combined because it is unrealistic to screen, consent, 
randomize, obtain study drug, and complete additional measures after an already lengthy 
clinical appointment.  
• 
The Children’s Hospital Colorado Lifestyle Medicine weight management program’s clinical 
protocols for anti-obesity pharmacotherapy require monthly clinic visits for the first three 
months after initiation for monitoring of effects and side effects. The proposed study protocol 
follows this standard. 
 
Data Collection Tools (See Table 3. below for Schedule of Measures) 
a) Sociodemographic characteristics: age, sex, race/ethnicity, insurance, highest level of primary 
caregiver’s education, household size and income, government-based assistance, and 
presence/absence of food insecurity will be obtained from the medical record and the 
Demographics Form.  
b) Feasibility of protocol implementation: rates of recruitment, enrollment, randomization, and 
dropout  
c) Study medication adherence & tolerability: assessed by 1) Questionnaire: description/dose/start 
date of medications, missed doses, and checklists of: effects, adverse effects, and evidence-
based barriers to adherence51,52; 2) Pill counts; 3) Urine amphetamine screen 
d) Self-reported changes to all non-study medications: name/dose, interim changes 
e)  Patient/family satisfaction questionnaire will assess: reasons for participation, experience 
during study visits, satisfaction with the effect of the study medication/placebo, ease of 
communication with study staff, and time burden/inconvenience 
f) Biological outcome and safety measures: Weight, height, heart rate (HR), BP, basic metabolic 
panel, lipids, ALT, HbA1c, and pregnancy test 
g) Optional Biobanking: Gold top (serum-3.5mL blood), Purple top (EDTA-4mL whole blood), 
Green top (heparinized plasma-4mL blood), and Urine (volume that remains after the urine 
pregnancy test for females and a separate urine collection for males) will be collected with 
participant assent/consent for future research questions.  
h) 3-day dietary record: Participants will complete a dietary record on 3 consecutive days (2 
weekday, 1 weekend day) based on standardized protocols for dietary assessment.53 
i) 
Previous Day Physical Activity Recall (PDPAR): validated and reliable questionnaire that 
detects changes in physical activity behavior.54   
j) 
Impact of Weight On Quality of Life-Kids & Lite (IWQOL-Kids & Lite): Kids: 27-item self 
(validated up to age 19) + parent-report assesses the impact of weight on: physical comfort, 
body esteem, social life, and family relations, and has known minimally clinically important 
difference scores and high test-retest reliability.55,56 Adult (> age 20): 31-item validated tool that 
assesses overall, physical, self-esteem, sexual, public distress, and work.57   
k) PedsQL: a validated measure of overall health-related quality of life 
l) 
Center for Epidemiologic Studies Depression Scale (CES-D): a 20-item self-report questionnaire 
that covers areas including depressed mood, feelings of guilt/worthlessness, helplessness, 
psychomotor retardation, loss of appetite and sleep disturbance over the previous week. It has 
good internal reliability that is robust to age, clinical vs. nonclinical setting, and risk of bias.47 

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m) Columbia Suicide Severity Rating Scale (C-SSRS): a validated, clinician-administered 
assessment of suicidal ideation and behavior among adolescents and adults.48   
n) Resting Metabolic Rate: using a canopy system 
o) DEXA-3 site: total body scan to measure body composition; hip and spine scans to determine 
bone density, all using standardized protocols  
p) Visual Analogue Appetite Ratings (VAS): self-reported assessment of hunger/satiety before and 
after meals and snacks 
q) Three Factor Eating Questionnaire (TFEQ): validated questionnaire that measures cognitive 
restraint, uncontrolled eating, and emotional eating58 
r) Eating in the Absence of Hunger (EAH) parent-report: validated measure that describes eating 
when not hungry59  
 
Route of Data Collection: To reduce in-person time on campus for participants, components of 
Study Visits 1-4 will be collected remotely (designated by superscript “R” in Table 3 below) either 
via secure video call or telephone call (with questionnaires emailed) in the participant’s/guardian’s 
preferred language within the same week and ideally on the same day as the study visit. These 
measures will be conducted remotely unless it is not possible or places an undue burden on the 
participant to do so (e.g. participant does not have a reliable internet connection or has a limited 
phone data plan that incurs significant charges). Pill count will require a video connection. All other 
measures require in-person collection/administration to appropriately collect outcome/safety data.  
 
Table 3. Schedule of Measures 
“X”= Study specific                   
“O”= Standard of Care 
#= Bariatric Clinic or CHCO CTRC  
‡= + Adult CTRC or CHCO 
Radiology/CTRC  
R= can be delivered remotely 
 
 
 
SCREENING/ 
ENROLLMENT#  
6-12 mo post-
op 
 
STUDY VISIT 1#,‡ 
~1wk after 
Enrollment 
STUDY VISIT 2# 
4wks after Visit 1 
 
STUDY VISIT 3# 
4 wks after Visit 2 
 
 
 
STUDY VISIT 4#,‡ 
4 wks after Visit 3 
 
 
 
Review of Inclusion/Exclusion 
criteria 
X 
 
 
 
 
Echocardiogram (ONLY for those 
with Hypertension or Severe OSA 
with poor PAP adherence IF not 
obtained in the prior 6 months) 
O 
 
 
 
 
Demographics Form 
 
XR 
 
 
 
Feasibility of protocol 
implementation (e.g. enrollment 
rates, dropout rates) 
X 
X 
X 
X 
X 
Study medication adherence & 
tolerability- Study Med Form 
 
 
XR 
XR 
XR 
Study medication adherence-
(pill count)- Study Med Form 
 
 
XR 
XR 
XR 
Study medication adherence 
(urine amphetamine screen) 
 
X 
X 
X 
X 
Review of all non-study 
medications (self-report) 
X 
XR 
XR 
XR 
XR 
Patient/family satisfaction 
survey 
 
 
 
 
XR 
Weight, Height, Temperature, 
HR, BP; Review of Systems;  
Physical exam 
 
X 
X 
X 
X 
Urine pregnancy test 
X 
X 
X 
X 
X 
Lipid panel, ALT, HbA1c  
X 
 
 
 
X 
Basic metabolic panel 
X 
 
X 
 
X 
Optional Biobanking  
X 
 
X 
 
X 
3-day diet record review  
 
XR 
 
 
XR 
Previous Day Physical Activity 
Recall (PDPAR) 
 
XR 
 
 
XR 

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IWQOL-Kids (£19yo)/-Lite (³ 
20yo) & Parent Report 
 
XR 
 
 
XR 
PedsQL (general health-related 
quality of life) 
 
XR 
 
 
XR 
CES-D (Depression Screen) 
O 
X 
X 
X 
X 
C-SSRS (Suicide Screen) 
X 
X 
X 
X 
X 
Resting metabolic rate 
 
X 
 
 
X 
DEXA-3 site 
 
X 
 
 
X 
Clinical Intervention/Translation 
Core: Eating behavior 
questionnaires (VAS, TFEQ, 
EAH) 
 
XR 
XR 
XR 
XR 
 
In addition to the above in-person study visits and designated remote data collection, there are 
eight standard study phone calls in the protocol:  
• 
Phone Call 1: 1-2 days before the Screening/Enrollment Visit 0 (Reminder to fast) 
• 
Phone Call 2: 1 week before Visit 1 (Phone Call Script 1) 
• 
Phone Call 3: 1 week after Visit 1 (Phone Call Script 2)  
• 
Phone Call 4: 2 weeks after Visit 1 (Phone Call Script 2) 
• 
Phone Call 5: 3 weeks after Visit 1 and 1 week before Visit 2 (Phone Call Scripts 1 & 2) 
• 
Phone Call 6: 1 week before Visit 3 (Phone Call Script 1) 
• 
Phone Call 7: 1 week before Visit 4 (Phone Call Script 1)  
• 
Phone Call 8: 1 week after last dose of study drug (Phone Call Script 2)  
If a participant requires additional dose titration during the protocol, the PI will conduct additional 
weekly phone calls until study medication dosage is stable.  
 
 
    
E.   Potential Scientific Problems:   
Benchmarks for success, pitfalls, and alternatives:  
Primarily, we expect this protocol to demonstrate feasibility, which will form the foundation for a 
larger study of pharmacotherapy as an adjunct to bariatric surgery. Secondarily, we expect to 
demonstrate short-term efficacy of pharmacotherapy in terms of promoting additional weight loss 
and improving biological markers.  
Pitfalls: The perioperative bariatric surgery process is time-intensive, which may impact a 
family’s decision to enroll/complete a study that requires three to four visits outside of routine 
clinical care. Each of the 4 study visits will be reimbursed at $100/visit, with an additional possible 
$50 earned at Visit 4 if pre-defined medication adherence targets are met (total $400-$450). 
Participants traveling specifically for this research study (i.e. not already traveling for a clinical 
reason) who live >100 miles away from the Anschutz Medical Campus, will be reimbursed up to 
$300 for lodging, flight, and/or gas mileage expenses per study visit. Additionally, study medications 
will be provided at no cost. And, those in the placebo group may benefit relative to those not in the 
study because of the association between increased medical contacts and improved obesity 
outcomes. Our inclusion criteria combines two patient subgroups- those who do not achieve 
adequate weight loss and those who remain severely obese regardless of adequate weight loss. 
Although response to surgery is different, the ongoing risk for obesity-related morbidity is expected 
to be similar. Preliminary analysis of initial efficacy measures (Aims 2,3) for these two groups will be 
conducted to allow for detection of differences. Finally, we recognize that this “12 week” intervention 
includes 4 weeks of up-titration of medication. Thus, the duration on goal therapeutic doses of 
16mg phentermine and 100mg immediate release topiramate is only 9 weeks. This decision was 
driven by the primary feasibility aim, and reduces participant burden. Depending on the outcome of 
this study, future studies with primary aims of efficacy and safety could prolong the duration of 
exposure at the goal doses of medication.  

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Alternatives: Given our success in using these anti-obesity medications clinically and previous 
experience and success of the study mentors in clinical trials, we feel confident in our ability to 
recruit and retain participants. However, if study numbers fall short within the timeframe of the 
funding, we can recruit older adolescents and young adults within the 18-24 year age range through 
an established relationship with the adult bariatric surgery program and Anschutz Health and 
Wellness Center at the University of Colorado. Regardless of the outcomes, the skills I will develop 
from this study will still be highly applicable to future studies. Specifically, as a PI of an investigation 
that uses RCT methodology, intervention development and testing, analysis, and dissemination, I 
would be well positioned to investigate other adjunctive perioperative therapies for severe obesity 
(e.g. intensive nutritional strategies). 
 
F.   Data Analysis Plan:   
Sample size justification: Based on recommended practice for pilot studies,60 the minimum sample 
size (10 total participants, 5 per arm) is driven by the primary aim of the study and represents a 
balance between participant availability (patient volume and recruitment timeline), and acceptable 
precision around feasibility estimates (Aim 1), which will be used for subsequent study planning. It is 
not based on a power calculation for group differences seen in any Aim 2 or 3 measures. To 
estimate precision around dropout and medication tolerability rates, we used a confidence interval 
approach with normal approximation of the binomial calculation60–62: First, we estimate that a 
realistic dropout rate is 25%, based on 3 prior anti-obesity medication RCTs conducted in obese 
adolescents.22,63,64 A realistic medication tolerability rate (% who do not discontinue medication 
because of adverse effects) is 85%, based on the single RCT of topiramate in adolescents and two 
larger RCTs of phentermine/topiramate XR in adults.22,65,66 Dropout: With the minimum of 10 
adolescent/young adult participants, if our observed dropout rate is 25%, we can be 68% confident 
that the enrollment rate estimate is accurate within 13 percentage points (or 90% confident that it is 
accurate within 20%). With 14 adolescent/young adult participants, if our observed dropout rate is 
25%, we can be 68% confident that the enrollment rate estimate is accurate within 11 percentage 
points (or 90% confident that it is accurate within 18%). Medication tolerability: With 10 
adolescent/young adult participants, if our observed medication tolerability rate is 85%, we can be 
68% confident that the tolerability estimate is accurate within 9 percentage points (or 90% confident 
that it is accurate within 16%). With 14 adolescent/young adult participants, if our observed 
medication tolerability rate is 85%, we can be 68% confident that the tolerability estimate is accurate 
within 9 percentage points (or 90% confident that it is accurate within 15%). Given possible 
constraints around enrollment, the level of precision with 10 or 14 adolescents/young adults was 
deemed acceptable to achieve protocol refinement for future RCT development.  
 
Planned analyses: Descriptive statistics will characterize the study population. Independent samples 
t-tests will be performed for continuous variables and chi-square for categorical variables to 
determine statistically significant differences between experimental and control groups. Aim 1: 
Feasibility of acceptability (adherence, tolerability, and satisfaction) will be descriptively assessed 
using differences in proportions between experimental and control groups. Feasibility of protocol 
implementation will be established by determining the proportions (rates) of recruitment, enrollment, 
randomization, and dropout. Aims 2,3: Estimated means and variability of continuous health 
outcome variables (e.g. % change in weight) and intra- and intersubject variability of repeated 
measures (e.g. loss of control eating) will be graphically presented and visually compared for 
experimental vs. control groups, as this aim is not powered to run inferential statistics. 
 
 
G.  Summarize Knowledge to be Gained:   
The goal of this study is to establish the feasibility and initial efficacy of two common anti-obesity 
medications for adolescents who require additional risk reduction following bariatric surgery. 

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Adolescents with severe obesity who don’t achieve optimal weight loss and co-morbidity 
improvement after bariatric surgery have few evidence-based treatment options to mitigate 
significant health risks through the remainder of adulthood. This study has the potential for 
substantial impact regardless of results, given that anti-obesity medications are currently being 
used in the post bariatric surgery setting without an evidence base. A recent international pediatric 
obesity webinar (4/2019) with contributors from leading adolescent bariatric surgery centers 
strongly expressed need and enthusiasm for studying the role of pharmacotherapy after surgery. 
Our center’s volume, interdisciplinary expertise, and existing IND to study these medications 
in this setting sets us apart as the best positioned adolescent bariatric surgery center to 
carry out this initial pilot, with high potential for a subsequent larger multi-site RCT to evaluate 
safety and efficacy, mechanism of action, and predictors of response.  
  
 
 H. References: 
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