Use of an Herbal Preparation to Prevent and Dissolve Kidney Stones: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Use of an Herbal Preparation to Prevent and Dissolve Kidney Stones (NCT00381849), a randomized phase 1, phase 2 study. The primary outcome is 24 Hour Urine Supersaturation of Calcium Oxalate (CaOx).

2. Clinical Question

The clinical question combines a short-term comparison of Cystone with placebo and a longer open-label observation during Cystone use. These parts address different questions. The randomized crossover phase can compare urine measurements under the two assigned treatments within participants, subject to the actual analysis and assumptions. The subsequent open-label period describes outcomes during continued Cystone use, but without a concurrent placebo group it does not provide the same randomized comparison.

The registry also identifies a secondary outcome: change in stone burden as assessed by a radiologist at one year. That outcome concerns imaging-assessed stone burden rather than urine chemistry. The record does not provide its numerical findings or enough detail to characterize the analysis. Neither endpoint should be interpreted as a reported clinical benefit based on the information available in the registry record.

3. Trial Design

The registry describes a randomized, double-masked, crossover trial with enrollment of 20 and phase designations of Phase 1 and Phase 2. Mayo Clinic is listed as sponsor. The recorded start is 2006-04, primary completion is 2009-09, and status is completed. The study conditions are cystinuria and calcium oxalate nephrolithiasis.

In the initial phase, each participant was assigned to one of two sequences. One sequence received Cystone for 6 weeks, had a 1 week washout, and then received sugar pill placebo for 6 weeks. The other sequence received placebo first, followed by the washout and then Cystone. The registry describes the study as double-masked for this phase. A crossover design exposes participants to both treatments in sequence, rather than keeping each participant in only one treatment group throughout the comparison.

After these treatment periods, the registry describes an open-label phase in which all subjects received Cystone for 46 weeks. Open-label means the treatment was not masked. The study summary describes the overall trial as 59 weeks. The open-label phase is distinct from the randomized placebo comparison: it provides follow-up during Cystone use, but the record does not describe a concurrent placebo group for that period.

The primary endpoint was 24-hour urine supersaturation of calcium oxalate. Measurements were specified at baseline, after 6 weeks of placebo, after 6 weeks of Cystone, and at the end of the open-label treatment period. The record also names radiologist-assessed change in stone burden at one year as a secondary outcome. It lists 7 outcome measures and 20 analyses, but does not provide the detailed analysis plan, the allocation procedure, or numerical endpoint results.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

First Intervention

Wash Out

Reasons for not completing this period:

Second Intervention

Open-label

Analysis population for the primary outcome, as defined in the registry: CaOx was not analyzed for the Cystine Stone subjects.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as 24 Hour Urine Supersaturation of Calcium Oxalate (CaOx), measured over baseline, after 6 weeks treatment on placebo, after 6 weeks treatment on cystone, at end of 46 weeks of open label cystone treatment.

The primary endpoint is 24-hour urine supersaturation of calcium oxalate, expressed in KJoules/mol. Supersaturation describes the balance between the concentration of ions that can form a crystalline phase and conditions that favor precipitation. As the registry explanation notes, supersaturation does not mean crystals must form: crystallization inhibitors in urine can also influence whether crystals develop.

The endpoint is calculated from measured concentrations of relevant ions using a computer program to estimate theoretical supersaturation with respect to calcium oxalate. It is a urine chemistry measure, not a direct count of stones or a measure of symptoms. The rationale in the registry is that calcium oxalate supersaturation is relevant to the chemical conditions associated with crystal formation.

The endpoint is described as a mean of a continuous measure, with standard deviation as the dispersion statistic. The scheduled assessment points were baseline, after 6 weeks of placebo, after 6 weeks of Cystone, and at the end of 46 weeks of open-label Cystone. The registry states that calcium oxalate was not analyzed for the cystine stone subjects. Numerical means, standard deviations, changes, and uncertainty estimates are not reported in the registry record, so the size and precision of any endpoint change cannot be assessed from that record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a crossover design compare?

In a crossover trial, each participant receives more than one study treatment in a planned sequence. Here, participants were assigned to Cystone followed by placebo, or placebo followed by Cystone. This allows the study to compare measurements made while participants receive each treatment, rather than relying only on a comparison between separate groups of people.

As a general statistical concept, a within-participant contrast can account for characteristics that remain stable within a person across the treatment periods. It does not automatically remove differences that change over time. Period effects, treatment order, and carryover from an earlier treatment can matter. A washout period is intended to separate treatment periods, but the registry record does not report evidence that the 1 week washout eliminated carryover for this urine measure.

A crossover analysis generally needs to respect the paired nature of the observations and the order and period in which they were collected. The registry record does not name the statistical model, test, or adjustment used for the primary endpoint. It also does not state whether treatment-by-period effects or carryover were assessed. Consequently, the analysis method and its assumptions cannot be reconstructed from the design description alone.

What does the endpoint summary measure?

The primary outcome is continuous: 24-hour urine supersaturation of calcium oxalate, with the registry identifying the mean as the summary measure and standard deviation as the measure of dispersion. A mean describes the central value of observations on the measurement scale. A standard deviation describes the spread of individual observations around their mean; it is not the uncertainty in the estimated mean and is not a confidence interval.

In general, a confidence interval expresses uncertainty around an estimated quantity under the assumptions of the analysis. It can help readers assess the range of effect sizes compatible with the data, rather than relying only on a point estimate. No confidence interval or numerical estimate for the primary endpoint is reported in the registry record, so its precision cannot be evaluated.

The endpoint is derived from urine ion concentrations to estimate theoretical supersaturation. The registry explanation notes that supersaturation favors precipitation but is balanced by crystallization inhibitors. Thus, the measure is a chemical indicator, not a direct observation that crystals formed or stones changed. The registry does not report numerical findings for any of the scheduled measurement points.

Why are masking and randomization relevant?

Random assignment to treatment order can reduce systematic differences in who receives each sequence, while masking can limit the influence of treatment expectations on participant behavior or outcome assessment. These are general design principles, not proof that bias was absent in this study. The registry labels the trial randomized and double-masked, but does not give operational details of sequence generation, concealment, or masking procedures.

The later open-label phase differs because participants and investigators were not masked to Cystone use. In general, an open-label follow-up can describe the course of measurements during treatment, but it is more vulnerable to influences that a masked randomized comparison is designed to limit. Because all subjects received Cystone during the 46-week phase, that period does not supply a concurrent placebo comparison as described in the record.

How should repeated outcomes and planning assumptions be understood?

The endpoint has multiple scheduled assessment points, and the registry lists 7 outcome measures and 20 analyses. Repeated observations from the same participant are related, so an analysis should account for that dependence rather than treating every measurement as unrelated. This is a general statistical consideration. The registry record does not state the model used to handle repeated measurements or explain how the analyses were selected.

When many outcomes or comparisons are examined, the chance of at least one apparently unusual result can increase. Statistical methods for multiplicity can address that concern, but the registry record does not report whether any correction or hierarchy was planned. Without the complete analysis plan and results, it is not possible to determine how multiplicity affected interpretation.

The registry describes assumptions for sample-size planning illustrations: two-sided significance level 0.05, equal allocation between the two arms, a normal approximation, and effects expressed as a stated fraction of the observed effect. Such calculations are planning illustrations, not observed power and not evidence that a particular effect was detected. The assumptions do not reveal the trial’s own design rationale, and the sample-size justification is not reported in the registry record.

More generally, power is a design-stage probability tied to assumptions about an effect, variability, and analysis. It is not a measure of the probability that a result is true after a study has been completed. The registry record does not report the trial’s original power calculation, its assumed effect size, or its statistical plan. These omissions limit any assessment of whether the planned study was designed to estimate a particular treatment contrast with a specified precision.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 7 outcome measures and 20 analyses. It names 24-hour urine supersaturation of calcium oxalate as the primary endpoint and radiologist-assessed change in stone burden at one year as a secondary outcome. However, the detailed hierarchy of outcomes and analyses, the comparisons designated as primary, and any multiplicity strategy are not reported in the registry record. When multiple outcomes or comparisons are examined, chance findings become a general interpretive concern; the record does not establish how that concern was handled.

The record describes several measurement times for the primary endpoint, including baseline, the placebo and Cystone periods, and the end of open-label treatment. It does not report which time-point contrast was the principal treatment comparison or whether all time points were included in a single model. Nor does it describe an approach for accounting for dependence among repeated measurements. These analysis details affect what an estimate would mean and how its uncertainty should be interpreted.

Missing-data handling is not reported in the registry record. The record does not state whether all enrolled participants contributed endpoint measurements, how incomplete observations were handled, or whether any sensitivity analyses were conducted. The analysis population is also not specified. It is therefore not possible to tell whether the reported analyses, if any, followed randomized sequence assignment or included only participants with particular observed measurements.

The record states that calcium oxalate was not analyzed for the cystine stone subjects. That is a specific limitation of the primary endpoint’s population and should not be conflated with ordinary missing measurement data. No numerical endpoint results or analysis-population counts are reported in the registry record, so the impact of exclusions or incomplete follow-up cannot be evaluated.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

The registry’s adverse-event entries list Calcium Stone Subjects and Cystine Stone Subjects separately. For each group, 10 are recorded as at risk for serious adverse events and 0 as having a serious adverse event. The entries also record 10 at risk for other adverse events and 0 with other adverse events. These are the posted event counts; they should be read as registry-reported observations, not as proof that no adverse events could occur.

The deaths field is null for both groups. A null entry does not provide a death count, so deaths are not reported in the registry record. The list of top serious terms is empty. This indicates that no serious-event terms are listed in that part of the record; it does not supply additional detail about event monitoring or ascertainment.

Safety counts are not the same as treatment-specific rates in the crossover phase. The registry presents these entries by stone-subject group, not by randomized treatment sequence or exposure period. It does not provide the timing of events, severity details beyond the serious-versus-other categories, or an account of how adverse events were collected. The counts therefore have limited context for comparing Cystone with placebo.

12. What the Result Does, and Does Not, Mean

The record establishes that investigators planned a randomized, double-masked crossover comparison of Cystone and placebo, followed by open-label Cystone use. It identifies a continuous urine chemistry endpoint and a secondary imaging-based stone-burden outcome. It also identifies the population conditions and the study’s treatment sequence structure. These design details explain what the trial set out to examine.

The record does not report numerical results for the primary endpoint or the secondary outcome. It supplies no treatment contrast, mean change, confidence interval, or p-value for those outcomes. As a result, the posted information does not show how much supersaturation changed, in which direction it changed, or how precisely any change was estimated. It also does not report a numerical stone-burden result.

That absence of results is not evidence that the treatments were equivalent, that no effect occurred, or that an effect occurred. Establishing equivalence or ruling out an effect would require appropriate estimates and uncertainty bounds, along with a prespecified framework. The registry record does not report those elements. No conclusion that Cystone prevents or dissolves stones can be drawn from the trial description or the safety counts alone.

The randomized crossover portion and open-label follow-up should also remain distinct in interpretation. A placebo-controlled comparison during the crossover phase is designed to assess a treatment contrast under its stated design. The later period, in which all subjects received Cystone, can describe observations during use but lacks the concurrent placebo comparison described for the earlier phase. The record does not provide numerical findings for either period.

The registry’s 0 serious and 0 other adverse-event entries are limited to the reported categories and at-risk groups. They do not establish the absence of unreported events or address treatment-specific risks across the trial periods. The null death entries mean that deaths are not reported in the registry record. Overall, the record is informative about trial structure and intended measurement, but does not permit a quantitative assessment of benefits, harms, or the precision of treatment effects.

13. Why This Trial Matters Statistically

This trial is statistically notable for combining a randomized crossover comparison with a later open-label treatment period. Those phases answer different kinds of questions. The crossover phase compares measurements under Cystone and placebo within the assigned treatment sequences. The open-label phase follows all subjects during Cystone use. Treating them as one undifferentiated comparison would obscure the role of randomization and the presence or absence of a concurrent comparator.

The study also illustrates the difference between a biological or chemical marker and a clinical outcome. Urine supersaturation is a continuous chemistry measure intended to characterize conditions relevant to calcium oxalate crystallization. The secondary outcome, radiologist-assessed stone burden, is an imaging assessment. Their definitions, measurement properties, and interpretation differ, so a result on one would not automatically establish a result on the other.

The endpoint population is narrower than the full set of stated conditions: calcium oxalate was not analyzed for cystine stone subjects. This makes it important to identify which participants contribute to a particular endpoint rather than assuming that every outcome applies to everyone enrolled. The registry does not provide the numerical outcome analyses needed to assess their population-specific estimates.

Finally, the record lists multiple outcomes and analyses without reporting a detailed analysis plan or multiplicity approach. That makes the distinction between prespecified comparisons and exploratory analyses especially important, but the record does not permit that distinction to be made. The trial is therefore a useful example of why design information alone cannot replace outcome estimates, uncertainty intervals, and transparent analysis details. Its registry record allows a careful account of what was planned, while leaving the treatment effects and their precision unreported.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The principal limitation for interpretation is that numerical outcome results are not reported in the registry record. Without endpoint estimates or uncertainty measures, the primary treatment comparison cannot be quantified. The same limitation applies to the secondary stone-burden outcome. The record’s description of the intended measurements cannot substitute for observed results.

The primary endpoint is not reported for the cystine stone subjects. It therefore does not provide a single endpoint assessment across both stated condition groups. The record does not describe a separate primary endpoint for the cystine group, so its outcomes cannot be inferred from the calcium oxalate measure.

The treatment sequence includes a washout period of 1 week, but the record does not report evidence about carryover or explain how treatment-period effects were analyzed. It also does not provide the randomization procedure, masking details, or the statistical model. These omissions prevent a full evaluation of the crossover analysis and its assumptions.

The longer phase was open-label and all subjects received Cystone. The registry does not describe a concurrent comparator for that period, limiting causal interpretation of any change during follow-up. It also does not report how missing observations, analysis populations, or multiple outcomes and analyses were handled.

The safety entries provide counts by stone-subject group but no timing, treatment-specific breakdown, or further event detail. Deaths are not reported in the registry record. The enrollment and design descriptions alone do not resolve these limitations or establish a treatment effect.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Use of an Herbal Preparation to Prevent and Dissolve Kidney Stones — NCT00381849.
• Registry record last updated 2016-02-04; status last verified 2016-01.
• Results first posted 2012-08-06.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

The registry record describes a completed, randomized, double-masked crossover study sponsored by Mayo Clinic, with enrollment of 20 and Phase 1 and Phase 2 designations. The study concerned cystinuria and calcium oxalate nephrolithiasis. Participants received Cystone and sugar pill placebo in randomized order during 6-week treatment periods separated by a 1 week washout, followed by 46 weeks of open-label Cystone.

The primary endpoint was 24-hour urine supersaturation of calcium oxalate, summarized as a mean with standard deviation. Calcium oxalate was not analyzed for the cystine stone subjects. A secondary outcome was radiologist-assessed change in stone burden at one year. Numerical results for these outcomes and detailed statistical methods are not reported in the registry record. The adverse-event entries list 0 serious and 0 other events in each stone-subject group; deaths are not reported in the registry record.