Cystinuria, Nephrolithiasis, Calcium Oxalate
Conditions
Keywords
Cystone, Uricare, Computerized tomography, Kidney calculi, Supersaturation, Nephrolithiasis, Quantitative CT
Brief summary
We will investigate the safety and effectiveness of a mixture of 9 east Indian herbs known as Cystone regarding their ability to dissolve existing kidney stones and prevent formation of new ones. Cystine and calcium stone formers will be recruited for a 59 week trial. The first phase of the study will be two 6 weeks periods during which each subject will receive Cystone or placebo in random order (with a one-week wash out between 6 week treatment periods). The remaining 46 weeks, each subject will receive Cystone. End points are changes in urinary chemistries and stone burden by Computerized Tomography (CT) scanning.
Detailed description
Cystone will be used in proven cystine and calcium stone forming adults who are not pregnant. Subjects must have a measurable stone by CT. The first phase is a double blind, randomized, placebo controlled cross-over of Cystone and placebo for 6 weeks each separated by a 1 week washout. Entry, 6 and 12 week 24 hour urine supersaturations or cystine, pH and sodium determinations will be collected. Then all patients enter an open label phase of 46 weeks, ensuring a 52-week total exposure to Cystone during the 59 week study. Baseline and 1 year stone quantification CT scans will be performed. End points will be changes in urine chemistry/supersaturation and stone burden. Stone burden was measured by CT, quantitatively for stone density and volume. All CT images were also reviewed in a blinded fashion by a radiologist to score each kidney as increased, no change or decreased stone burden. Statistics and Randomization: Randomization was accomplished using a table provided by the department of statistics to the study coordinator who was blinded as to whether the patients received placebo or Cystone®. Biochemical and supersaturation results were analyzed via a matched pair analysis using the JMP software package (SAS Instituted, Inc.); P values \< 0.05 were deemed significant.
Interventions
DRUGCystone
Participants will take 2 pills, 2 times a day. Each tablet of Cystone contains: Shilapushpha (Didymocarpus pedicellata) 130 mg, Pasanabheda (Saxifraga ligulata Syn. Bergenia ligulata/cilata) 98 mg, Indian madder/ Manjishtha (Rubia cordifolia) 32 mg, Umbrella's edge/ Nagarmusta (Cyperus scariosus) 32 mg, Prickly chaff flower/ Apamarga (Achyranthes aspera) 32 mg, Sedge/ Gojiha (Onosma bracteatum) 32 mg, Purple fleabane/ Sahadeve (Veronoia Cinerea) 32 mg, Lime silicate calx/ Hajrul yahood Bhasma/ Badrashma bhasma) 32 mg, Shilajit 26 mg.
Participants will take 2 pills, 2 times a day for 6 weeks.
Sponsors
Himalaya Herbal Healthcare
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent In the cystine arm, all patients will have the diagnosis of cystinuria, made on the basis of a 24-hour urine cystine containing more than 1500 umol of cystine, or a stone compositional analysis of cystine * Presence of an existing cystine stone in one or both kidneys In the calcium arm, all patients will have a history of a calcium stone as determined by laboratory analysis. * Medically effective birth control if fertile female * Able to comply with protocol
Exclusion criteria
* Pregnant * Subjects under age 18 years * Obstructing stones * Urinary Tract Infection that cannot be cleared with single course of antibiotic * Subjects who decline to provide informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 24 Hour Urine Supersaturation of Calcium Phosphate (Hydroxyapatite) | baseline, after 6 weeks treatment on placebo, after 6 weeks treatment on cystone, at end of 46 weeks of open label cystone treatment | Urine is often supersaturated, which favors precipitation of crystalline phases such as calcium oxalate. However, crystals do not always form in supersaturated urine because supersaturation is balanced by crystallization inhibitors that are also present. Supersaturation is calculated by measuring the concentration of all the ions that can interact. Once these concentrations are known, a computer program can calculate the theoretical supersaturation with respect to the important crystalline phases, eg, calcium oxalate. |
| 24 Hour Urine Supersaturation of Calcium Oxalate (CaOx) | baseline, after 6 weeks treatment on placebo, after 6 weeks treatment on cystone, at end of 46 weeks of open label cystone treatment | Urine is often supersaturated, which favors precipitation of crystalline phases such as calcium oxalate. However, crystals do not always form in supersaturated urine because supersaturation is balanced by crystallization inhibitors that are also present. Supersaturation is calculated by measuring the concentration of all the ions that can interact. Once these concentrations are known, a computer program can calculate the theoretical supersaturation with respect to the important crystalline phases, eg, calcium oxalate. |
| 24 Hour Urine Supersaturation of Calcium Phosphate (Brushite) | baseline, after 6 weeks treatment on placebo, after 6 weeks treatment on cystone, at end of 46 weeks of open label cystone treatment | Urine is often supersaturated, which favors precipitation of crystalline phases such as calcium oxalate. However, crystals do not always form in supersaturated urine because supersaturation is balanced by crystallization inhibitors that are also present. Supersaturation is calculated by measuring the concentration of all the ions that can interact. Once these concentrations are known, a computer program can calculate the theoretical supersaturation with respect to the important crystalline phases, eg, calcium oxalate. |
| Volume of Kidney Stones as Measured on Computerized Tomography | Baseline, approximately 52 weeks after baseline | Measurement of kidney stone volume in cubic millimeters. |
| 24 Hour Urinary Cystine Excretion | baseline, after 6 weeks treatment on placebo, after 6 weeks treatment on cystone, at end of 46 weeks of open label cystone treatment | — |
| Stone Density as Measured by Agatston Score Via Computerized Tomography | Baseline, approximately 52 weeks after baseline | Agatston results are a measure of calcium typically used for measuring coronary artery calcification. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Stone Burden as Assessed by Radiologist at One Year | Baseline, approximately 52 weeks after baseline | Stone burden will be quantitated using the stone quantification protocol currently available at Mayo that quantitates kidney stones both by volume and by density measured in Agatston units. |
Countries
United States
Participant flow
Recruitment details
Patients with recurring and analytically confirmed kidney stones were recruited from the Mayo Stone Clinic in Rochester, MN.
Participants by arm
| Arm | Count |
|---|---|
| Calcium Stone Subjects Subjects with confirmed calcium kidney stone(s) | 10 |
| Cystine Stone Subjects Subjects with confirmed cystine kidney stone(s) | 10 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Wash Out | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Calcium Stone Subjects | Cystine Stone Subjects | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 1 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 9 Participants | 17 Participants |
| Region of Enrollment United States | 10 participants | 10 participants | 20 participants |
| Sex: Female, Male Female | 6 Participants | 4 Participants | 10 Participants |
| Sex: Female, Male Male | 4 Participants | 6 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 10 | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 |
Outcome results
Primary
24 Hour Urinary Cystine Excretion
Time frame: baseline, after 6 weeks treatment on placebo, after 6 weeks treatment on cystone, at end of 46 weeks of open label cystone treatment
Population: Cystine excretion was not applicable to the Calcium Stone subjects.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cystine Stone Subjects | 24 Hour Urinary Cystine Excretion | Cystine at Baseline | 2770 mcmol/24 hours | Standard Deviation 947 |
| Cystine Stone Subjects | 24 Hour Urinary Cystine Excretion | Cystine after placebo (6 wks) | 3183 mcmol/24 hours | Standard Deviation 1898 |
| Cystine Stone Subjects | 24 Hour Urinary Cystine Excretion | Cystine after Cystone (6 wks) | 2948 mcmol/24 hours | Standard Deviation 2021 |
| Cystine Stone Subjects | 24 Hour Urinary Cystine Excretion | Cystine at end of Cystone (46 weeks) | 4140 mcmol/24 hours | Standard Deviation 2398 |
Comparison: Paired t test for urinary cystine between baseline and after 6 weeks' treatment on placebo.p-value: 0.69t-test, 1 sided
Comparison: Paired t test for urinary cystine between baseline and after 6 weeks' treatment on cystone.p-value: 0.25t-test, 1 sided
Comparison: Paired t test for urinary cystine between six weeks' treatment on cystone and 6 weeks' treatment on placebo.p-value: 0.15t-test, 1 sided
Comparison: Paired t test for urinary cystine between baseline and after 46 weeks' treatment on cystone.p-value: 0.2t-test, 1 sided
Primary
24 Hour Urine Supersaturation of Calcium Oxalate (CaOx)
Urine is often supersaturated, which favors precipitation of crystalline phases such as calcium oxalate. However, crystals do not always form in supersaturated urine because supersaturation is balanced by crystallization inhibitors that are also present. Supersaturation is calculated by measuring the concentration of all the ions that can interact. Once these concentrations are known, a computer program can calculate the theoretical supersaturation with respect to the important crystalline phases, eg, calcium oxalate.
Time frame: baseline, after 6 weeks treatment on placebo, after 6 weeks treatment on cystone, at end of 46 weeks of open label cystone treatment
Population: CaOx was not analyzed for the Cystine Stone subjects.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Calcium Stone Subjects | 24 Hour Urine Supersaturation of Calcium Oxalate (CaOx) | CaOx after placebo (6 wks) | 1.83 KJoules/mol | Standard Deviation 0.42 |
| Calcium Stone Subjects | 24 Hour Urine Supersaturation of Calcium Oxalate (CaOx) | CaOx at Baseline | 1.83 KJoules/mol | Standard Deviation 0.28 |
| Calcium Stone Subjects | 24 Hour Urine Supersaturation of Calcium Oxalate (CaOx) | CaOx after Cystone (6 wks) | 1.87 KJoules/mol | Standard Deviation 0.43 |
| Calcium Stone Subjects | 24 Hour Urine Supersaturation of Calcium Oxalate (CaOx) | CaOx at end of Cystone (46 weeks) | 1.78 KJoules/mol | Standard Deviation 0.47 |
Comparison: Paired t test for supersaturation of CaOx between baseline and after 6 weeks' treatment on placebo.p-value: 0.32t-test, 1 sided
Comparison: Paired t test for supersaturation of CaOx between baseline and after 6 weeks' treatment on cystone.p-value: 0.23t-test, 1 sided
Comparison: Paired t test for supersaturation of CaOx between six weeks' treatment on cystone and 6 weeks' treatment on placebo.p-value: 0.41t-test, 1 sided
Comparison: Paired t test for supersaturation of CaOx between baseline and after 46 weeks' treatment on cystone.p-value: 0.32t-test, 1 sided
Primary
24 Hour Urine Supersaturation of Calcium Phosphate (Brushite)
Urine is often supersaturated, which favors precipitation of crystalline phases such as calcium oxalate. However, crystals do not always form in supersaturated urine because supersaturation is balanced by crystallization inhibitors that are also present. Supersaturation is calculated by measuring the concentration of all the ions that can interact. Once these concentrations are known, a computer program can calculate the theoretical supersaturation with respect to the important crystalline phases, eg, calcium oxalate.
Time frame: baseline, after 6 weeks treatment on placebo, after 6 weeks treatment on cystone, at end of 46 weeks of open label cystone treatment
Population: Brushite was not analyzed for the Cystine Stone subjects.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Calcium Stone Subjects | 24 Hour Urine Supersaturation of Calcium Phosphate (Brushite) | Brushite at Baseline | 0.35 KJoules/mol | Standard Deviation 1.04 |
| Calcium Stone Subjects | 24 Hour Urine Supersaturation of Calcium Phosphate (Brushite) | Brushite after placebo (6 wks) | 0.73 KJoules/mol | Standard Deviation 0.83 |
| Calcium Stone Subjects | 24 Hour Urine Supersaturation of Calcium Phosphate (Brushite) | Brushite after Cystone (6 wks) | 0.38 KJoules/mol | Standard Deviation 0.98 |
| Calcium Stone Subjects | 24 Hour Urine Supersaturation of Calcium Phosphate (Brushite) | Brushite at end of Cystone (46 weeks) | 0.09 KJoules/mol | Standard Deviation 1.29 |
Comparison: Paired t test for supersaturation of Brushite between baseline and after 6 weeks' treatment on placebo.p-value: 0.49t-test, 1 sided
Comparison: Paired t test for supersaturation of Brushite between baseline and after 6 weeks' treatment on cystone.p-value: 0.64t-test, 1 sided
Comparison: Paired t test for supersaturation of Brushite between six weeks' treatment on cystone and 6 weeks' treatment on placebo.p-value: 0.72t-test, 1 sided
Comparison: Paired t test for supersaturation of Brushite between baseline and after 46 weeks' treatment on cystone.p-value: 0.84t-test, 1 sided
Primary
24 Hour Urine Supersaturation of Calcium Phosphate (Hydroxyapatite)
Urine is often supersaturated, which favors precipitation of crystalline phases such as calcium oxalate. However, crystals do not always form in supersaturated urine because supersaturation is balanced by crystallization inhibitors that are also present. Supersaturation is calculated by measuring the concentration of all the ions that can interact. Once these concentrations are known, a computer program can calculate the theoretical supersaturation with respect to the important crystalline phases, eg, calcium oxalate.
Time frame: baseline, after 6 weeks treatment on placebo, after 6 weeks treatment on cystone, at end of 46 weeks of open label cystone treatment
Population: Hydroxyapatite was not analyzed for the Cystine Stone subjects.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Calcium Stone Subjects | 24 Hour Urine Supersaturation of Calcium Phosphate (Hydroxyapatite) | Hydroxyapatite at Baseline | 4.25 KJoules/mol | Standard Deviation 2.02 |
| Calcium Stone Subjects | 24 Hour Urine Supersaturation of Calcium Phosphate (Hydroxyapatite) | Hydroxyapatite after placebo (6 wks) | 5.03 KJoules/mol | Standard Deviation 1.23 |
| Calcium Stone Subjects | 24 Hour Urine Supersaturation of Calcium Phosphate (Hydroxyapatite) | Hydroxyapatite after Cystone (6 wks) | 4.65 KJoules/mol | Standard Deviation 1.86 |
| Calcium Stone Subjects | 24 Hour Urine Supersaturation of Calcium Phosphate (Hydroxyapatite) | Hydroxyapatite at end of Cystone (46 weeks) | 4.09 KJoules/mol | Standard Deviation 2.06 |
Primary
Stone Density as Measured by Agatston Score Via Computerized Tomography
Agatston results are a measure of calcium typically used for measuring coronary artery calcification.
Time frame: Baseline, approximately 52 weeks after baseline
Population: One subject was excluded from CT analysis because of bilateral stone removal surgery during the study
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Calcium Stone Subjects | Stone Density as Measured by Agatston Score Via Computerized Tomography | Baseline Left Kidney Agatston Score | 166.13 Agatston Score | Standard Deviation 143.16 |
| Calcium Stone Subjects | Stone Density as Measured by Agatston Score Via Computerized Tomography | Baseline Right Kidney Agatston Score | 49.75 Agatston Score | Standard Deviation 60.24 |
| Calcium Stone Subjects | Stone Density as Measured by Agatston Score Via Computerized Tomography | 52 week Left Kidney Agatston Score | 247.71 Agatston Score | Standard Deviation 371.46 |
| Calcium Stone Subjects | Stone Density as Measured by Agatston Score Via Computerized Tomography | 52 week Right Kidney Agatston Score | 56.13 Agatston Score | Standard Deviation 74.23 |
| Cystine Stone Subjects | Stone Density as Measured by Agatston Score Via Computerized Tomography | 52 week Left Kidney Agatston Score | 1,801 Agatston Score | — |
| Cystine Stone Subjects | Stone Density as Measured by Agatston Score Via Computerized Tomography | Baseline Right Kidney Agatston Score | 2,107 Agatston Score | — |
| Cystine Stone Subjects | Stone Density as Measured by Agatston Score Via Computerized Tomography | Baseline Left Kidney Agatston Score | 383 Agatston Score | Standard Deviation 560 |
| Cystine Stone Subjects | Stone Density as Measured by Agatston Score Via Computerized Tomography | 52 week Right Kidney Agatston Score | 2,183 Agatston Score | — |
Comparison: Right Kidney Stone Density; P-value comparing one year to baselinep-value: 0.85t-test, 2 sided
Comparison: Left Kidney Stone Density; P-value comparing one year to baselinep-value: 0.63t-test, 2 sided
Comparison: Right Kidney Stone Density; P-value comparing one year to baselinep-value: 0.97t-test, 2 sided
Comparison: Left Kidney Stone Density; P-value comparing one year to baselinep-value: 0.15t-test, 2 sided
Primary
Volume of Kidney Stones as Measured on Computerized Tomography
Measurement of kidney stone volume in cubic millimeters.
Time frame: Baseline, approximately 52 weeks after baseline
Population: One subject was excluded from CT analysis because of bilateral stone removal surgery during the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Calcium Stone Subjects | Volume of Kidney Stones as Measured on Computerized Tomography | Baseline Right Kidney Stone Volume | 45.5 mm^3 | Standard Deviation 52.03 |
| Calcium Stone Subjects | Volume of Kidney Stones as Measured on Computerized Tomography | 52 Week Right Kidney Stone Volume | 52.75 mm^3 | Standard Deviation 66.44 |
| Calcium Stone Subjects | Volume of Kidney Stones as Measured on Computerized Tomography | Baseline Left Kidney Stone Volume | 141.25 mm^3 | Standard Deviation 198.98 |
| Calcium Stone Subjects | Volume of Kidney Stones as Measured on Computerized Tomography | 52 Week Left Kidney Stone Volume | 174.25 mm^3 | Standard Deviation 265.73 |
| Cystine Stone Subjects | Volume of Kidney Stones as Measured on Computerized Tomography | 52 Week Left Kidney Stone Volume | 2,064 mm^3 | Standard Deviation 688 |
| Cystine Stone Subjects | Volume of Kidney Stones as Measured on Computerized Tomography | Baseline Right Kidney Stone Volume | 1,602 mm^3 | — |
| Cystine Stone Subjects | Volume of Kidney Stones as Measured on Computerized Tomography | Baseline Left Kidney Stone Volume | 301 mm^3 | Standard Deviation 422 |
| Cystine Stone Subjects | Volume of Kidney Stones as Measured on Computerized Tomography | 52 Week Right Kidney Stone Volume | 1,677 mm^3 | — |
Comparison: Right Kidney Stone Volume; P-value comparing one year to baselinep-value: 0.81t-test, 2 sided
Comparison: Left Kidney Stone Volume; P-value comparing one year to baselinep-value: 0.78t-test, 2 sided
Comparison: Right Kidney Stone Volume; P-value comparing one year to baselinep-value: 0.96t-test, 2 sided
Comparison: Left Kidney Stone Volume; P-value comparing one year to baselinep-value: 0.13t-test, 2 sided
Secondary
Change in Stone Burden as Assessed by Radiologist at One Year
Stone burden will be quantitated using the stone quantification protocol currently available at Mayo that quantitates kidney stones both by volume and by density measured in Agatston units.
Time frame: Baseline, approximately 52 weeks after baseline
Population: One subject in the Calcium group was excluded from the CT analysis because of bilateral stone removal surgery during the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Calcium Stone Subjects | Change in Stone Burden as Assessed by Radiologist at One Year | Right kidney no change in stone burden | 6 Kidneys |
| Calcium Stone Subjects | Change in Stone Burden as Assessed by Radiologist at One Year | Right kidney stone burden increased | 2 Kidneys |
| Calcium Stone Subjects | Change in Stone Burden as Assessed by Radiologist at One Year | Right kidney stone burden decreased | 1 Kidneys |
| Calcium Stone Subjects | Change in Stone Burden as Assessed by Radiologist at One Year | Left kidney no change in stone burden | 2 Kidneys |
| Calcium Stone Subjects | Change in Stone Burden as Assessed by Radiologist at One Year | Left kidney stone burden increased | 6 Kidneys |
| Calcium Stone Subjects | Change in Stone Burden as Assessed by Radiologist at One Year | Left kidney stone burden decreased | 1 Kidneys |
| Cystine Stone Subjects | Change in Stone Burden as Assessed by Radiologist at One Year | Left kidney stone burden increased | 5 Kidneys |
| Cystine Stone Subjects | Change in Stone Burden as Assessed by Radiologist at One Year | Right kidney no change in stone burden | 7 Kidneys |
| Cystine Stone Subjects | Change in Stone Burden as Assessed by Radiologist at One Year | Left kidney no change in stone burden | 2 Kidneys |
| Cystine Stone Subjects | Change in Stone Burden as Assessed by Radiologist at One Year | Right kidney stone burden increased | 2 Kidneys |
| Cystine Stone Subjects | Change in Stone Burden as Assessed by Radiologist at One Year | Left kidney stone burden decreased | 2 Kidneys |
| Cystine Stone Subjects | Change in Stone Burden as Assessed by Radiologist at One Year | Right kidney stone burden decreased | 0 Kidneys |