Phentermine/tOpiramate to eND Obesity and Uric Acid Stones Trial (POuND OUT)
Phase: PHASE3
Conditions: Obesity, Uric Acid Stones, Type 2 Diabetes Mellitus in Obese, Pre-Diabetes
Sponsor: University of Florida

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
1 
Phentermine/tOpiramate to eND Obesity and Uric acid 
stones Trial (POuND OUT) 
Unique Protocol Identification Number: NIH R21 DK122317 
National Clinical Trial (NCT) Identified Number: 04621929 
Principal Investigator: Benjamin K. Canales MD 
[IND/IDE] Sponsor: Benjamin K. Canales MD 
Funded by: NIDDKD 
Draft Number: 4.0  
 
December 17,2021 
 
 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
  
  
  
  
  
  
 
 
Table of Contents 
Statement of Compliance .............................................................................................................................................. 4 
1 Protocol Summary ...................................................................................................................................................... 5 
1.1 Synopsis ............................................................................................................................................................... 5 
1.2 Schema ................................................................................................................................................................ 6 
1.3 Schedule of Activities (SoA) ................................................................................................................................. 7 
2 Introduction ................................................................................................................................................................ 8 
2.1 Study Rationale .................................................................................................................................................... 8 
2.2 Background .......................................................................................................................................................... 9 
2.3 Risk/Benefit Assessment.................................................................................................................................... 11 
2.3.1 Known Potential Risks ................................................................................................................................. 11 
2.3.2 Known Potential Benefits ........................................................................................................................... 13 
2.3.3 Assessment of Potential Risks and Benefits ............................................................................................... 13 
3 Objectives and Endpoints ......................................................................................................................................... 14 
4 Study Design ............................................................................................................................................................. 15 
4.1 Overall Design .................................................................................................................................................... 15 
4.2 Scientific Rationale for Study Design ................................................................................................................. 17 
4.3 Justification for Dose ......................................................................................................................................... 17 
4.4 End of Study Definition ...................................................................................................................................... 18 
5 Study Population ...................................................................................................................................................... 18 
5.1 Inclusion Criteria ................................................................................................................................................ 18 
5.2 Exclusion Criteria ............................................................................................................................................... 18 
5.3 Lifestyle Considerations ..................................................................................................................................... 19 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
2 
5.4 Screen Failures ................................................................................................................................................... 19 
5.5 Strategies for Recruitment and Retention ......................................................................................................... 19 
6 Study Intervention .................................................................................................................................................... 21 
6.1 Study Intervention(s) Administration ................................................................................................................ 21 
6.1.1 Study Intervention Description ................................................................................................................... 21 
6.1.2 Dosing and Administration ......................................................................................................................... 21 
6.2 Preparation/Handling/Storage/Accountability .................................................................................................. 22 
6.2.1 Acquisition and accountability .................................................................................................................... 22 
6.2.2 Formulation, Appearance, Packaging, and Labeling ................................................................................... 22 
6.2.3 Product Storage and Stability ..................................................................................................................... 22 
6.2.4 Preparation ................................................................................................................................................. 23 
6.3 Measures to Minimize Bias: Randomization and Blinding ................................................................................. 23 
6.4 Study Intervention Compliance ......................................................................................................................... 23 
6.5 Concomitant Therapy ........................................................................................................................................ 24 
6.5.1 Rescue Medicine ......................................................................................................................................... 24 
7 Study Intervention Discontinuation and Participant Discontinuation/Withdrawal ................................................. 24 
7.1 Discontinuation of Study Intervention .............................................................................................................. 24 
7.2 Participant Discontinuation/Withdrawal from the Study .................................................................................. 24 
7.3 Lost to Follow-Up ............................................................................................................................................... 24 
8 Study Assessments and Procedures ......................................................................................................................... 26 
8.1 Efficacy Assessments ......................................................................................................................................... 26 
8.2 Safety and Other Assessments .......................................................................................................................... 26 
8.3 Adverse Events and Serious Adverse Events ..................................................................................................... 27 
8.3.1 Definition of Adverse Events (AE) ............................................................................................................... 27 
8.3.2 Definition of Serious Adverse Events (SAE) ................................................................................................ 27 
8.3.3 Classification of an Adverse Event .............................................................................................................. 28 
8.3.4 Time Period and Frequency for Event Assessment and Follow-Up ............................................................ 29 
8.3.5 Adverse Event Reporting ............................................................................................................................ 29 
8.3.6 Serious Adverse Event Reporting................................................................................................................ 31 
8.3.7 Reporting Events to Participants ................................................................................................................ 31 
8.3.8 Events of Special Interest ........................................................................................................................... 31 
8.3.9 Reporting of Pregnancy .............................................................................................................................. 31 
8.4 Unanticipated Problems .................................................................................................................................... 32 
8.4.1 Definition of Unanticipated Problems (UP) ................................................................................................ 32 
8.4.2 Unanticipated Problem Reporting .............................................................................................................. 32 
8.4.3 Reporting Unanticipated Problems to Participants .................................................................................... 32 
9 Statistical Considerations ......................................................................................................................................... 33 
9.1 Statistical Hypotheses ........................................................................................................................................ 33 
9.2 Sample Size Determination................................................................................................................................ 33 
9.3 Populations for Analyses ................................................................................................................................... 34 
9.4 Statistical Analyses............................................................................................................................................. 34 
9.4.1 General Approach ....................................................................................................................................... 34 
9.4.2 Analysis of the Primary Efficacy Endpoint(s) .............................................................................................. 34 
9.4.3 Analysis of the Secondary Endpoint(s) ....................................................................................................... 34 
9.4.4 Safety Analyses ........................................................................................................................................... 35 
9.4.5 Baseline Descriptive Statistics .................................................................................................................... 35 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
3 
9.4.6 Planned Interim Analyses ........................................................................................................................... 35 
9.4.7 Sub-Group Analyses .................................................................................................................................... 35 
9.4.8 Tabulation of Individual Participant Data ................................................................................................... 35 
9.4.9 Exploratory Analyses .................................................................................................................................. 35 
10 Supporting Documentation and Operational Considerations ................................................................................ 35 
10.1 Regulatory, Ethical, and Study Oversight Considerations ................................................................................ 35 
10.1.1 Informed Consent Process ........................................................................................................................ 35 
10.1.2 Study Discontinuation and Closure ........................................................................................................... 37 
10.1.3 Confidentiality and Privacy ....................................................................................................................... 37 
10.1.4 Future Use of Stored Specimens and Data ............................................................................................... 37 
10.1.5 Key Roles and Study Governance ............................................................................................................. 37 
10.1.6 Safety Oversight ........................................................................................................................................ 37 
10.1.7 Clinical Monitoring .................................................................................................................................... 37 
10.1.8 Quality Assurance and Quality Control ..................................................................................................... 38 
10.1.9 Data Handling and Record Keeping .......................................................................................................... 38 
10.1.10 Protocol Deviations................................................................................................................................. 39 
10.1.11 Publication and Data Sharing Policy ....................................................................................................... 39 
10.1.12 Conflict of Interest Policy ........................................................................................................................ 40 
10.2 Additional Considerations ............................................................................................................................... 40 
10.3 Abbreviations ................................................................................................................................................... 40 
10.4 Protocol Amendment History .......................................................................................................................... 42 
11 References .............................................................................................................................................................. 43 
 
 
 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
4 
STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Council on Harmonisation Good 
Clinical Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and the 
National Institute of Diabetes and Digestive and Kidney Diseases at the NIH. The Principal Investigator 
will assure that no deviation from, or changes to the protocol will take place without prior agreement 
from the funding agency and documented approval from the Institutional Review Board (IRB), and the 
Investigational New Drug (IND) sponsor, if applicable, except where necessary to eliminate an 
immediate hazard(s) to the trial participants. All personnel involved in the conduct of this study have 
completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent form(s) 
must be obtained before any participant is consented. Any amendment to the protocol will require 
review and approval by the IRB before the changes are implemented to the study. All changes to the 
consent form(s) will be IRB approved; a determination will be made regarding whether a new consent 
needs to be obtained from participants who provided consent, using a previously approved consent 
form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
5 
1 PROTOCOL SUMMARY 
1.1 SYNOPSIS 
Title: 
Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Study 
Description: 
Mounting evidence indicates that obesity, diabetes mellitus, and kidney stones are inter-connected 
diseases, particularly uric acid nephrolithiasis (UAN) with or without components of calcium oxalate (CO). 
Obese or overweight diabetics have a six-fold increased risk to develop UAN/COUAN because they are 
unable to properly add buffer (ammonium) to their urine. The FDA-approved weight loss drug Qsymia® 
(15mg/92 mg; phentermine/topiramate-ER, Vivus Inc.) is the most effective weight loss drug (of the five 
currently on the market) and has a unique side effect of alkalinizing the urine, or making it less acidic. We 
hypothesize that treatment of obese, diabetic patients with phentermine/topiramate will reduce the 
incidence of UAN/COUAN by 1) direct urinary alkalinization and 2) weight loss. Weight loss will indirectly 
improve urinary buffering ability through improvement in insulin sensitivity and will decrease renal 
oxidative stress. Our group proposes an 18 month, feasibility pilot study, randomizing up to 40 obese and 
diabetic individuals with UAN/COUAN to either phentermine/topiramate (n=20) or a pragmatic control 
group (n=10) who would remain on their standard medication regimen (citrate salts, allopurinol, diet, 
etc). 
Objectives: 
Primary Objective: new stone formation, kidney stone growth 
Secondary Objectives: weight loss, urinary parameters 
Endpoints: 
Primary Endpoint: 1) kidney stone growth (mm2) as determined by non-contrast CT scan; 2) new kidney 
stone growth (mm2) as determined by non-contrast CT scan 
Secondary Endpoints: 1) change in weight over 18 months expressed by total % body weight loss (total 
weight loss in pounds/starting weight in pounds); 2) % change in urinary parameters (urine pH, urinary 
citrate, urinary calcium, urinary 8-isoprostane, urinary hydrogen peroxide) end of study compared to 
baseline; 3) mean change in hemoglobin A1c end of study compared to baseline. 
Study 
Population: 
We plan to enroll up to 40 adults (male and female) age 18 years – 75 years with recurrent uric acid or 
mixed calcium oxalate/uric acid stones (defined by at least two spontaneous kidney stone passages or 
procedures and at least one stone analysis >80% uric acid) who are diabetic (as demonstrated by use of 
anti-hyperglycemic meds or insulin) and obese (defined as BMI > 30 kg/m2) and live in north central 
Florida or south Georgia (southern US). 
Phase: 
3 
Site 
Description 
Single site within the United States (University of Florida) 
Description of 
Study 
Intervention: 
Participants will take once daily oral phentermine and twice daily topiramate for weight loss and urinary 
alkallinization 
Study 
Duration: 
3 years 
Participant 
Duration: 
18 months 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
6 
1.2 SCHEMA 
 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
7 
1.3 SCHEDULE OF ACTIVITIES (SOA) 
a – All subjects will be expected to continue on treatment until end of month 17 when a medication taper x 9 days 
will occur. If a subject withdraws from the study after starting drug Treatment Period, an ETV should be conducted 
b - Visit 1 (screening), 3 will be conducted by phone interview; Visit 7 is a home 24 hour urine 
c - Height will only be taken at first visit. 
d - Subjects will provide one 24-hour urine collection. The collection does not occur at the site visit. Recollection of 
inadequate sample will be allowed. 
e - A baseline study scan is not necessary as long as one scan has been performed within last 6 months. End of study 
CT scan may be performed by primary physician as standard of care imaging. 
f – Baseline urine pH < 5.8, ≥80% uric acid mineral, and adequate imaging are necessary to confirm eligibility prior 
to randomization. If subject is randomized to drug, he/she will pick up Rx at CTSI pharmacy 
g – At Visit #4: At the discretion of the Benjamin Canales, MD (PI) 1) if TBWL < 5%, increase phentermine dose to 
37.5 mg daily for remainder of study; 2) if urine pH < 6.5, increase topiramate to 150 mg daily and repeat 24 hour 
urine 6 weeks later (Visit #5). At Visit #6, if urine pH < 6.5, increase topiramate to 200 mg daily for remainder of 
study.   
h-Medical history including medications. For visits 3-8 changes to medical history or medications will be noted. 
Abbreviations: CT = computed tomography; ETV = Early Termination Visit; FUV = Follow-up Visit; TBWL 
= Total Body Weight Loss 
 
Assessments 
 
Screening 
Timeline Encounters 
Baseline 
 
 
 
 
 
 
Visit Number 1b 
2 
3b 
4 
5 
6 
7b 
8 
Visit Day ~ -180 to -7 
1 
30 
90 
180 365 515 545 
Visit Week ~ -24 to -1 
0 
4 
13 
26 
52 
74 
78 
Informed Consent 
X 
X 
 
 
 
 
 
 
Entry Criteria 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical Historyh 
X 
X 
X 
X 
X 
X 
X 
X 
Heightc,Weight,Hip and 
Waist Circumference 
 
X 
 
X 
X 
X 
 
X 
24-Hour Urine Collectiond X 
X 
 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
 
 
 
 
 
 
Pregnancy Test 
X 
X 
 
X 
X 
X 
 
X 
Vital Signs 
 
X 
 
X 
X 
X 
 
X 
Diet History/Dietician 
 
X 
 
X 
X 
 
 
X 
Imaging: CT scane 
X 
 
 
 
 
 
 
X 
Imaging:  BC DEXA Scan  
X 
 
 
 
 
 
X 
Serum Labs 
 
X 
 
X 
X 
X 
 
X 
PHQ-9 Assessment 
 
X 
 
X 
X 
X 
 
X 
Subject Randomizationf 
 
X 
 
 
 
 
 
 
Study Medication 
Dispensed 
 
X 
 
X 
X 
X 
 
 
Med Reconcil, 
Compliance 
 
 
X 
X 
X 
X 
 
X 
Dose Adjust Decisiong 
 
 
 
X 
 
 
 
 
Adverse Event 
Assessment 
 
 
X 
X 
X 
X 
X 
X 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
8 
2 INTRODUCTION 
2.1 STUDY RATIONALE 
Study Rationale 
Kidney Stones and Obesity: Mounting evidence indicates that obesity, diabetes mellitus, and kidney 
stones are inter-connected diseases increasing in prevalence across the entire spectrum of American 
citizens1-3. Linking these three disease states is intuitive, since food quantity, dietary factors, and body 
size all affect urinary composition and mineral excretion. Uric acid nephrolithiasis (UAN), with or without 
components of calcium oxalate (CO), is the second most common kidney stone type in the US and 
occurs only in acidic urine (pH < 5.8)4,5. Obese or overweight diabetics have a six-fold increased risk to 
develop UAN/COUAN because they are unable to properly add buffer (ammonium) to their urine6. Alkali 
therapy, most commonly in the form of citrate salts, is the most widely used treatment for UAN/COUAN 
and has been reported in small series with limited follow-up to completely alkalinize urine to a normal 
range – thus, ridding patients of their disease7,8. Despite its reported simplicity, practical UAN/COUAN 
management with citrate salts is complicated by poor patient tolerance, early cessation, and 
questionable efficacy. Furthermore, diabetics with renal disease may develop hyperkalemia on the 
required doses of potassium citrate, and effective blood pressure medications, such as angiotensin 
converting enzyme inhibitors or receptor blockers, can worsen the hyperkalemia risk. Finally, these 
therapies do not address the two important health epidemics underlying UAN/COUAN: obesity and 
diabetes. 
Novel Indication: Weight Loss + Urinary Alkalinzation: Phentermine plus topiramate-ER (Qsymia ®), the 
most successful FDA-approved drug for weight loss9, has the unique drug side effect of urinary 
alkalinzation due to excessive bicarbonate excretion. Since no new drugs have been introduced for 
kidney stone prevention in over 30 years, the potential impact of this proposal will be to establish 
phentermine/topiramate as a novel alternative stone disease therapy for obese and diabetic 
UAN/COUAN prevention. 
CAI Raise Urine pH: The intended use of phentermine/topiramate in this proposal is unique given that 
no study to date has examined the impact of topiramate in combination with phentermine (and 
attendant weight loss) on urinary alkalinization. However, the urinary alkalinizing properties of CAI like 
topiraminate have long been recognized. In 1975, Freed first described how acetazolamide, an older CAI, 
stabilized both cystine and UAN in 12 patients recalcitrant to citrate therapy10 while Sterrett (200811) 
described the urinary changes in a similar group of 5 patients (Table 1). Two separate prospective 
collections of 24-hour urines have been performed before and after starting the CAI topiramate in non-
stone formers with chronic headaches12,13. Although small in number, both studies suggest that CAI can 
substantially increase urine pH while decreasing relative supersaturation of uric acid. The study we 
propose, has not been undertaken prospectively in obese, diabetic uric acid stone formers. 
  
 
 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
9 
2.2 BACKGROUND 
I. Study Background and Significance 
The Kidney Stone Epidemic is Fueled by Obesity and DM: Kidney stones are a painful and costly 
disease. Hospitalizations, interventions, and work days lost due to kidney stones impose a major 
economic burden, estimated in 2006 to be greater than $10 billion14. A 2010 survey estimated that US 
adults have a 1/12 (8.4%) lifetime chance of having a kidney stone, up from 1/20 (5.3%) 15 years ago1. 
Epidemiologically linked to this rise in stone prevalence is the rampant increase of obesity, metabolic 
syndrome, and type 2 diabetes mellitus (DM) in the US. After adjusting for age, dietary factors, fluid 
intake, and thiazide use across three large cohorts (n>240,000), obesity increased kidney stone risk by 
44% in obese men of any age, 89% in older women, and 92% in young women15,16. Furthermore, cross-
sectional data in a cohort of over 12,000 diabetic men and women from NHANES (2007-2010) found 
that those with poor glycemic control (hemoglobin A1C >6.5% versus <5.7%) were 2 times more likely to 
have a history of kidney stones, despite multivariate adjustment17. 
Food Quality and Positive Energy Balance Affect Stone Risk: The urinary components that raise stone 
risk (elevated urinary calcium, oxalate, uric acid, sodium; reduced urinary citrate) have repeatedly been 
shown to be more common in patients with obesity and/or DM versus non-obese/DM patients18-20. 
Although body size and renal mechanisms may be partially responsible for these findings, diet high in 
salt/animal protein and low in fruits/vegetables also plays a role16. 
Obesity and DM Cause Acidic Urine: A number of elegant metabolic studies have demonstrated that 
DM and obese patients with insulin resistance have decreased renal ammonium production, resulting in 
overly acidic urine pH21,22. This condition predisposes DM and obese patients to pure UAN (10% of US 
stones)4,5 as well as mixed COUAN (5-8% of US stones5,23), even in the presence of normal urinary uric 
acid excretion24,25. Daudon analyzed ~2500 stones and found that the proportion of UA stones was 
35.7% in patients with type 2 diabetes and 11.3% in patients without type 2 diabetes (P < 0.0001)26,27. 
Reciprocally, the proportion of patients with type 2 diabetes was significantly higher among UA than 
among calcium stone formers (27.8% vs 6.9%; P < 0.0001). Furthermore, stepwise regression analysis 
identified DM and obesity as independent predictors of UAN, with proportion of UAN ranging from 6% 
in non-obese, 17% in obesity only, and 36% in patients who were both obese and diabetics26,27. 
Obesity and DM Cause Renal Oxidative Stress: Finally, the ability of adipose tissue to secrete pro-
inflammatory molecules and generate a chronic, low grade inflammatory state has long been studied in 
cardiovascular disease states such as atherosclerosis28. Moreover, inflammatory mediators, such as 
tumor necrosis factor, vascular NAD(P)H oxidase, and monocyte chemoattractant protein-1, are 
believed to be at least partly responsible for systemic oxidative stress and excessive production of 
reactive oxygen species (ROS) seen in obese kidney stone formers29,30. These mediators are thought to 
promote crystal adherence to renal tubular epithelial cells, one of the first phases in stone formation31. 
  
 
 
 
 
 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
10 
FIGURE 1: Conceptual Model of UAN and COUAN 
  
 
  
II. UAN and COUAN Formation/Prevention 
UAN: Uric acid is poorly soluble at pH<5.35 and forms crystals, even in low UA concentration32. 
Conversely, 95% of uric acid exists in the more soluble sodium urate form at urine pH>6.5 (Figure 2). 
Based on this, urinary alkalinization using alkali salts (potassium citrate, sodium bicarbonate) is more 
important than reduction of uricosuria for UAN prevention. Thus, a common strategy for most UA 
patients is to alkalinize first-line and reserve urinary uric acid lowering drugs such as allopurinol for 
resistant cases, such as in patients with bowel disease, DM, or gout. In fact, alkali therapy is so clinically 
effective that no randomized controlled trial (RCT) has been performed for UAN33,34. 
COUAN: High urine uric acid (hyperuricosuria) can promote CO stones by reducing the solubility of CO 
(termed “salting out” or “gouty diathesis”), acting as a crystal seed to initiate CO stones35,36. This type of 
heterogeneous nucleation explains why the urate-lowering drug allopurinol reduced CO recurrence by 
50% in a RCT of hyperuricosuric patients37. 
Modern Medical Prevention/Citrate Shortfalls: Despite its reported simplicity, practical UAN/COUAN 
medical management is complicated by poor patient tolerance, early cessation, and questionable 
efficacy. In a review of all citrate RCT for stones, 20% of patients developed upper GI disturbance and/or 
rash leading to a four-fold increase in drop-out compared to placebo38. In a retrospective study of 144 
stone formers prescribed citrate salts, over half discontinued the medication within 2 years of the 
prescription39. This citrate noncompliance is also supported by recent claims data40. Finally, in a large 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
11 
series of stone formers prescribed citrate salts who were compliant in taking their potassium citrate, 
less than half were able to raise their urine pH or citrate levels to a normal range, even on the 
prescribed dose41. This proposed intervention will offer an alternative to this poorly-tolerated, 
ineffective therapy while targeting both obesity and DM that drives UAN/COUAN. 
 
2.3 RISK/BENEFIT ASSESSMENT 
2.3.1 KNOWN POTENTIAL RISKS 
Patients will be asked to take a combination of two drugs, phenteramine and topiramate. First, a brief 
overview of both drugs and risks is appropriate. 
I. Phentermine: Phentermine hydrochloride is a sympathomimetic agent approved by the US Food and 
Drug Administration (FDA) in 1959 as an appetite suppressant for short-term weight loss in doses up to 
37.5 mg/daily42. Phentermine is the most widely used anti-obesity drug in the US and is the agent-of-
choice among physicians specializing in obesity treatment43. Like other amphetamines in this class, side 
effects include hypertension, CNS stimulation, and tachyphylaxis or diminished response to drug over 
time. Because of this relationship with amphetamines, it was determined by the FDA to have the 
potential for abuse and designated as a Schedule IV controlled substance. These expectations were 
based on the chemical structural similarities between phentermine and amphetamine and on evidence 
in rats that phentermine stimulated spontaneous activity. However, after almost 60 years of use, there 
is no evidence in the peer-reviewed medical literature to support the hypothesis that phentermine has 
significant human addiction potential42-44. Although a part of the Fen-Phen and Dex-Phen scandal of 
1997, Phentermine was shown not be the causative agent of valvular heart disease and was never 
withdrawn by the FDA45. Study participants will be reassured in this regard. 
II. Topiramate: Topiramate was approved by the FDA in 1996 for the treatment of epilepsy and in 2004 
for migraine prophylaxis46. Its “calming” central nervous system effects, and perhaps even its satiety and 
weight loss effects, occur through blockade of voltage-gated sodium and calcium channels, potentiation 
of γ-aminobutyric acid activity, and inhibition of glutamate receptor function and carbonic anhydrase II 
and IV46. In migraine studies at doses 100-200 mg, adverse effects occurred in 65-82% of subjects and 
were generally mild to include paresthesias, fatigue, weight loss, cognitive complaints, dry mouth, taste 
perversion, and nausea47. Less common adverse effects of TPM include kidney stones (primarily calcium 
phosphate due to alkaline urine), acute angle closure glaucoma, palinopsia, Stevens–Johnson syndrome, 
tremor, and myoclonus48. One long-term safety study of topiramate in epileptic patients (mean use 5.3 
years, dose ranging from 200 to 600 mg) showed a non-surgical stone incidence rate of 1.5%47. Other 
studies report symptomatic stone rates of 2.1-10.7% and asymptomatic stone in up to 20% of TPM 
users49. Based on the pathophysiology of UAN and the reported difficulty in alkalinizing urine in this 
population, we do not expect the development of calcium phosphate stones on topiramate. However, 
as this medication has not previously been studied for UAN, patients at one year may be noted to have 
an increase in UAN/COUAN stone size or new stone development if the drug does not effectively change 
urine parameters. In these cases, we will counsel with the patient and consider adding alkali therapy 
with the expectation of stone stabilization and perhaps even dissolution. 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
12 
III. Combination therapy: Phentermine/topiramate-ER (Qsymia ®15mg phentermine hydrochloride/92 
mg topiramate extended-release; Vivus Inc.) was approved by the FDA in 2012 for use along with 
reduced dietary caloric intake for the management of obese subjects or overweight subjects with at 
least one weight related comorbidity50. The Table discusses the major findings from the three Phase III 
RCTs and one extension study, including changes in total body weight, blood pressure and fasting 
glucose. 
  
Table: Overview of outcomes, safety, and tolerability of Qsymia ®15/92 mg in Phase III RCTs 
  
Study Name 
Study 
Population 
Study 
Duration 
P=# 
placebo 
Q=# 
Qsymia 
Total 
Weight 
Loss (%) 
Δ BP 
Systolic 
(%) 
Δ fasting 
glucose, 
mg/dl 
SAE 
(%) 
Δ in 
HCO3, 
mEq/L 
EQUATE50 2012 
BMI ≥ 35 No 
DM 
28 weeks P=103 
-1.7 
-1.8 
NR 
2.7 
NR 
Q=103 
-9.2 
-5.2 
NR 
3.1 
NR 
EQUIP51 2012 
BMI ≥ 35 
56 weeks P=498 
-1.6 
+0.9 
+1.9 
2.5 
-0.3 
Q=498 
-10.9 
-2.9 
-0.6 
2.5 
-1.7 
CONQUER52 2011 BMI 27-45 + 
comorbid 
56 weeks P=979 
-1.2 
-2.4 
+0.13 
4.0 
+0.5 
Q=981 
-9.8 
-5.6 
-0.07 
5.0 
-1.0 
SEQUEL53 2012 
BMI 27-45 + 
comorbid 
2 years 
P=227 
-1.8 
-3.2 
+3.7 
6.2 
+2.2 
Q=295 
-10.5 
-4.3 
-1.2 
8.1 
+0.2 
  
Overall, Qsymia > was generally well tolerated and the reported drug side effects were as anticipated 
based on the individual component medications. The most common and important side effects 
observed (noted in 5% of study participants, observed at least 1.5 x more than in the placebo treatment 
arms) were paraesthesia, weight loss, dizziness, dysguesia, insomnia, constipation and dry mouth42. 
Serious adverse events (Table) were not significantly different between placebo and treatment groups, 
and rates of discontinuation were 3.1 – 9.0% for placebo and 4.4-19.3% for Qsymia54. As expected given 
the inhibition of carbonic anhydrase by topiramate, a decrease in the concentration of serum 
bicarbonate was observed in two of the three studies. However, the decrements were small and 
bicarbonate levels tended to return toward baseline over time without need for clinical intervention. 
Finally, antiepileptic drugs, including topiramate, carry a label precaution that they may increase the risk 
of suicidal thoughts or behavior54. Across all trials including those open to patients with controlled 
depression at baseline, incidence of suicidality or suicidal behaviors were not increased versus placebo. 
However, each of the potential risks will be reviewed in detail with the patients, and they will be 
questioned at each study visit as to suicidal thoughts or behaviors. Should these develop, the patient will 
immediately be referred to psychiatry, and the medication discontinued. 
IV. Other potential risks: #1- Because CAI cause urinary alkalinization through persistent bicarbonuria, 
its long-term use can cause mild metabolic acidosis (Table). The renal response to acidosis is to retain 
urinary macromolecules that can be used systemically as buffers – namely urinary citrate. Since citrate is 
a natural inhibitor of calcium oxalate crystal growth, hypocitraturia is a risk factor for kidney stones 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
13 
disease. Qsymia® (15/92 mg) decreased serum bicarbonate levels by 1.0 – 1.7 mEq/L in one year cohort 
trials (EQUIP51, n=498; CONQUER52, n=981) but increased serum bicarbonate by 0.2 mEq/L in the two-
year cohort trial (SEQUEL53, n=295). Urinary citrate levels have not previously been reported for 
Qsymia®. Finally, although calcium phosphate (alkaline) kidney stones have been reported with 
topiramate use49, kidney stones were not reported as an adverse event in any Qsymia® trial to date. As 
an alternative to this, all patients recruited to the study will have baseline and follow-up interviews with 
dieticians who will disclose this pitfall. All patients will be asked to increase their dietary citrate intake 
can increase urinary citrate up to 250 mg/day (normal is >350 mg/day). We expect the bicarbonaturia 
effect of CAI and the increase in dietary citrate to counter any potential citrate side effect of the drug. 
Should hypocitraturia persist despite dietary intervention, patients will be asked to supplement with 400 
ml of low calorie Crystal Light or lemonade 2-3x daily, which has been shown to normalize urinary citrate 
levels55,56. 
V. Other potential risks: #2- Bone density and weight are tightly regulated and interconnected 
processes. Intentional weight loss up to 10% is associated with a 1-2% total bone loss, termed “skeletal 
unloading,” which is a normal physiologic response to decreased body weight57. This unloading coupled 
with the potential for metabolic acidosis, could cause calcium bone mobilization and, potentially, 
hypercalciuria. As an alternative, all recruited patients will be counseled to increase urinary volume to 
>2 liters/day which should offset any transient rise in urinary calcium, and this will be followed by serial 
24-hour urine collections. 
2.3.2 KNOWN POTENTIAL BENEFITS 
  
I. Weight loss benefits : Obesity and DM adversely affect mortality, morbidity, and quality of life58. Since 
we are targeting obese patients with DM, there is potential for benefit to the subject related to weight 
loss Qsymia with respect to reducing obesity-related complications, such as improved cardiovascular 
and glycemic control (see Table in section 2.3.1). 
II. UAN/COUAN : In addition to weight loss, Qsymia treatment is expected to alter urinary pH and solute 
concentrations to favor decreased urinary supersaturations of not only UAN but also mixed COUAN and 
reduced related kidney stone disease - a hypothesis based on preliminary and historical data. However, 
in order to prove the benefit of this combination drug, the experimental portion of this study must be 
performed. The risks listed in section II are generally similar to those of placebo and are extremely 
reasonable in relation to the anticipated benefits of weight loss, improvement in DM and stone 
dissolution in UAN/COUAN. 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
Over 1,300 patients like the ones we will be recruiting (patients who are obese and have diabetes) have 
been studied on Qsymia® for one to two year periods. Using this randomized trial data, the FDA 
approved the sale of Qsymia® in the US in 201250. We plan to study the same population that was 
studied by investigators in the CONQUER trial (201152) and SEQUEL trial (201253). However, the specific 
endpoints such as acid stones or urinary alkalinization were not examined in those studies. Overall, the 
benefits to the patients of having 18 months on the best weight loss drug on the market should far 
outweigh any potential risk of this drug therapy. 
 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
14 
3 OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
1) New uric acid/mixed uric 
acid kidney stone formation 
2) Existing uric acid/mixed 
uric acid kidney stone 
growth 
1) Kidney stone growth (mm2) as 
determined by non-contrast CT scan. 
2) New kidney stone growth (mm2) as 
determined by non-contrast CT scan 
Ultimately, stone recurrence 
or growth prevention is the 
target for this patient 
population because it leads 
to morbidity and high cost of 
care. Uric acid stones are 
poorly seen on plain 
radiography, and the 
specificity and sensitivity of 
renal ultrasonography in the 
setting of obesity is low. 
Non-contrast CT scan is the 
gold standard for the 
assessment of uric acid 
stones. 
Secondary 
1) Weight loss 
2) Urinary parameters 
3) Body Composition 
DEXA, Hgb A1c 
1) Change in weight over 18 months 
expressed by total % body weight loss (total 
weight loss in pounds/starting weight in 
pounds). 
2) % change in urinary parameters (urine 
pH, urinary citrate, urinary calcium, urinary 
8-isoprostane, urinary hydrogen peroxide) 
end of study compared to baseline. 
3) Mean change in insulin resistance end of 
study compared to baseline as calculated 
by the homeostasis model assessment 
method (HOMA-IR) using fasting glucose 
and insulin levels 
 Total body weight loss is the 
standard way of reporting 
the effect of weight loss 
drugs in the literature.  We 
have chosen a number of 
secondary endpoints that 
may reflect improvement in 
reactive oxygen species in 
the urine. Finally, HOMA-IR is 
the gold standard to assess 
improvements in fasting 
glucose compared to insulin 
over time. 
Tertiary/Exploratory 
  
  
  

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
15 
4 STUDY DESIGN 
4.1 OVERALL DESIGN 
The study is a prospective, randomized clinical trial utilizing a pragmatic control group. The experimental 
arm will consist of 20 individuals randomized to treatment regimen phentermine/topiramate x 18 
months who have stopped all oral alkalinization agents (potassium citrate, sodium bicarbonate). To 
compare outcomes, a control group consisting of 10 individuals will be randomized to remain on their 
current medication regimen (citrate salts, allopurinol, diet, etc). 
 
 
 
 
Pre-
Study 
Enrollment 
Baseline 
1M 
Visit 
3M 
Visit 
6M 
Visit 
12M 
Visit 
17M 
Visit 
18M 
Visit 
Visit Number 
#1 
#2 
#3 
#4 
#6 
#7 
#8 
#9 
Phone Call 
XX 
 
XX 
 
 
 
XX 
 
On-site Visit 
 
XX 
 
XX 
XX 
XX 
 
XX 
 
This protocol involves 8 study encounters: 
Encounter #1: This is a pre-study phone call to discuss enrollment. Participants will be contacted by 
phone via three previously identified sources (see Section 5.5). Study coordinator will review entry 
criteria, and if subject appears to meets entry criteria. The study coordinator or PI will review the 
"screening" consent over the phone. The participant will have the option to complete the initial 
screening consent in paper form sent to them or online through RedCap. If the consent is mailed two 
copies will be sent. One for the participant to sign and return in the self-addressed envelope and one for 
them to keep. The consent checklist that has been uploaded to IRB will be used to document both 
procedures. Note: participants on the diabetic medications Canagliflozin (Invokana, Ivokamet), or 
Dapagliflozin (FARXIGA, Qtern, Qternmet Xigduo) or Empagliflozin (Jardiance, Glyxambi, Synjardy) must 
be taking them for at least 12 weeks prior to entering the participation part of the study. 
The second "participation" consent will be completed with a face to face meeting with the study 
coordinator in the CRC. In both cases the consent will be reviewed, questions answered and checked for 
understanding. Coordinator will review consent and complete consent checklist.  Stage 1 Informed 
Consent (screening).  This consent will allow study coordinator to capture all external medical records (if 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
16 
necessary), and to ask patient to hold all alkalinizing urine pH medications (potassium citrate, sodium 
bicarbonate). Participant will then be asked to complete a 24 hour urine after HOLDING all oral 
alkalinizing agents (potassium citrate, sodium bicarbonate) for ~4 weeks. Encounter #2 will also be 
scheduled. 
 
Encounter #2: This baseline, on-site, face to face visit will involve: confirmation of entry criteria, medical 
history, height/weight, waist and hip circumference, completion of the PHQ-9 mental health 
questionnaire, 24-hour urine, vital signs, dietary history/dietician visit#1, blood collection for serum labs, 
signing of Stage 2 Informed Consent (study participation), subject randomization, and body composition 
DEXA scan. Should it be necessary, an enrollment study non-contrast CT scan will also be performed (if 
none over previous 6 months). If subject is randomized to medication, he/she will be dispensed on this 
day by CRC pharmacy.  If subject is female and of child-bearing age, she will be asked to take a 
pregnancy test as part of your screening for enrollment. 
 
Encounter #3: This 1-month follow-up phone call will be to review medication compliance/ 
reconciliation as well as assess adverse events. 
  
Encounter #4: This 3-month, on-site, face to face visit will involve: weight, hip and waist circumference, 
vital signs, dietary history/ dietician visit#2, 24-hour urine, and serum labs. For those randomized to 
drug, medication compliance/reconciliation, adverse events, and PHQ-9 will be assessed. If total body 
weight loss is>5% and urine pH>6.5 (24 hr urine month 3), medications for months 4, 5, 6 will be 
dispensed by CRC pharmacy.  
 
At the discretion of Dr. Canales, MD (PI), If total body weight is <5%, phentermine dose will be increased 
to 37.5 mg and subject will remain on this through study duration.  If urine pH<6.5 (24 hr. urine month 
3), topiramate dose will be increased to 150 mg daily. Medications will be adjusted appropriately for 
months 4, 5, 6 and dispensed by CRC pharmacy. 
 
Encounter #5: This 6-month, face to face, on-site visit will involve: weight, hip and waist circumference, 
vital signs, dietary history/ dietician visit#3, 24-hour urine, PHQ-9, and serum labs. For those randomized 
to drug, medication compliance/ reconciliation, adverse events will be assessed. 
 
Encounter #6: This 12-month, face to face, on-site visit will involve: weight, hip and waist circumference, 
vital signs, 24-hour urine, PHQ-9, and serum labs. For those randomized to drug, medication 
compliance/reconciliation, adverse events will be assessed. 
 
Encounter #7: This 17-month phone call is to remind subjects to collect their fifth 24-hr urine. For those 
randomized to drug, adverse events will be assessed and study coordinator will also remind participants 
to begin a 9-day topiramate drug taper as soon as collection is completed and to collect a final 24 hour 
urine sample 3 weeks after drug washout.   
 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
17 
Encounter #8: This 18-month, face to face, end-of study, on-site visit will involve: weight, hip and waist 
circumference, physical examination/vital signs, dietary history/dietician visit # 4, 24-hour urine, blood 
collection for serum labs, PHQ-9 assessment, and body composition DEXA scan. For those randomized to 
drug, final drug reconciliation and adverse events will be recorded. Should it be necessary, an end-of-
study non-contrast CT scan will also be performed (if none performed for standard of care). 
 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
Because we do not know the long-term effect of phentermine/topiramate on uric acid stone disease, 
a prospective feasibility trial is the most appropriate study design. However, a control group is needed 
to compare outcomes. Therefore, our pragmatic control group will consist of a small number of uric acid 
stone formers who will remain on their current medication regimen (citrate salts, allopurinol, diet, etc).  
4.3 JUSTIFICATION FOR DOSE 
     Phentermine 15 mg and topiramate at a dose of 92 mg (Qsymia™) was approved by the FDA in 2012 
for use along with reduced dietary caloric intake for the management of obese subjects or overweight 
subjects with at least one weight related comorbidity52. We will be performing a dose titration study of 
the generic equivalent to assess both weight loss and 24Hr urine pH in our population. This titration is 
necessary, since we do not know the extent to which these medications will alter urine pH or if urine pH 
will change over the duration of the study time. 
      For phentermine generic, the tablet is 37.5 mg and is scored. We will start our dosing at 1/2 generic 
pill or 18.75 mg daily. At the discretion of Benjamin Canales, MD (PI) At month 3 mark, we will measure 
total body weight loss. If it is >5%, the participant would remain on 18.75 mg dose throughout the 
remainder of study. If total body weight loss <5%, we will discuss increasing the dose to a full tablet 
(37.5 mg) with the participant. He/she would then remain on this dose throughout the remainder of the 
study. 
      We will use generic capsules of topiramate at daily dosages: 25 mg, 50 mg, 100 mg, or 150 mg.  
Based on package insert and manufacturer recommendations, participants will be asked to take one 
Topiramate 25 mg capsule QHS x 1 week, then two 25 mg capsules (50 mg) QHS x 1 week, then 25 mg 
topiramate QAM and 50 mg topiramate QHS x 1 week (75 mg), then move to 50 mg topiramate QAM 
and 50 mg topiramate QHS until Study month 3 (100 mg). At this point, participant will collect a 24-hour 
urine. If 24-Hr urine pH >6.5, he/she will continue at this dose until Study month 6. However, if 24-Hr 
urine pH<6.5, he/she will be asked to increase topiramate dose to 50 mg topiramate QAM and 100 mg 
topiramate QHS x 6 weeks (150 mg). A repeat 24-Hr urine will be collected and participant will remain at 
that dose for study duration (150 mg is the maximum dose in the trial.)  
     At the end of month 17, participants will discontinue phentermine and being a 9-day topiramate 
taper (per package insert recommendations). This is due to the possibility of precipitating a seizure if 
topiramate is discontinued abruptly. Thus, on days 1-3, participants will take 25 mg topiramate QAM 
and 50 mg topiramate QHS. During days 4-6, participants will take 25 mg topiramate QAM and 25 mg 
QHS topiramate. Finally, on days 7-9, participants will take 25 mg topiramate QHS only, and cease 
topiramate on day 10. 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
18 
 
  
4.4 END OF STUDY DEFINITION 
The final point of data capture will be 18 months after enrollment.  Study participants will begin a 9 day 
topiramate drug taper after month 17 and will be asked to provide one final 24 hour urine sample 3 
weeks after drug washout in order to capture the effect of weight loss (in the absence of drug) on 24 
hour urine parameters. 
5 STUDY POPULATION 
 
5.1 INCLUSION CRITERIA 
We will enroll up to 40 adults (to reach goal of 30) age 18 years – 75 years who: 
1) have recurrent pure uric acid nephrolithiasis (UAN) or mixed calcium oxalate (CO)/UAN. Recurrent 
stone disease is defined as at least two spontaneous kidney stone passages, two previous kidney stone 
procedures, or one previous stone passage and one previous procedure. Pure UAN is defined as at least 
one previous stone analysis demonstrating 100% uric acid mineral content. Mixed COUAN will be 
defined as at least one previous stone analysis with any mix of uric acid ≥80% and ≤20% calcium oxalate. 
If participant has more than one stone analysis, the most recent will be considered the current stone 
type. 
2) have obesity, defined as BMI > 30 kg/m2. 
3) have type 2 diabetes mellitus or pre-diabetes, defined as previously diagnosed by laboratory testing 
(hemoglobin A1c, fasting plasma glucose, or oral glucose tolerance test) or as demonstrated by use of 
anti-hyperglycemic medications or insulin. 
4) have at least one 24-hour urine study off medications demonstrating urine pH < 5.8 or a study 24-hr 
urine demonstrating urine pH < 5.8 
 
5.2 EXCLUSION CRITERIA 
Based on label warnings, we will exclude patients with: 
1) contraindications to topiramate, including: recurrent major depression, current substantial depressive 
symptoms, uncontrolled depression by PHQ 9 score >= 10, history of suicidal ideation or behavior with 
intent to act (versus exclude those with depression); current pregnancy or attempting to conceive; pre-
existing chronic kidney disease with eGFR < 60 at time of enrollment; active cancer or active treatment 
for cancer (chemotherapy, radiation); and non-ambulatory. 
2) contraindications to phentermine, including: unstable cardiovascular disease defined as 
decompensated heart failure, unstable angina, atrial fibrillation, uncontrolled blood pressure (>160 
systolic), hyperthyroidism; monoamine oxidase inhibitor use; current history of drug or alcohol abuse. 
 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
19 
5.3 LIFESTYLE CONSIDERATIONS 
The largest lifestyle consideration in this trial is the expectation of weight loss and diet. With the help of 
the co-investigators, a registered dietitian at our CRC will meet with all participants (treatment and 
controls) at several pre-determined visits (regularly (see Figure: Baseline and Months 3, 6, and 18) to 
develop specific dietary and behavioral targets for each individual participant’s weight loss program. 
This comprehensive program will include tailored calorie reduction, increased physical activity, and 
behavioral changes. Participants will be encouraged to adopt components of “Dietary Approaches to 
Stop Hypertension” (DASH) diet59, which can lower blood pressure and calcium stone risk. Other than 
verbal feedback, no other form of dietary compliance will be assessed during the trial, and lack of 
compliance with dietary recommendations will not be a reason to withdraw a study subject. 
 
5.4 SCREEN FAILURES 
We plan to use the NIH Tool “Site Screening and Enrollment Log” to record the consent and screening of 
all subjects and the outcome of each screening. The log will provide a comprehensive list of all subjects 
who were consented and screened for eligibility, including screen failures. The log will not contain any 
identifying information. 
 
5.5 STRATEGIES FOR RECRUITMENT AND RETENTION 
We will recruit participants for this study from three sources. 
#1: Any uric acid stone former at the University of Florida who has previously signed “Consent2Share” 
identified using diagnosis codes through the integrated data repository (IDR). 
#2: Uric acid stone formers identified by their kidney stone provider. 
#3: Members of the community who contact our research group based on flyers, or e-mails.  for the 
study 
 
Recruitment will begin by accessing source #1. Uric acid stone formers at the University of Florida who 
have previously signed “Consent2Share” will be identified by chart review using diagnosis codes through 
the integrated data repository (IDR). IDR will provide MRNs for Consent2Share patients who meet 
inclusion criteria. If the patient appears to meet eligibility criteria [diabetes/prediabetes; obesity BMI > 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
20 
30 kg/m2; and either recurrent pure uric acid stones (100%) or mixed uric acid/calcium oxalate stones 
(≥80%/≤20%)] by chart review, he/she will be placed in random order and will be called by study 
coordinator to gauge their interest in participating in this study. During that call, study coordinator will 
review study entry criteria and take every measure to provide an easy exit for patients who are 
contacted such that, if they are not interested, the conversation ends quickly. If he/she is interested in 
potentially enrolling in the study, he/she will be directed to the University of Florida REDCap site or 
mailed a paper consent. Coordinator will review the consent and complete the consent checklist for the  
Stage 1 informed consent for screening. This consent will allow study coordinator to capture all external 
medical records (if necessary), and to ask patient to hold all alkalinizing urine pH medications (potassium 
citrate, sodium bicarbonate). They will then receive a letter from our research team containing details of 
1) study overview, 2) expectation for their upcoming visit, 3) blank POuND OUT Informed Consent Form, 
and 4) an invitation for face to face study along with a date and time of their visit. In addition, they will 
also be mailed a home 24-hour urine kit and will be provided direction on when to collect it, roughly 30 
days after stopping alkalinizing urine pH medications.  
 
Concurrently, individuals who present in nephrology or urology clinic (source #2) may be identified as 
meeting study criteria by their clinical provider and will gauge his/her interest in learning more about 
this particular research study. The clinician will give the patient an IRB approved recruitment flier. If 
patient is interested in hearing more about the research project, the clinic staff will invite a research 
staff member to meet and discuss the study with the patient/family during that clinic visit (should the 
patient desire) or provide the consent to contact form. Any research staff discussing, recruiting, or 
enrolling/consenting research participants will be listed on the IRB protocol and approved by the IRB. 
 
Study coordinator will then have a face to face visit with the individual to evaluate his/her potential 
participation. General study inclusion criteria will be reviewed during that visit. Should study coordinator 
identify that the patient does not meet criteria or should the patient not seem interested in study 
participation, the conversation ends quickly. If he/she is interested in potentially enrolling in the study, 
he/she will be directed to the University of Florida REDCap site or consented over the phone after they 
receive paper consent. The coordinator will review the consent and complete the consent checklist for 
the Stage 1 informed consent for screening. This consent will allow study coordinator to capture all 
external medical records (if necessary), and to ask patient to hold all alkalinizing urine pH medications 
(potassium citrate, sodium bicarbonate). They will then receive a letter from our research team 
containing details of 1) study overview, 2) expectation for their upcoming visit, 3) blank POuND OUT 
Informed Consent Form, and 4) an invitation for face to face study along with a date and time of their 
visit. In addition, they will also be mailed a home 24-hour urine kit and will be provided direction on 
when to collect it, roughly 30 days after stopping alkalinizing urine pH medications. 
 
Finally, members of the community who respond to flyers,  etc (source #3) will contact study 
coordinator who will review study criteria and evaluate his/her potential for enrollment. During that 
call, every measure will be taken to provide an easy exit for patients if they are not appropriate study 
candidates. Should he/she be potential candidates for study enrollment, he/she will be directed to the 
University of Florida REDCap site or sent a paper consent. The coordinator will review the consent and 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
21 
complete the consent checklist for the Stage 1 informed consent for screening. This consent will allow 
study coordinator to capture all external medical records (if necessary), and to ask patient to hold all 
alkalinizing urine pH medications (potassium citrate, sodium bicarbonate). They will then receive a letter 
from our research team containing details of 1) study overview, 2) expectation for their upcoming visit, 
3) blank POuND OUT Informed Consent Form, and 4) an invitation for face to face study along with a 
date and time of their visit. In addition, they will also be mailed a home 24-hour urine kit and will be 
provided direction on when to collect it, roughly 30 days after stopping alkalinizing urine pH 
medications. This process will continue until the target sample of 30 is achieved. We expect we may 
need 26 individuals (25-30% drop-out) in drug group and 13 in controls to reach target sample of 30. 
 
6 STUDY INTERVENTION 
6.1 STUDY INTERVENTION(S) ADMINISTRATION 
6.1.1 STUDY INTERVENTION DESCRIPTION 
All participants in the experimental group (n=20) will receive oral generic tablet phentermine (18.75 or 
37.5 mg dose) and topiramate (daily 100 mg or 150 mg dose) after completing initial visit requirements, 
enrollment, and randomization.  Control participants (n=10) will complete initial visit requirements and 
study enrollment and will be maintained on their current therapy. 
  
With the help of the co-investigators, a registered dietitian at our CRC will meet regularly with all 
participants (treatment and controls) at the baseline visit and others to develop specific dietary and 
behavioral targets for each individual participant’s weight loss program. This comprehensive program 
will include tailored calorie reduction, increased physical activity, and behavioral changes. Participants 
will be encouraged to adopt components of “Dietary Approaches to Stop Hypertension” (DASH) diet, 
which can lower blood pressure and calcium stone risk60. 
6.1.2 DOSING AND ADMINISTRATION 
All participants in the experimental group (n=20) will begin by breaking in half the scored generic tablet 
form of phentermine hydrochloride (37.5 mg; Teva Pharma, Inc). Participants will be asked to take 1/2 
pill PO QD 2 hours after breakfast (or 12 hours prior to expected bedtime) until end of Study month 3. At 
that time, total body weight loss will then be calculated. At the discretion of Benjamin Canales, MD (PI) 
If it is >5%, participant will continue at this dose for the remainder of study duration. If total body weight 
loss is <5%, participants will be asked to increase dose to one 37.5 mg pill daily through study end. In 
addition, If participant is unable to tolerate phentermine dosage of 18.75 it will be reduced to 8mg 
(Lomaira). 
  
Concomitantly, participants will be asked to take one Topiramate 25 mg capsule QHS x 1 week, then two 
25 mg capsules (50 mg) QHS x 1 week, then 25 mg topiramate QAM and 50 mg topiramate QHS x 1 
week, then move to 50 mg topiramate QAM and 50 mg topiramate QHS until Study month 3. At this 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
22 
point, participant will collect a 24-hour urine. At the discretion of Benjamin Canales, MD (PI), If 24-Hr 
urine pH >6.5, he/she will continue at this dose until Study month 6. However, if 24-Hr urine pH<6.5, 
he/she will be asked to increase topiramate dose to 50 mg topiramate QAM and 100 mg topiramate 
QHS x 6 weeks. A repeat 24-Hr urine will be collected and participant will remain at that dose for study 
duration (150 mg is the maximum dose in the trial.)  
 
Although participants with pre-existing chronic kidney disease (eGFR < 60 or creatinine clearance less 
than 50 mL/min) will not be enrolled in this study, it is possible that a participant may develop kidney 
disease over the course of the study.  Should this occur, the doses of both medications will be lowered 
and dispensed as 18.75 mg phentermine and 50 mg topiramate for the remainder of the study (total 18 
months) or until renal impairment improves.  As recommended by manufacturer, all participants at the 
end of study month 17 will discontinue topiramate gradually by taking a 75 mg dose x 3 days, a 50 mg 
dose x 3 days, and a 25 mg dose x 3 days, then complete drug cessation. This is due to the possibility of 
precipitating a seizure. 
6.2 PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
The two drug study agents will be shipped to the principal investigator directly from the manufacturer 
and will be acquired by the participants through the UF Health/Shands Clinical Research 
Center pharmacy. 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
  
Both these generic medications are commercially available for human use in the form, route, and dose 
planned in this trial. The formulations used for this trial will appear as the following: 
Phentermine hydrochloride tablets (37.5 mg, Teva Pharma) is equivalent to the 30 mg phentermine 
base. This scored white capsule shaped tablet is imprinted with letter "b" on one side, " E 7" on the 
other. Phentermine is packaged in bottles of #100. 
Topiramate 25 mg is a coated, off-white, round tablet with “OMN” and "25" on opposing sides.  
Topiramate 50 mg is a coated, yellow, round tablet with “OMN” and "50" on opposing sides.  
  
Participants will be dispensed tablets and capsules in a unit of use bottle #60. 
  
6.2.3 PRODUCT STORAGE AND STABILITY 
Bottles should be stored at room temperature. Container should be closed tightly and protected from 
moisture.  
Stability studies have been carried out on production-scale batches of phentermine/topiramate. The 
parameters tested during stabilities studies were: assay, appearance, related substances and 
moisture.  Long term studies for up to 5 years at 25°C /60% RH and accelerated studies for up to 6 
months at 40 C/75% RH showed that no significant degradation could be observed and all the results 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
23 
remained within the specification. Stress stability studies under heat, acid, basic, light and oxidative 
conditions were performed. Minimal degradation was observed under light and oxidative conditions. 
  
6.2.4 PREPARATION 
Phentermine and topiramate will be delivered in two separate medication forms. All the excipients used 
in both phentermine and topiramate tablets are compendial excipients and made with pharmaceutical 
grade raw materials. 
 
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
In an effort to reduce selection bias, we will block randomize up to 40 participants in a 2:1 ratio 
(treatment: control respectively) with a block size of 6, resulting in approximately 20 in treatment 
(phentermine/topiramate) group and 10 controls. While we lack sufficient information for a formal 
power analysis, this data will prove instrumental to obtain a power analysis for further larger scale 
study. 
  
We are primarily interested in estimates of outcome variability and covariability that will aid in the 
proper planning of a larger, sufficiently powered and planned efficacy trial. Our total sample size, 
allowing for a 20% attrition rate by 18 months, would give us reliable estimates of recurrence rates as 
well as the variability in change in stone size (Aim 1) and other continuous measures (Aim 2). We also 
want to establish preliminary evidence of efficacy; thus a power analysis was performed on the change 
from baseline in kidney stone size as the primary outcome. Based our center’s data, approximately 30% 
of UA stone formers had CT-documented stone recurrence at 18 months. We found that every 0.2 
increase in urine pH was associated with a 15% decrease in stone size compared to those whose urine 
pH did not change. Based on our best estimates, we expect to see a 0.6 increase in urine pH on 
phentermine/topiramate (45% decrease in stone recurrence size) and a 0.2 urine pH increase in our 
control group (15% decrease in stone recurrence size). Using this 30% difference in stone recurrence size 
and with an assumed 20% attrition rate, we would have >90% power (two-sided α=0.05) to detect a 4 
mm difference in stone growth relative to controls. This size difference would be considered clinically 
significant. 
 
6.4 STUDY INTERVENTION COMPLIANCE 
At each study visit, participants randomized to study drugs will be asked about study drug compliance. 
Additionally, pharmacy records will be reviewed and documented by the study nurse coordinator to 
ensure appropriate drug quantity is being dispensed.  
 Study control participants in the pragmatic arm will be asked during dietary counseling and routine 
physician visits regarding his/her compliance with standard dietary and/or medication regimen (citrate 
salts, allopurinol, diet, etc.). No attempts will be made to confirm this by pharmacy records, as this is not 
a controlled factor in the study. 
 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
24 
6.5 CONCOMITANT THERAPY 
Not applicable.  
6.5.1 RESCUE MEDICINE 
  
Not applicable. 
 
7 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 DISCONTINUATION OF STUDY INTERVENTION 
Participants are free to withdraw from participation in the study at any time upon request. Although a 
subject is not obliged to give his/her reason(s) for withdrawing prematurely from a trial, the investigator 
will make all reasonable efforts to ascertain the reason(s), while fully respecting the participant's rights. 
  
An investigator may terminate participation in the study if: 
1) Any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation occurs 
such that continued participation in the study would not be in the best interest of the participant 
2) The participant meets an exclusion criterion (either newly developed or not previously recognized) 
that precludes further study participation. 
  
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. Although a 
subject is not obliged to give his/her reason(s) for withdrawing prematurely from a trial, the investigator 
will make all reasonable efforts to ascertain the reason(s), while fully respecting the participant's rights. 
  
7.3 LOST TO FOLLOW-UP 
We will consider any participant "lost to follow-up" should, without properly informing the investigator 
associated with the clinical trial, they not be contactable. This includes participants who have opted to 
withdraw from the clinical trial, moved away from the particular study site during the clinical trial, or 
become ill and unable to communicate or are deceased. Although a subject is not obliged to give his/her 
reason(s) for withdrawing prematurely from a trial, the investigator will make all reasonable efforts to 
ascertain the reason(s), while fully respecting the participant's rights. 
  
Data gained from these participants through the date of their loss to follow-up will not be excluded from 
final analysis. However, total study power will be affected. 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
25 
 
 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
26 
8 STUDY ASSESSMENTS AND PROCEDURES 
8.1 EFFICACY ASSESSMENTS 
Assessments for urine pH efficacy will be made as per study assessment flow chart and evaluated in real 
time by the PI per our dose titration protocol. Ultimate and final assessment of efficacy, however, will 
not be made until study completion when final CT imaging is performed to ascertain stone formation or 
growth, our primary outcome. Furthermore, final efficacy to affect 24-hour urine stone parameters will 
be made when the final 24-hour urine is collected at 18 months. Beyond stone formation/growth and 
24-hour urine parameters, assessment of efficacy on weight loss will be noted with each study visit 
(participant is weighed) but final assessment will not be made until 18-month follow-up is complete. 
Specific study procedures will be defined in our Manual of Procedure (MOP). 
8.2 SAFETY AND OTHER ASSESSMENTS 
Mental Health: Antiepileptic drugs, including topiramate, carry a label precaution that they may increase 
the risk of suicidal thoughts or behavior. Across all randomized controlled trials of this drug including 
those open to patients with controlled depression at baseline, incidence of suicidality or suicidal 
behaviors were not increased versus placebo. However, each of the potential risks will be reviewed in 
detail with the patients, and they will be questioned at each study visit as to suicidal thoughts or 
behaviors. Increases in participant PHQ-9 score to > 10 along with 50% increase from the pretreatment 
score will be identified by study nurse coordinator as a sign of clinically significant worsening of 
depression. The patient's primary care physician will be contacted, and we will discuss psychiatric 
intervention along with discontinuation of study drug. 
Specifically, for PHQ-9 Section 1, question on line i: “Over the last two weeks, how often have you been 
bothered by…Thoughts that you would be better off dead or of hurting yourself in some way”  
Should participant have any positive response (several days, more than half the days, nearly every day) 
to this question, study coordinator will refer the individual to the Crisis Hot Line and offer to call and 
connect the individual with the Crisis Hot Line on his/her behalf. Study PI will also be contacted and will 
document the referral. 
 
Hypocitraturia and/or calcium phosphate stones: Because CAI cause urinary alkalinization through 
persistent bicarbonuria, its long-term use can raise urine pH and cause mild metabolic acidosis. The 
renal response to acidosis is to retain the urinary macromolecule citrate. Because citrate is urinary 
macromolecule that naturally inhibits crystal aggregation and stone growth, low urinary citrate levels 
(hypocitraturia) and/or the development of alkaline-based stones (calcium phosphate) are possible. In 
long term trials, Qsymia® (15/92 mg) decreased serum bicarbonate levels by 1.0 – 1.7 mEq/L in one year 
cohort trials (EQUIP51, n=498; CONQUER52, n=981) but increased serum bicarbonate by 0.2 mEq/L in the 
two-year cohort trial (SEQUEL53, n=295). Urinary citrate levels have not previously been reported for 
Qsymia®. Although calcium phosphate (alkaline) kidney stones have been reported with topiramate 
use49, kidney stones were not reported as an adverse event in any Qsymia® trial to date. Far more 
common in the medical literature is prescription of topiramate for prevention of headache or seizure – 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
27 
both of which are FDA-approved indications. When this literature is reviewed, some associations with 
topiramate-induced acid-base side effects such as metabolic acidosis, hypokalemia, and stone disease, 
have all been noted. The best systematic review article was published in 2014 by Dell’Orto et al49. Their 
group reviewed 47 reports published between 1996 and 2013 (5 case–control studies, 6 longitudinal 
studies) that addressed these potential topiramate side effects. At doses of topiramate in 200-600 mg 
range (far higher than the range of our proposal), they noted a significant tendency towards the 
development of mild-to-moderate hyperchloremic metabolic acidosis (serum bicarbonate ≤21.0 mmol) 
in ~30% of cases and mild hypokalaemia (serum potassium ≤3.5 mmol) in ~10% of cases. They also 
report that patients on topiramate who developed kidney stones tended to have significantly lower 
urinary citrate levels (hypocitraturia, recognized promoter of renal stone formation) when on the drug. 
None of the patients included in these reports had uric acid stones – instead, they all developed 
calcium-based alkaline-stones as a result of excessive bicarbonuria effect of topiramate61-65.   
Two of the better studies in this area were done prospectively, collecting 24-hour urines before and 
after starting the topiramate in neurology patients with chronic headaches12,13. Welch et al performed a 
short-term (3 month) longitudinal study in 7 neurology patients who were about to start topiramate (6F, 
1 M; mean age 44+/-15 yrs, 2 previously had kidney stones; all had normal renal function, Table)12. At 
mean dose of 107 +/- 45 mg/day (range 50 - 200 mg), they found a urine pH increase 6.18 to 6.76 (only 
one individual had pH <6 prior to starting therapy). All individuals ended up with urine pH ≥6.5 with a 
decrease in urinary citrate from mean 819 to 378 mg/day12. Jhagroo et al found a similar (0.4) increase 
in urine pH 60 days after starting topiramate in 7 non-kidney stone formers with chronic headache13. 
Urinary citrate was also noted to decrease from mean 526 to 218 mg/day.  
 
In total, the CAI-effect of topiramate is expected to cause bicarbonuria, raise urine pH, and may 
temporarily lower serum bicarbonate levels. In obese diabetics, topiramate combined with phentermine 
has been shown to cause between +0.2-1.7 changes in serum bicarbonate levels, out to 2 years. Urinary 
citrate levels were not monitored in these major prospective trials but are expected to decline. For this 
reason, we have proposed serial monitoring of urinary citrate over the entire course of the study. 
Dieticians will consistently discuss methods for participants to increase dietary forms of citrate, 
including fruits, vegetables, and fruit juices (lemonade, orange juice, etc) in order to obviate this 
potential side effect55,56.    In our population, we feel that changes in urine pH will affect uric acid 
mineral supersaturations much more significantly than any mild decrease in urinary citrate level. 
 
8.3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 We define adverse event as untoward medical occurrence associated with the use of an intervention, 
whether or not considered intervention-related. 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
A suspected adverse reaction is considered "serious" if, in the view of either the investigator or sponsor, 
it results in any of the following outcomes: death, a life-threatening adverse event, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
28 
substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth 
defect. Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse.  
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
  
8.3.3.1 SEVERITY OF EVENT 
We will assess severity of events by the following method of grading: 
1) Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities. 
2) Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
3) Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually potentially life-threatening or incapacitating. 
  
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 The examining clinician will determine the AE’s causality based on temporal relationship and his/her 
clinical judgment. The degree of certainty about causality will be graded using the categories below: 
1) Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test result, 
occurs in a plausible time relationship to drug administration and cannot be explained by concurrent 
disease or other drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be 
clinically plausible. The event must be pharmacologically or phenomenologically definitive, with use of a 
satisfactory rechallenge procedure if necessary.  
 2) Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a 
reasonable time after administration of the drug, is unlikely to be attributed to concurrent disease or 
other drugs or chemicals, and follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information is not required to fulfill this definition. 
3) Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event occurred 
within a reasonable time after administration of the trial medication). However, other factors may have 
contributed to the event (e.g., the participant’s clinical condition, other concomitant events). Although 
an AE may rate only as "possibly related" soon after discovery, it can be flagged as requiring more 
information and later be upgraded to "probably related" or"definitely related," as appropriate. 
4) Unlikely to be related – A clinical event, including an abnormal laboratory test result, whosetemporal 
relationship to drug administration makes a causal relationship improbable (e.g., theevent did not occur 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
29 
within a reasonable time after administration of the trial medication) and inwhich other drugs or 
chemicals or underlying disease provides plausible explanations (e.g., theparticipant’s clinical condition, 
other concomitant treatments). 
5) Not Related – The AE is completely independent of study drug administration, and/or evidenceexists 
that the event is definitely related to another etiology. There must be an alternative,definitive etiology 
documented by the clinician. 
  
8.3.3.3 EXPECTEDNESS 
Dr. Benjamin Canales will be responsible for determining whether an AE is expected or unexpected. An 
AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent with 
the risk information previously described for the study agent.  
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews of a study participant presenting for medical care, or upon review by a study monitor. All AEs 
including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate RF. 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 will 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. UPs will be recorded in the data collection system 
throughout the study. Changes in the severity of an AE will be documented to allow an assessment of 
the duration of the event at each level of severity to be performed. AEs characterized as intermittent 
require documentation of onset and duration of each episode. 
The PI will record all reportable events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation. At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit. Events 
will be followed for outcome information until resolution or stabilization. 
8.3.5 ADVERSE EVENT REPORTING 
The Principal Investigator, Dr. Benjamin K. Canales, will be responsible for subject safety and well-being 
as well as adverse event monitoring and reporting procedures during the conduct of the study. Due to 
potential side effects, our study team has created a DSMB composed of three members of medical 
disciplines necessary to interpret the data from the clinical trial and to fully evaluate participant safety.  
We have created a 3-member DSMB panel that will meet quarterly once all patients have been enrolled 
along with one “pre-study” meeting. Our panel will be composed of experts in endocrinology, obesity 
clinical trials, and nephrology/stone disease, to include: 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
30 
Megan A. McVay, Ph.D. 
Assistant Professor of Psychology 
UF Department of Health Education and Behavior 
1600 SW Archer Road, PO Box 118210 
Gainesville, FL 32611 
Phone: (352) 294-7029 
Fax: (352) 392-1909 
Email: megan.mcvay@ufl.edu 
 
David S. Goldfarb, M.D. 
Clinical Chief; Professor of Medicine and Physiology NYU School of Medicine, Nephrology Section/111G 
423 E. 23rd Street 
New York, NY 10010 
Phone: (212) 686-7500 x 3877 
Fax: (212) 951-6842 
Email: david.goldfarb@nyulangone.org 
 
Diana Barb, MD 
Clinical Assistant Professor of Endocrinology UF Dept of Medicne, Division of Endocrinology, Diabetes & 
Metabolism 
1600 SW Archer Road, P.O. Box 100226 
Gainesville, FL  32610 
Phone: (352) 273-8656 
Fax: (352) 273-7441 
Email: Diana.Barb@medicine.ufl.edu 
 
Initial DSMB meeting will occur just prior to study initiation. At this meeting, the DSMB will discuss the 
protocol and analytic plan, model informed consent form, data collection instruments, other important 
trial documents, and present any suggestions for modifications to the sponsor and/or steering 
committee. At this meeting, we will discuss regulatory considerations and complete plans for monitoring 
the safety and effectiveness data, including: meeting schedule; format for submission of interim reports; 
timing of the DSMB report delivery; definition of DSMB "quorum”; and handling of meeting 
minutes/other aspects. 
 
Based on expected rate of accrual over a 6 month period and low expected event occurrence rate, we 
will most likely schedule quarterly meetings once all participants have been randomized. Should a 
concern about emerging safety problem arise, the frequency will be increased or an “emergency” 
meeting called. Each quarterly meeting, most likely by Zoom as a closed meeting, is expected to last no 
more than one hour to discuss study concern. Documents describing the organization, responsibilities, 
and operation of this monitoring entity will be provided to the IRB and the CRC Research Subject 
Advocate. The results of these reviews will be distributed to the CRC Research Subject Advocate through 
the IRB. Components of the study to be monitored for safety purposes will be 1) study accrual rate, 2) 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
31 
compliance with eligibility criteria, 3) participant adherence with assigned intervention or control, 4) 
study adherence with the approved protocol/investigative plan, 5) adverse events and other problems 
or trends that may indicate a safety concern for participants, and 6) an interim analysis to determine if 
the study will be able to answer the study hypotheses or meet study aims. 
  
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report forms (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 will be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution.  
  
8.3.6 SERIOUS ADVERSE EVENT REPORTING 
The study clinician will complete a SAE Form within the following timelines: 
1) All deaths and immediately life-threatening events, whether related or unrelated, will be recorded on 
the SAE Form and submitted to the NIDDK, UF IRB, and sponsor within 24 hours of site awareness.  
2) Other SAEs regardless of relationship, will be submitted to the DCC/study sponsor within 72 hours of 
site awareness. 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be 
chronic or the adherence to be stable. Other supporting documentation of the event may be requested 
by the NIDDK or UF IRB and should be provided as soon as possible. The study sponsor will be 
responsible for notifying FDA of any unexpected fatal or life-threatening suspected adverse reaction as 
soon as possible but in no case later than 7 calendar days after the sponsor's initial receipt of the 
information. In addition, the Principal Investigator will follow the reporting requirements for serious and 
unexpected adverse events outlined in the UF IRB Adverse Event Policy. All unanticipated, serious, fatal 
and/or life-threatening adverse events will be reported to the UF IRB, CRC Program Director and 
Research Subject Advocate, and the sponsor within 24 hours of occurrence or recognition. Aggregate 
reports of adverse events will be prepared and reported on a quarterly basis to the DSMB and 
forwarded to the IRB and CRC at annual review. 
8.3.7 REPORTING EVENTS TO PARTICIPANTS 
We will report serious adverse events to participants if requested by UF IRB, DSMB, or study sponsor or 
if the PI feels participants may be impacted by the adverse event in a similar manner.  
8.3.8 EVENTS OF SPECIAL INTEREST 
Not applicable. 
8.3.9 REPORTING OF PREGNANCY 
Topiramate can cause fetal harm, specifically increased risk of oral cleft defects during first trimester of 
pregnancy. Therefore, all females of reproductive age will be required to have a negative pregnancy test 
before starting topiramate and will be required to use effective contraception (barrier) during 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
32 
topiramate therapy. Additionally, the study participant will be counseled of the potential risk to the 
fetus should she become pregnant. We will exclude any woman who is currently pregnant, attempting 
to conceive, or becomes pregnant at any time during the study. Should a study participant become 
pregnant while taking topiramate, we will discontinue treatment immediately, and the patient will be 
once again apprised of the potential hazard to the fetus.  
 
8.4 UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
  
We will consider unanticipated problems involving risks to participants or others to include, in general, 
any incident, experience, or outcome that meets all of the following criteria:  
1) Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and informed 
consent document; and (b) the characteristics of the participant population being studied; 
2) Related or possibly related to participation in the research ("possibly related" means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and  
3) Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
8.4.2 UNANTICIPATED PROBLEM REPORTING 
  
The PI will record all unanticipated problems with start dates occurring any time after informed consent 
is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation. At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit. These 
problems will be followed for outcome information until resolution or stabilization 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS 
 We will report unanticipated problems to participants if requested by UF IRB or study sponsor or if the 
PI feels participants may be impacted by the problem in a similar manner.  

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
33 
9 STATISTICAL CONSIDERATIONS 
9.1 STATISTICAL HYPOTHESES 
• 
Primary Efficacy Endpoint(s): 
The objective for Aim 1 is two-fold: to investigate the 18 month phentermine/topiramate effects on 1) 
uric acid/mixed uric acid kidney stone growth compared to baseline and 2) uric acid/mixed uric acid 
kidney stone size change from baseline with respect to controls. We will use CT scan parameters to 
evaluate for stone growth, which will increase study precision. We will conduct both parametric and 
nonparametric test. To compare kidney stone growth between baseline and 18 month 
within phentermine/topiramate group, we would use paired samples t-test and Wilcoxon signed rank 
sum test. To compare the kidney stone size at 18 month change from baseline between drug and control 
group, we will fit an ANCOVA model with the baseline kidney stone size included as an independent 
variable (ANCOVA is more efficient than ANOVA). Alternatively, we will also conduct non-parametric test 
by using permutation test. 
• 
Secondary Efficacy Endpoint(s): 
Outcomes for Aim 2 are change in key 24-hour urine parameters (urine pH, urinary citrate, urinary 
calcium), serum diabetic labs (as calculated by hemoglobin A1c), fat/lean muscle/bone by body 
composition DEXA, weight (total % body weight loss ), and urinary markers of oxidative stress (urinary 8-
isoprostane, urinary hydrogen peroxide) over the 18 months of follow-up time. We will use a mixed 
effects model to take into account the correlation among observations within each subject. In this pilot 
study with small sample size, within group comparison would adopt ANCOVA model and evaluate the 
treatment effects at each fixed time point for those repeatedly measured outcomes and include the 
baseline of the dependent variable and other factors such as BMI and age in the model. To compare 
secondary efficacy end points between groups, pairwise comparisons will be made using contrast 
statements within the framework of ANOVA with treatment group as a factor. 
 
9.2 SAMPLE SIZE DETERMINATION 
Sample size considerations are driven by published guidance regarding pilot study planning. We are 
primarily interested in estimates of outcome variability and covariability that will aid in the proper 
planning of a larger, sufficiently powered and planned efficacy trial. Our total sample size, allowing for a 
20% attrition rate by 18 months, would give us reliable estimates of recurrence rates as well as the 
variability in change in stone size (Aim 1) and other continuous measures (Aim 2). We also want to 
establish preliminary evidence of efficacy; thus a power analysis was performed on the change from 
baseline in kidney stone size as the primary outcome. Based our center’s data, approximately 30% of UA 
stone formers had CT-documented stone recurrence at 18 months. We found that every 0.2 increase in 
urine pH was associated with a 15% decrease in stone size compared to those whose urine pH did not 
change. Based on our best estimates, we expect to see a 0.6 increase in urine pH on 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
34 
phentermine/topiramate (45% decrease in stone recurrence size) and a 0.2 urine pH increase in our 
control group (15% decrease in stone recurrence size). Using this 30% difference in stone recurrence size 
and with an assumed 20% attrition rate, we would have >90% power (two-sided α=0.05 ) to detect a 4 
mm difference in stone growth relative to controls. This size difference would be considered clinically 
significant. 
 
9.3 POPULATIONS FOR ANALYSES 
We will be recruiting thirty adults age 18 years – 75 years who have recurrent uric acid or mixed uric 
acid kidney stones, have diabetes mellitus, are obese, and have a 24 hour urine demonstrating "acidic" 
urine pH < 5.8 within the last year. We will be recruiting in the southeast United States from a single 
academic center (University of Florida) and the surrounding areas. Taking advantage of north Florida’s 
large patient population including two large medical centers that are unrelated to University of Florida, 
we plan IRB approval of advertisements, flyers, information sheets, notices, internet postings and social 
media to recruit subjects should we not be able to recruit enough through our existing UF 
Health/Shands Nephrology and Urology Stone database. 
 
9.4 STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
This is a limited feasibility study using a small control group to compare outcomes. Therefore, the 
statistical approach is relatively straightforward. 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
We will conduct both parametric and nonparametric tests. To compare kidney stone growth between 
baseline and 18 month within treatment group, we would use paired samples t-test and Wilcoxon 
signed rank sum test. To compare the kidney stone size at 18 month change from baseline between 
treatment and control group, we will fit an ANCOVA model with the baseline kidney stone size included 
as an independent variable (ANCOVA is more efficient than ANOVA). Alternatively, we will also conduct 
non-parametric test by using permutation test. 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
We will use a mixed effects model to take into account the correlation among observations within each 
subject. In this pilot study with small sample size, within group comparison would adopt ANCOVA model 
and evaluate the treatment effects at each fixed time point for those repeatedly measured outcomes 
and include the baseline of the dependent variable and other factors such as BMI and age in the model. 
To compare secondary efficacy end points between groups, pairwise comparisons will be made using 
contrast statements within the framework of ANOVA with treatment group as a factor. 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
35 
9.4.4 SAFETY ANALYSES 
As the study is single site and involves an FDA-approved drug administered to non-high risk individuals, a 
local Data and Safety Monitoring plan will created through UF CTSI. A local Safety Officer (Dr Diana 
Barb) will serve in a safety advisory capacity to monitor participant safety, evaluate the progress of the 
study, review procedures for maintaining the confidentiality, quality, management, and analysis of the 
data and data collection. Due to the small number of participants, no additional safety analysis of data is 
required unless specified by UF IRB or the requesting agency. 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
The study groups will be compared at baseline for important demographic and clinical characteristics 
(including outcome variable) to assess similarities. Continuous variables will be summarized for each 
group by the mean and standard deviation. For an asymmetrical data, the median and a centile range 
(such as the 25th and 75th centiles) will be given.  Simple paired t-test will be used to compare means of 
two related observations (i.e., before-after per subject) while independent sample t-test will be used 
to compare means of two independent groups. Correlation statistics will be used to measure linear 
association between two continuous variables while simple linear regression will be used to observe the 
linear relationship between our predictors and outcome variable. 
9.4.6 PLANNED INTERIM ANALYSES 
As this is a feasibility study, there are no planned interim analyses.  
9.4.7 SUB-GROUP ANALYSES 
Due to the small number of recruits, there will be no sub-group analyses performed. 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
Individual participant data will be collected and compared by use of paired t-test or mixed effects model 
to take into account the correlation among observations within each subject. 
9.4.9 EXPLORATORY ANALYSES 
 Not applicable. 
 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
Our study requires enrollment of individuals with acidic urine (pH <5.8) while NOT on medication. Thus, 
in order to determine the urine pH of all our participants’ urine, we felt that two separate informed 
consents were appropriate – one consent for screening and another consent for randomization/study 
participation. 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
36 
#1) Our Screening Informed Consent will be performed during the initial phone call visit. Study 
coordinator will “walk” the participant through the online “REDCap” website consenting process or the 
paper consent sent to their home. The consent process will be documented on the consent checklist. 
The consent allows our investigative team to freely ask participants about their medical and kidney 
stone history, to perform the mental health status questionnaire (PHQ-9), and to determine if 
participant has contra-indications to drugs phentermine and topiramate. If patient appears to be a 
candidate for enrollment in randomization/study participation AND in order to provide potential 
participants ample time to review the informed consent and discuss with family or other support 
persons, we will mail a copy of the Participation Informed Consent and an information packet to the 
potential participant prior to their study date. The next face to face visit will also be scheduled.  
Meanwhile, participant will be asked to hold any urinary alkalinizing medications (potassium citrate, 
sodium bicarbonate) for a 30 day washout period. After this washout, each participant will collect a 24-
hour urine to assess urine pH at baseline, off all medications. 
 
#2) Our Participation Informed Consent will be done at the first face to face study visit after participant 
complete baseline 24-hour urine. Within the Clinical Research Center located on first floor of CTSI 
building, study personnel will review informed Participation Informed Consent form in great deal to the 
potential participant in a private setting but in the presence of any family or relatives they desire to have 
in the room. They will be given as much time as needed to ask questions and have those questions 
answered.  
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 The study participant will receive a copy of their signed consent form to keep for their records. We will 
also provide them with a paper outlining information about the dosing and potential side effects of the 
study drug (if they are randomized to drug). Even though this information will be in the consent form, 
we want to be sure the participants have this information again clearly stated. 
 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
  
We plan to use the NIH Tool “Site Screening and Enrollment Log” to record the consent and screening of 
all subjects and the outcome of each screening. The log will provide a comprehensive list of all subjects 
who were consented and screened for eligibility, including screen failures. The log will not contain any 
identifying information. 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
37 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 Upon study completion, the participant will be given an outgoing letter of appreciation for their 
participation. 
10.1.3 CONFIDENTIALITY AND PRIVACY 
 All informed consents will be taken at the UF CTSI Clinical Research Center in a private room. Family and 
relatives will be allowed to be present during the process if so desired by the potential participant. The 
participant will be allowed to ask question and have their questions answered. Once informed consent is 
complete, the paper copy of the informed consent will be stored in a secure location in a locked office in 
a locked cabinet accessible only by the PI and the study coordinator. 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA 
We currently have no plans to collect or store specimens for future research use. 
  
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
PI: Benjamin K. Canales MD 
Study Trial Nurse: John Marks 
 Co-I: Muna T. Canales, MD 
Diana Barb, MD (DSMB Member) 
 Co-I: Michelle Cardel, PhD, RD 
David S. Goldfarb, MD (DSMB Member) 
 Co-I: W. Troy Donahoo, MD 
 Megan A. McVay, PhD (DSMB Member) 
 Co-I: Xiang Yang, PhD 
 Dietician: Jean Michelson 
  
10.1.6 SAFETY OVERSIGHT 
As there is more than minimal risk to the participants, a DSMB will be appointed by the study PI to 
oversee a clinical research project and patient safety.   At each monitoring interval, DSMB will notify 
NIDDK Program Official that they reviewed the research protocol and ongoing study activities with 
emphasis on data integrity, protocol adherence, and study participant safety issues.  This review will 
focus on AEs and reasons for losses to follow up, raising any concerns or issues with the NIDDK and the 
PI, and recommending to the NIDDK and PI the continuation, modification or conclusion of the trial, 
while protecting the confidentiality of the trial data and the results of monitoring. 
10.1.7 CLINICAL MONITORING 
This proposal involves up to 40 recurrent uric acid stone formers randomized to either weight loss 
drugs plus diet counseling OR to a pragmatic group receiving dietary counseling alone. They will be 
asked to collect 6 different 24-hour urine specimens over the 18 months of the study duration (Baseline, 
3-month, 6 month, 12 month, 17 month, 18 month), and these will be reviewed "real time" by the PI 
and study nurse coordinator. We expect the bicarbonaturia effect of topiramate and the increase in 
dietary citrate to counter any potential citrate side effect of the drug. Should hypocitraturia persist 
despite dietary intervention, patients will be asked to supplement with 400 ml of low-calorie Crystal 
Light or lemonade 2-3x daily, which has been shown to normalize urinary citrate levels. In addition to 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
38 
monitoring of metabolic urinary values, a 3-month basic metabolic serum chemistry panel will be 
performed to rule out metabolic acidosis or electrolyte abnormalities. 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Dr. Benjamin K. Canales will be responsible for QA/QC of the study. QC procedures will be implemented 
beginning with the data entry system and data QC checks that will be run on the database will be 
generated. Any missing data or data anomalies will be communicated to the site(s) for 
clarification/resolution. Following written SOPs, the monitors will verify that the clinical trial is 
conducted and data are generated, documented (recorded), and reported in compliance with the 
protocol, GCP, and the applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)). The investigational site will provide direct access to all trial related 
sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, 
and inspection by local and regulatory authorities. 
10.1.9 DATA HANDLING AND RECORD KEEPING 
Our team will use University of Florida CTSI electronic data capture software called REDCap (Research 
Electronic Data Capture). This secure, Web-based application will be used to support data capture for all 
elements of this research proposal. The PI and his team are familiar with REDCap’s streamlined process 
and have a number of previously developed databases within this system. In addition to ease of use, 
REDCap features include automated export procedures for seamless data downloads to Excel and 
common statistical packages (SPSS, SAS, Stata, R), as well as a built-in project calendar, on-line 
consenting modules, ad hoc reporting tools, and advanced features, such as branching logic, file 
uploading, and calculated fields.  
For initial record keeping, patient name and medical record number will serve as the identifier until all 
data has been collected, cleaned, and verified (36 months). At that point, participants will be assigned a 
unique subject ID code and all PHI will be eliminated from the database. Only the PI, study co-
investigators, and study nurse coordinator will have access to subject identities. 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
 
Ms. Guanhong Miao is a data management analyst and graduate student in the Department of Health 
Outcomes and Biomedical Informatics at the University of Florida. Ms. Miao has a BS in Statistics and is 
completing her doctorate in Epidemiology. Under the direction of Drs. XiangYang Lou and Canales along 
with input from the entire study team, Ms. Miao will develop the online data collection forms through 
REDCap. The data entry forms will be designed with as few open-ended text fields, and as many user-
friendly drop-down answer boxes or check boxes as possible with little opportunity for responses to be 
provided with implausible values. The entry forms will be developed with built-in range checks and 
automatically-calculated fields to reduce the possibilities of data entry errors. The database will be pilot-
tested after development, with feedback from the study team on ease of use. During participant 
enrollment, Ms. Miao will regularly check for data inconsistencies, omissions, and errors, confirming 
with the study team when outliers and unusual values are observed. Ms. Miao will randomly select 5% 
of data on a quarterly basis to be checked for data entry quality. Discrepancies will trigger review of data 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
39 
collection and entry procedures as appropriate. Upon completion of the study, Ms. Miao will create 
analysis data sets from the REDCap database to be used for statistical analysis for each aim of the study. 
She will also generate analysis reports and work with Dr. Lou on the final data analysis. She will also 
communicate results to the study team and will contribute to the manuscripts that arise from the study. 
Dr. Lou and Ms. Miao will attend all study meetings to ensure constant communication about data 
issues that may arise throughout the study. 
 
Laboratory data (serum chemistries, urine) and imaging will be reviewed real time. Any alert lab values 
or abnormal imaging findings will be reviewed by study PI and managed appropriately. For values felt to 
require emergent attention, the participant will be immediately notified and asked to go to the 
emergency room. For values felt to be more elective in nature, results will be mailed to both participant 
and his/her primary care physician. 
 
10.1.9.2 STUDY RECORDS RETENTION 
Per NIH policy, research records will be retained for a minimal of 3 years after the research is completed 
and the study closed with the IRB, approximately 6 total years.  
 
10.1.10 PROTOCOL DEVIATIONS 
Protocol deviations will first be classified as due to subject, the sponsor, or the investigational team. 
Minor divergence of a study from the approved protocol will be classified as a deviation while one that 
which affects the quality of data or impacts subjects’ safety will be classified as a protocol violation. 
Examples of protocol deviations/violations may include, but are not limited to, the following: 
• 
Randomization of an ineligible participant 
• 
Failure to obtain Informed Consent 
• 
Enrollment of a participant into another study  
• 
Failure to keep IRB approval up to date 
• 
Wrong treatment administered to participant 
Site study coordinator will maintain a log of all protocol deviations using the NIH template “Protocol 
Deviation Log” form.  All deviations, when discovered, will immediately be reported to site PI Dr. 
Benjamin K. Canales, where it will be classified as deviation or violation. Protocol violations that impact 
participant safety will be reported to the IRB within 24 hours of occurrence, if possible, or as soon as 
they are discovered. All other deviations will be reported routinely to IRB and the independent data 
safety monitoring body. We will follow all local UF IRB requirements for reporting protocol deviations to 
the Board. 
 
10.1.11 PUBLICATION AND DATA SHARING POLICY 
As NIH resources will be used for the development of these research findings, we plant to make them 
readily available for research purposes to qualified individuals within the scientific community. 
We are committed to resource sharing the data generated by this project using several mechanisms: 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
40 
1) Clinical trials information will be entered into the clinicaltrials.gov database. Relevant design 
information will also be provided as a file on our local research server as this information will be needed 
to interpret and analyze any data. 
2) Any raw data deemed to be useful to the research community will also be provided on appropriate 
websites, according to UF and institutional guidelines and consistent with the archiving goals of this 
program. 
 
10.1.12 CONFLICT OF INTEREST POLICY 
 
Based on NIH requirements, we will disclose all potential conflicts for all study investigators in order to 
be free from investigator bias. We will define "investigator" as the PD/PI or any other person, regardless 
of title or position, who is responsible for the design, conduct, or reporting of research funded by PHS, 
or proposed for such funding which may include, for example, collaborators or consultants. We will 
respect UF Institutional policies that require up-to-date, written disclosure of all financial conflicts of 
interest to comply with federal regulations. These policies are available via a publicly accessible Web 
site.  
 
10.2 ADDITIONAL CONSIDERATIONS 
 
 
10.3 ABBREVIATIONS 
AE 
Adverse Event 
ANCOVA Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
41 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS Least-squares Means 
MedDRA Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH 
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
42 
 
10.4 PROTOCOL AMENDMENT HISTORY 
Version 
Date 
Description of Change  
Brief Rationale 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
43 
11 REFERENCES 
 
1 
Scales, C. D., Jr., Smith, A. C., Hanley, J. M. & Saigal, C. S. Prevalence of kidney stones 
in the United States. Eur Urol 62, 160-165, doi:10.1016/j.eururo.2012.03.052 (2012). 
2 
Middleton, K. M., Patidar, S. M. & Perri, M. G. The impact of extended care on the long-
term maintenance of weight loss: a systematic review and meta-analysis. Obes Rev 13, 
509-517, doi:10.1111/j.1467-789X.2011.00972.x (2012). 
3 
Wadden, T. A. et al. Managing obesity in primary care practice: an overview with 
perspective from the POWER-UP study. Int J Obes (Lond) 37 Suppl 1, S3-11, 
doi:10.1038/ijo.2013.90 (2013). 
4 
Sakhaee, K. Epidemiology and clinical pathophysiology of uric acid kidney stones. J 
Nephrol 27, 241-245, doi:10.1007/s40620-013-0034-z (2014). 
5 
Lieske, J. C. et al. Stone composition as a function of age and sex. Clin J Am Soc 
Nephrol 9, 2141-2146, doi:10.2215/CJN.05660614 (2014). 
6 
Daudon, M., Traxer, O., Conort, P., Lacour, B. & Jungers, P. Type 2 diabetes increases 
the risk for uric acid stones. J Am Soc Nephrol 17, 2026-2033, 
doi:10.1681/ASN.2006030262 (2006). 
7 
Rodman, J. S. Prophylaxis of uric acid stones with alternate day doses of alkaline 
potassium salts. J Urol 145, 97-99, doi:10.1016/s0022-5347(17)38258-7 (1991). 
8 
Pak, C. Y., Fuller, C., Sakhaee, K., Preminger, G. M. & Britton, F. Long-term treatment 
of calcium nephrolithiasis with potassium citrate. J Urol 134, 11-19 (1985). 
9 
Yanovski, S. Z. & Yanovski, J. A. Long-term drug treatment for obesity: a systematic 
and clinical review. Jama 311, 74-86, doi:10.1001/jama.2013.281361 (2014). 
10 
Freed, S. Z. The alternating use of an alkalizing salt and acetazolamide in the 
management of cystine and uric acid stones. J Urol 113, 96-99 (1975). 
11 
Sterrett, S. P., Penniston, K. L., Wolf, J. S., Jr. & Nakada, S. Y. Acetazolamide is an 
effective adjunct for urinary alkalization in patients with uric acid and cystine stone 
formation recalcitrant to potassium citrate. Urology 72, 278-281, 
doi:10.1016/j.urology.2008.04.003 (2008). 
12 
Welch, B. J., Graybeal, D., Moe, O. W., Maalouf, N. M. & Sakhaee, K. Biochemical and 
stone-risk profiles with topiramate treatment. Am J Kidney Dis 48, 555-563, 
doi:10.1053/j.ajkd.2006.07.003 (2006). 
13 
Jhagroo, R. A., Wertheim, M. L. & Penniston, K. L. Alkali replacement raises urinary 
citrate excretion in patients with topiramate-induced hypocitraturia. Br J Clin Pharmacol 
81, 131-136, doi:10.1111/bcp.12751 (2016). 
14 
Scales, C. D., Jr. et al. The impact of unplanned postprocedure visits in the management 
of patients with urinary stones. Surgery 155, 769-775, doi:10.1016/j.surg.2013.12.013 
(2014). 
15 
Taylor, E. N., Stampfer, M. J. & Curhan, G. C. Obesity, weight gain, and the risk of 
kidney stones. Jama 293, 455-462, doi:10.1001/jama.293.4.455 (2005). 
16 
Curhan, G. C., Willett, W. C., Rimm, E. B., Speizer, F. E. & Stampfer, M. J. Body size 
and risk of kidney stones. J Am Soc Nephrol 9, 1645-1652 (1998). 
17 
Weinberg, A. E., Patel, C. J., Chertow, G. M. & Leppert, J. T. Diabetic severity and risk 
of kidney stone disease. European urology 65, 242-247, 
doi:10.1016/j.eururo.2013.03.026 (2014). 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
44 
18 
Eisner, B. H., Porten, S. P., Bechis, S. K. & Stoller, M. L. Diabetic kidney stone formers 
excrete more oxalate and have lower urine pH than nondiabetic stone formers. J Urol 
183, 2244-2248, doi:10.1016/j.juro.2010.02.007 (2010). 
19 
Hartman, C. et al. Differences in 24-h urine composition between nephrolithiasis patients 
with and without diabetes mellitus. BJU Int 115, 619-624, doi:10.1111/bju.12807 (2015). 
20 
Powell, C. R. et al. Impact of body weight on urinary electrolytes in urinary stone 
formers. Urology 55, 825-830 (2000). 
21 
Maalouf, N. M., Cameron, M. A., Moe, O. W., Adams-Huet, B. & Sakhaee, K. Low 
urine pH: a novel feature of the metabolic syndrome. Clin J Am Soc Nephrol 2, 883-888, 
doi:10.2215/CJN.00670207 (2007). 
22 
Abate, N., Chandalia, M., Cabo-Chan, A. V., Jr., Moe, O. W. & Sakhaee, K. The 
metabolic syndrome and uric acid nephrolithiasis: novel features of renal manifestation of 
insulin resistance. Kidney Int 65, 386-392, doi:10.1111/j.1523-1755.2004.00386.x 
(2004). 
23 
Singh, P. et al. Stone Composition Among First-Time Symptomatic Kidney Stone 
Formers in the Community. Mayo Clin Proc 90, 1356-1365, 
doi:10.1016/j.mayocp.2015.07.016 (2015). 
24 
Sakhaee, K., Adams-Huet, B., Moe, O. W. & Pak, C. Y. Pathophysiologic basis for 
normouricosuric uric acid nephrolithiasis. Kidney Int 62, 971-979, doi:10.1046/j.1523-
1755.2002.00508.x (2002). 
25 
Rendina, D. et al. Characteristic clinical and biochemical profile of recurrent calcium-
oxalate nephrolithiasis in patients with metabolic syndrome. Nephrol Dial Transplant 26, 
2256-2263, doi:10.1093/ndt/gfq664 (2011). 
26 
Daudon, M., Lacour, B. & Jungers, P. Influence of body size on urinary stone 
composition in men and women. Urol Res 34, 193-199, doi:10.1007/s00240-006-0042-8 
(2006). 
27 
Daudon, M., Traxer, O., Conort, P., Lacour, B. & Jungers, P. Type 2 diabetes increases 
the risk for uric acid stones. J Am Soc Nephrol 17, 2026-2033, 
doi:10.1681/ASN.2006030262 (2006). 
28 
Pearson, T. A. et al. Markers of inflammation and cardiovascular disease: application to 
clinical and public health practice: A statement for healthcare professionals from the 
Centers for Disease Control and Prevention and the American Heart Association. 
Circulation 107, 499-511 (2003). 
29 
Huang, H. S., Ma, M. C., Chen, C. F. & Chen, J. Lipid peroxidation and its correlations 
with urinary levels of oxalate, citric acid, and osteopontin in patients with renal calcium 
oxalate stones. Urology 62, 1123-1128 (2003). 
30 
Rhee, E., Santiago, L., Park, E., Lad, P. & Bellman, G. C. Urinary IL-6 is elevated in 
patients with urolithiasis. J Urol 160, 2284-2288 (1998). 
31 
Baggio, B., Gambaro, G., Ossi, E., Favaro, S. & Borsatti, A. Increased urinary excretion 
of renal enzymes in idiopathic calcium oxalate nephrolithiasis. J Urol 129, 1161-1162 
(1983). 
32 
Doizi, S., Rodgers, K., Poindexter, J., Sakhaee, K. & Maalouf, N. M. Assessment of 
urinary inhibitor or promoter activity in uric acid nephrolithiasis. J Urol 195, 1799-1804, 
doi:10.1016/j.juro.2015.12.077 (2016). 
33 
Pak, C. Y., Sakhaee, K. & Fuller, C. Successful management of uric acid nephrolithiasis 
with potassium citrate. Kidney Int 30, 422-428 (1986). 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
45 
34 
Rodman, J. S. Intermittent versus continuous alkaline therapy for uric acid stones and 
ureteral stones of uncertain composition. Urology 60, 378-382 (2002). 
35 
Pak, C. Y. Medical stone management: 35 years of advances. J Urol 180, 813-819, 
doi:10.1016/j.juro.2008.05.048 (2008). 
36 
Grover, P. K. & Ryall, R. L. Urate and calcium oxalate stones: from repute to rhetoric to 
reality. Miner Electrolyte Metab 20, 361-370 (1994). 
37 
Ettinger, B., Tang, A., Citron, J. T., Livermore, B. & Williams, T. Randomized trial of 
allopurinol in the prevention of calcium oxalate calculi. N Engl J Med 315, 1386-1389, 
doi:10.1056/NEJM198611273152204 (1986). 
38 
Phillips, R. et al. Citrate salts for preventing and treating calcium containing kidney 
stones in adults. Cochrane Database Syst Rev, CD010057, 
doi:10.1002/14651858.CD010057.pub2 (2015). 
39 
Lee, Y. H., Huang, W. C., Tsai, J. Y. & Huang, J. K. The efficacy of potassium citrate 
based medical prophylaxis for preventing upper urinary tract calculi: a midterm followup 
study. J Urol 161, 1453-1457 (1999). 
40 
Dauw, C. A. et al. Medication nonadherence and effectiveness of preventive 
pharmacological therapy for kidney stones. J Urol 195, 648-652, 
doi:10.1016/j.juro.2015.10.082 (2016). 
41 
Astroza, G. M., Neisius, A., Tsivian, M., Preminger, G. M. & Lipkin, M. E. Treatment 
response in patients with stones, and low urinary pH and hypocitraturia stratified by body 
mass index. J Urol 195, 653-657, doi:10.1016/j.juro.2015.09.070 (2016). 
42 
Cosentino, G., Conrad, A. O. & Uwaifo, G. I. Phentermine and topiramate for the 
management of obesity: a review. Drug Des Devel Ther 7, 267-278, 
doi:10.2147/DDDT.S31443 (2013). 
43 
Srivastava, G. & Apovian, C. M. Current pharmacotherapy for obesity. Nat Rev 
Endocrinol 14, 12-24, doi:10.1038/nrendo.2017.122 (2018). 
44 
Hendricks, E. J. & Greenway, F. L. A study of abrupt phentermine cessation in patients 
in a weight management program. Am J Ther 18, 292-299, 
doi:10.1097/MJT.0b013e3181d070d7 (2011). 
45 
Connolly, H. M. et al. Valvular heart disease associated with fenfluramine-phentermine. 
N Engl J Med 337, 581-588, doi:10.1056/NEJM199708283370901 (1997). 
46 
Marmura, M. J. Safety of topiramate for treating migraines. Expert Opin Drug Saf 13, 
1241-1247, doi:10.1517/14740338.2014.934669 (2014). 
47 
Silberstein, S. D. et al. Efficacy and safety of topiramate for the treatment of chronic 
migraine: a randomized, double-blind, placebo-controlled trial. Headache 47, 170-180, 
doi:10.1111/j.1526-4610.2006.00684.x (2007). 
48 
Shorvon, S. D. Safety of topiramate: adverse events and relationships to dosing. Epilepsia 
37 Suppl 2, S18-S22 (1996). 
49 
Dell'Orto, V. G. et al. Metabolic disturbances and renal stone promotion on treatment 
with topiramate: a systematic review. Br J Clin Pharmacol 77, 958-964, 
doi:10.1111/bcp.12283 (2014). 
50 
Bays, H. E. & Gadde, K. M. Phentermine/topiramate for weight reduction and treatment 
of adverse metabolic consequences in obesity. Drugs Today (Barc) 47, 903-914, 
doi:10.1358/dot.2011.47.12.1718738 (2011). 

Phentermine/tOpiramate to eND Obesity and Uric acid stones Trial (POuND OUT) 
Version 2.5 
Protocol NIH R21 DK122317 
12/17/2021 
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
46 
51 
Allison, D. B. et al. Controlled-release phentermine/topiramate in severely obese adults: 
a randomized controlled trial (EQUIP). Obesity (Silver Spring) 20, 330-342, 
doi:10.1038/oby.2011.330 (2012). 
52 
Gadde, K. M. et al. Effects of low-dose, controlled-release, phentermine plus topiramate 
combination on weight and associated comorbidities in overweight and obese adults 
(CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet 377, 1341-1352, 
doi:10.1016/S0140-6736(11)60205-5 (2011). 
53 
Garvey, W. T. et al. Two-year sustained weight loss and metabolic benefits with 
controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a 
randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr 95, 297-308, 
doi:10.3945/ajcn.111.024927 (2012). 
54 
Qsymia.     (VIVUS, Inc. Mountain View, CA.). 
55 
Penniston, K. L., Steele, T. H. & Nakada, S. Y. Lemonade therapy increases urinary 
citrate and urine volumes in patients with recurrent calcium oxalate stone formation. 
Urology 70, 856-860, doi:10.1016/j.urology.2007.06.1115 (2007). 
56 
Kang, D. E. et al. Long-term lemonade based dietary manipulation in patients with 
hypocitraturic nephrolithiasis. J Urol 177, 1358-1362, doi:10.1016/j.juro.2006.11.058 
(2007). 
57 
Krez, A. N. & Stein, E. M. The Skeletal Consequences of Bariatric Surgery. Curr 
Osteoporos Rep, doi:10.1007/s11914-020-00579-2 (2020). 
58 
Kolotkin, R. L., Meter, K. & Williams, G. R. Quality of life and obesity. Obes Rev 2, 
219-229 (2001). 
59 
Juraschek, S. P., Miller, E. R., 3rd, Weaver, C. M. & Appel, L. J. Effects of Sodium 
Reduction and the DASH Diet in Relation to Baseline Blood Pressure. J Am Coll Cardiol 
70, 2841-2848, doi:10.1016/j.jacc.2017.10.011 (2017). 
60 
Juraschek, S. P. et al. Time Course of Change in Blood Pressure From Sodium Reduction 
and the DASH Diet. Hypertension 70, 923-929, 
doi:10.1161/HYPERTENSIONAHA.117.10017 (2017). 
61 
Kaplon, D. M., Penniston, K. L. & Nakada, S. Y. Patients with and without prior 
urolithiasis have hypocitraturia and incident kidney stones while on topiramate. Urology 
77, 295-298, doi:10.1016/j.urology.2010.06.048 (2011). 
62 
Kuo, R. L. et al. Topiramate-induced nephrolithiasis. J Endourol 16, 229-231, 
doi:10.1089/089277902753752188 (2002). 
63 
Lamb, E. J., Stevens, P. E. & Nashef, L. Topiramate increases biochemical risk of 
nephrolithiasis. Ann Clin Biochem 41, 166-169, doi:10.1258/000456304322880104 
(2004). 
64 
Maalouf, N. M., Langston, J. P., Van Ness, P. C., Moe, O. W. & Sakhaee, K. 
Nephrolithiasis in topiramate users. Urol Res 39, 303-307, doi:10.1007/s00240-010-
0347-5 (2011). 
65 
Warner, B. W., LaGrange, C. A., Tucker, T., Bensalem-Owen, M. & Pais, V. M., Jr. 
Induction of progressive profound hypocitraturia with increasing doses of topiramate. 
Urology 72, 29-32; discussion 32-23, doi:10.1016/j.urology.2008.01.042 (2008).