Obesity and Uric Acid Stones Study

Study Overview
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Brief Summary
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The investigator proposes an 18 month, feasibility pilot study, randomizing obese and diabetic individuals with pure uric acid nephrolithiasis (UAN) or mixed calcium oxalate (CO) UAN to either phentermine/topiramate or a pragmatic control group who will remain on their standard medication regimen (citrate salts, allopurinol, diet, etc.).

Detailed Description
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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 due to the inability to properly add buffer (ammonium) to urine. Of the FDA approved drugs in the weight loss market, the combination medication phentermine/ topiramate is the most effective and has a unique side effect of alkalinizing the urine (making it less acidic). The hypothesize of this project is 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. The investigative team proposes an 18 month, feasibility pilot study, randomizing 30 obese and diabetic individuals with UAN/COUAN to either phentermine/topiramate (n=20) or a pragmatic control group (n=10) who would remain on standard medication regimen (citrate salts, allopurinol, diet, etc).

Official Title
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Phentermine/tOpiramate to eND Obesity and Uric Acid Stones Trial (POuND OUT)

Conditions
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Obesity, Uric Acid Stones, Type 2 Diabetes Mellitus in Obese, Pre-Diabetes

Intervention / Treatment
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* Drug: Phentermine / Topiramate Oral Product
* Combination Product: Citrate Salts, Allopurinol, Diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. have obesity, defined as BMI > 30 kg/m2. 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. 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 Exclusion Criteria: 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 2:1 ratio block site of 6
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Allocated to intervention/treatment<br>Daily phentermine/topiramate x 18 months | Drug: Phentermine / Topiramate Oral Product<br>* All participants in the experimental group will receive oral generic tablet phentermine (18.75 or 37.5 mg dose) and topiramate (daily 100 mg or 150 mg dose)<br>|
| Active Comparator: Allocated to pragmatic control<br>Remain on their current regimen | Combination Product: Citrate Salts, Allopurinol, Diet<br>* Control participants will complete initial visit requirements and study enrollment and will be maintained on their current therapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kidney stone growth (mm2) as determined by non-contrast CT scan | Existing kidney stone growth | 18 months | 
| New kidney stone formation (mm2) as determined by non-contrast CT scan | Formation of a new kidney stone | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in weight | Expressed as total percent body weight loss (total weight loss in pounds/starting weight in pounds) | 18 months | 
| Change in urinary pH parameters | Absolute change in urine pH (end of study compared to baseline) | 18 months | 
| Change in hemoglobin A1c | Percent change in A1c (end of study compared to baseline) | 18 months | 
| Change in urinary citrate parameters | Percent change in urinary citrate | 18 months | 
| Change in urinary calcium parameters | Percent change in urinary calcium | 18 months | 
| Change in urinary uric acid parameters | Percent change in urinary uric acid | 18 months |