Obesity, Pre-Diabetes, Type 2 Diabetes Mellitus in Obese, Uric Acid Stones
Conditions
Brief summary
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
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).
Interventions
DRUGPhentermine / Topiramate Oral Product
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)
COMBINATION_PRODUCTCitrate Salts, Allopurinol, Diet
Control participants will complete initial visit requirements and study enrollment and will be maintained on their current therapy.
Sponsors
University of Florida
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
2:1 ratio block site of 6
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Kidney Stone Size (mm^3) Determined by Non-contrast CAT Scan | Baseline, 18 months | Stone perimeter within each cut of CT image was outlined using semiautomated volume tool (region of interest pen tool, CT software "Visage Imaging") and tallied to calculate stone volume (mm\^3) for each individual stone and recorded from right and left kidney from all study participants at baseline CT and at end of study CT (18 months) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Weight (kg) | Baseline, 18 months | total weight (baseline and end of study) |
| Urinary pH Parameters | Baseline, 18 months | urine pH (baseline and end of study). The pH scale ranges from 0 to 14. A pH of 7 is neutral. A pH less than 7 is acidic. A pH greater than 7 is basic. |
| %Hemoglobin A1c | Baseline, 18 months | %A1c (baseline and end of study) |
| Urinary Citrate Parameters | Baseline, 18 months | urinary citrate (baseline and end of study) |
| Urinary Calcium Parameters | Baseline, 18 months | urinary calcium (baseline and end of study) |
| Urinary Uric Acid Supersaturation (SS) | Baseline, 18 months | Urinary uric acid SS (before and end of study). Urinary Uric Acid Supersaturation (SS) is not measured in a specific unit, as it is a ratio. Result below 1: The urine is undersaturated, meaning that crystals are more likely to dissolve than form. Result equal to 1: The urine is in equilibrium with uric acid, so crystals will not grow or shrink. Result above 1: The urine is supersaturated, and the risk for crystals to form and grow is increased. A higher value indicates a greater risk. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORBenjamin Canales, MD
University of Florida
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 69.20 years STANDARD_DEVIATION 6.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Region of Enrollment United States | 19 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 6 |
| other Total, other adverse events | 12 / 13 | 5 / 6 |
| serious Total, serious adverse events | 0 / 13 | 0 / 6 |
Outcome results
None listed