This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Tetrahydrobiopterin in Patients With Chronic Kidney Disease (CKD) and Albuminuria (NCT00625820), a na phase 2 study. The primary outcome is The Primary Outcome Measure is Level of Albuminuria..
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00625820 |
| Phase | Phase 2 |
| Condition | Kidney Disease, Albuminuria |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 17 |
| Arms in the primary outcome | n/a |
| Lead sponsor | University of Michigan |
| Results posted | Yes |
2. Clinical Question
Population
Patients with chronic kidney disease and albuminuria. The registry record reports enrollment of 17 participants and says that all participants who finished the trial were analyzed for the primary outcome. It does not report the number who finished.
Intervention
Participants received 6R-BH4, also called sapropterin dihydrochloride, followed sequentially by 6R-BH4 with vitamin C. The record describes 400mg twice daily of 6R-BH4 for 6 weeks, followed by 6R-BH4 plus 500mg twice daily of vitamin C for another 6 weeks.
Comparator
There was no randomized or concurrent control group. The study is registered as single-group, with no masking and allocation listed as not applicable. The later combination-treatment period follows the BH4-only period; it is not a like-for-like control comparison.
Primary question
The primary outcome was albuminuria, measured as the urine albumin-to-creatinine ratio. Early morning urine specimens were used, with assessments at 6 and 12 weeks of therapy. The registry record does not report the numerical outcome values or the estimated change between assessments.
The clinical rationale in the registry concerns nitric oxide availability and vascular function in chronic kidney disease. The study description presents BH4 as an investigational treatment intended to affect nitric oxide availability, while albuminuria serves as the primary measured outcome. The record does not establish that a change in albuminuria would translate into a change in disease progression or cardiovascular outcomes. Its single-group, sequential structure means that observations during treatment can describe what happened over time in the enrolled participants, but cannot by themselves isolate a treatment effect from other explanations for change.
3. Trial Design
This completed Phase 2 study is titled “Tetrahydrobiopterin in Patients With Chronic Kidney Disease (CKD) and Albuminuria” and is described as an open-label pilot study. The registry lists the sponsor as the University of Michigan. The recorded study start is 2008-05, and primary completion is listed as 2008-09. Enrollment was 17.
The trial is registered as a single-group study, with allocation marked not applicable and masking marked none. Participants were scheduled to receive 6R-BH4 400mg twice daily for 6 weeks, then 6R-BH4 plus vitamin C 500mg twice daily for another 6 weeks. Planned visits were at Weeks 0, 3, 6, 9 and 12, with an exit visit at week 16. These details describe the registered sequence; the record does not report whether every participant completed each treatment period or visit.
The primary outcome was the level of albuminuria at 12 weeks, with albumin-to-creatinine ratio assessments described at 6 and 12 weeks. Secondary outcomes were systolic blood pressure and estimated glomerular filtration rate, each measured at 6 and 12 weeks of therapy. The registry lists three outcome measures, but does not give numerical results for these measures in the record.
Because all participants followed the same sequence, the later period combined BH4 with vitamin C after the earlier BH4-only period. Treatment and time therefore vary together. Without a randomized comparison group, changes across periods cannot be cleanly attributed to adding vitamin C, to continuing BH4, or to other changes over time. The registry record does not report a statistical analysis plan, sample-size justification, or interim analyses.
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.
Before assignment: Seventeen patients were recruited and all started the trial.
Overall Study
| Stage | 1BH4, BH4 + Vitamin C |
|---|---|
| STARTED | 17 |
| COMPLETED | 16 |
| NOT COMPLETED | 1 |
Reasons for not completing this period:
| Reason | 1BH4, BH4 + Vitamin C |
|---|---|
| Withdrawal by Subject | 1 |
Analysis population for the primary outcome, as defined in the registry: All participants who finished the trial were analyzed
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.
| Characteristic | Unit | 1BH4, BH4 + Vitamin C |
|---|---|---|
| Participants analysed | 17 | |
| Age, Categorical: <=18 years | Participants | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 10 |
| Age, Categorical: >=65 years | Participants | 7 |
| Age, Continuous | years | 59.9 (SD 11.2) |
| Sex: Female, Male: Female | Participants | 5 |
| Sex: Female, Male: Male | Participants | 12 |
| Region of Enrollment: United States | participants | 17 |
6. Primary Endpoint
The registry lists the primary outcome as The Primary Outcome Measure is Level of Albuminuria., measured over 12 weeks.
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | Standard Deviation |
| Unit | ratio |
| Endpoint classification | Continuous Endpoint |
Albuminuria is the amount of albumin in urine; this study used the albumin-to-creatinine ratio as its measure. The registry describes early morning urine specimens collected to calculate that ratio at 6 and 12 weeks of therapy. The primary outcome is identified as the level of albuminuria at 12 weeks, and the outcome type is a mean of a continuous measure with standard deviation as its dispersion.
The registry’s rationale is that albuminuria is an easily measured marker that has served as a predictor of kidney disease progression. This explains why it was selected as a measurable endpoint in a pilot study. A marker can be useful for tracking a biological or clinical state without itself establishing what will happen to longer-term health outcomes. The registry’s rationale discusses possible implications of reducing albuminuria, but the record does not report evidence that this study measured kidney-disease progression or cardiovascular events as outcomes.
The outcome description identifies assessments at both 6 and 12 weeks, while the primary timeframe is listed as 12 weeks. The record does not report the actual albumin-to-creatinine ratio values, the variability observed, or a numerical comparison between time points. It also does not report a confidence interval or a statistical test for the primary outcome. Consequently, the endpoint’s definition and timing are available, but the magnitude and precision of any observed change are not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record identifies a clinically relevant measurement and a treatment sequence, but it does not include numerical primary-outcome results. It therefore does not support a quantitative description of the direction, size, or precision of change in albuminuria. No conclusion about the observed albuminuria result can be drawn from the endpoint description alone.
The outcome was intended to be summarized as a mean with standard deviation. In general, a mean describes the average measured value in the analyzed observations, while a standard deviation describes variability among those observations. Neither quantity is present for the primary outcome in the registry record. The record also does not report an effect estimate, confidence interval, or p-value. Statistical significance and uncertainty therefore cannot be assessed from this record.
The analysis population is described as all participants who finished the trial. The record does not state how many participants finished, how many had measurements at each time point, or how missing measurements were handled. This matters because a result among completers may differ from the result that would have been obtained if all enrolled participants had complete measurements. Without participant flow and outcome data, the extent and potential influence of missingness cannot be evaluated.
The single-group sequence also limits causal interpretation. All participants were scheduled to receive BH4 before receiving BH4 plus vitamin C. A change between the assessments could coincide with treatment exposure, but also with time, measurement conditions, or other influences. Because the later regimen follows the earlier regimen in everyone, the record does not describe a randomized comparison that separates those explanations.
For the same reason, the sequence is not a direct test of BH4 plus vitamin C against BH4 alone under otherwise comparable conditions. The treatment periods occur at different times, and the registry does not report a control group or a method that adjusts for period or carryover effects. The record’s description of the design and endpoint supports an account of what was planned, not an estimate of the treatment’s causal effect.
The safety record lists no serious adverse events in the reported group and one other adverse event. These are descriptive counts in a small pilot record, not a basis for establishing safety. Deaths are not reported in the adverse-event entry. More broadly, the registry’s lack of numerical efficacy results and detailed analysis information leaves important questions about outcome magnitude, uncertainty, and the completeness of follow-up unresolved.
9. Statistical Methods Explained
The following statistical explanations are general. The registry record does not report a detailed statistical analysis plan, so the explanations describe how common methods would be interpreted rather than asserting that a particular method was used in this study.
What does a mean describe?
For a continuous measure such as an albumin-to-creatinine ratio, a mean is the arithmetic average of the measured values in the observations included in the calculation. It summarizes the center of those values, but does not show how each participant’s measurement changed or whether the values were concentrated or widely spread. The registry identifies the primary outcome as a mean and names standard deviation as its dispersion measure. It does not report either numerical summary.
A standard deviation describes the spread of individual observations around their mean. It is not the same as the uncertainty in the estimated mean. The standard error, in general, describes how much an estimate would vary across repeated samples under a statistical model. A confidence interval uses that sampling uncertainty to give a range of values compatible with the data and method. The registry record does not report a standard error or confidence interval for albuminuria.
Why does the sequence matter?
In a randomized parallel-group trial, random assignment aims to make the groups comparable, on average, with respect to factors that could affect the outcome. This study is registered as single-group and has no randomized comparison. Participants were scheduled to receive BH4 first and the BH4-plus-vitamin-C regimen later. Any difference between measurements across those periods combines changes associated with time and changes associated with the treatment sequence. The registry does not report a design feature that separates these influences.
For a sequential design, the measurement at a later time can reflect the history of prior treatment as well as the current regimen. General statistical concerns can include period effects, carryover, natural fluctuation, and changes in measurement conditions. These are considerations for interpreting this kind of sequence, not claims that any of them occurred. The registry record does not report an analysis of these issues.
What would a confidence interval add?
In general, a confidence interval communicates the uncertainty around an estimated quantity, such as a mean change or a difference between groups. A narrow interval indicates greater precision under the method’s assumptions; a wide interval indicates less precision. Its interpretation depends on the estimand, analysis population, and statistical method. No interval or numerical primary-outcome estimate is reported in the registry record, so precision cannot be judged for the albuminuria result.
A p-value, in general, measures how compatible the observed data are with a specified null hypothesis under a statistical model. It does not give the probability that the null hypothesis is true, and it does not measure clinical importance. The record reports no p-value or primary-outcome test. It would therefore be inappropriate to characterize the result as statistically significant or not statistically significant.
What is over-dispersion?
Over-dispersion is a general issue for outcomes whose variability is greater than a statistical model expects. For example, count data can vary more widely than a simple Poisson model allows. Models that account for extra variability may produce more realistic uncertainty estimates. The primary outcome in this study is described as a continuous mean, not a count, and the registry does not report an over-dispersion model. This concept does not establish that over-dispersion affected this study.
How should the sample-size illustration be read?
The planning illustration is described as a hypothetical calculation based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It considers detecting stated fractions of that effect. Such values are planning illustrations, not observed power and not evidence that the trial had a particular probability of detecting an effect. They do not show that the actual single-group study was designed with two equal randomized arms. The record does not report a sample-size justification for this pilot study, and the numerical illustration values are not stated in the registry record.
In general, a planning calculation depends on assumptions about the effect to detect, variability, significance level, allocation, and analysis. Changing those assumptions changes the sample size required for the calculation. A calculation anchored to an observed effect also inherits uncertainty in that estimate; it should not be read as proof that the effect is reliable or reproducible. No new sample-size value can be inferred from the registry entries alone.
Why are analysis details important?
An analysis plan specifies, among other things, which observations contribute to each outcome, how repeated measurements are handled, what model is used, and how missing data are addressed. These choices can affect estimates and uncertainty. The record identifies a completer population for the primary outcome and identifies the summary measure, but does not report a full analysis plan. It lists no analyses in the registry entry. That absence means the analysis methods and any inferential results cannot be reconstructed from the record.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists a primary outcome of albuminuria and two secondary outcomes: systolic blood pressure and estimated glomerular filtration rate. Each secondary outcome is listed at 6 and 12 weeks of therapy. Considering multiple outcomes or time points can raise a general multiplicity issue: the more statistical tests performed, the greater the chance of obtaining at least one apparently unusual result by chance if each test is interpreted separately. Researchers may prespecify a primary comparison or use methods to address multiplicity. The registry record does not report whether any multiplicity adjustment or hierarchy was planned.
The record reports zero analyses in its analysis listing, and it does not provide outcome estimates, test results, or a detailed statistical plan. It is therefore not possible to determine which comparisons were actually tested, whether time points were analyzed separately, or whether any adjustment was used. No claim about selective reporting or a particular testing strategy can be made from this absence alone.
The primary outcome population is described as all participants who finished the trial. The record does not report the number of completers, the number contributing data at each assessment, or reasons for missing observations. It does not specify whether missing outcomes were excluded, imputed, or handled using a model that could use incomplete repeated measurements. Those details are not reported in the registry record.
In general, complete-case analyses can be biased if the likelihood of having an observed measurement is related to the outcome or participant characteristics. Imputation and model-based approaches also require assumptions. Without information about missingness and its handling, the potential direction or size of any bias cannot be assessed. The described completer population should therefore not be assumed to represent every enrolled participant or to resolve missing-data concerns.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| BH4, BH4 + Vit C | 0 | 17 | 0.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| BH4, BH4 + Vit C | 1 of 17 |
Most frequent non-serious adverse event terms
| Event term | Organ system | BH4, BH4 + Vit C |
|---|---|---|
| Nephrolithiasis | Renal and urinary disorders | 1 of 17 |
The registry’s adverse-event entry describes a group labeled “BH4, BH4 + Vit C.” For serious adverse events, 17 participants were listed as at risk and 0 as affected. For other adverse events, 17 were listed as at risk and 1 as affected. The record does not provide serious-event terms, and the listed top serious terms are absent.
These counts should be read as the recorded event summary, not as proof that serious adverse events were impossible or that the regimen is safe. The entry combines the treatment sequence in one group and does not split events by the BH4-only and combination periods. It does not report event timing, severity details beyond the serious-versus-other classification, or a participant-level account of repeated events. The single other adverse event is not described by term in the record.
The death count is not reported in the adverse-event entry. It should not be interpreted as zero. More generally, a small pilot study and a brief registry summary cannot characterize uncommon harms reliably. These figures are descriptive, and the registry record does not provide comparative safety estimates against a control group.
12. What the Result Does, and Does Not, Mean
This trial record is useful for understanding how a pilot study of BH4 was structured in patients with chronic kidney disease and albuminuria. It identifies albuminuria as the primary outcome, specifies an albumin-to-creatinine ratio measured at 6 and 12 weeks, and describes a sequence in which BH4 was followed by BH4 plus vitamin C. It also records two secondary outcomes and a limited adverse-event summary.
The registry record does not report the numerical primary-outcome values, an estimate of change, or a measure of uncertainty. It therefore cannot establish from the posted results whether albuminuria increased, decreased, or remained similar during the study. Nor does it permit an assessment of the size or precision of any change. The endpoint rationale describes albuminuria as a marker associated with kidney disease progression, but this is not the same as measuring progression or demonstrating a change in long-term clinical outcomes.
The design does not include a randomized or concurrent control group. Because all participants were scheduled to receive BH4 before the combination regimen, the treatment phases cannot be treated as a controlled comparison. Differences over time could have explanations other than treatment, and the record does not report methods that disentangle them.
The adverse-event counts are descriptive and do not establish the absence of risk. The death entry is not reported, and the record does not provide detailed event descriptions or a control group for comparison. The findings and limitations should be understood as those of a completed open-label pilot study, not as a definitive estimate of efficacy or safety. The registry record also does not report a statistical analysis plan or a sample-size justification.
13. Why This Trial Matters Statistically
Statistically, this study illustrates the difference between measuring an outcome and establishing a treatment effect. The registry defines albuminuria using an albumin-to-creatinine ratio and states when it was assessed. Those details make the intended measurement understandable, but they do not supply the numerical observations needed to estimate a change or its uncertainty.
The single-group sequence is also important. Participants were scheduled to receive BH4 and then BH4 with vitamin C, so treatment exposure is tied to the order and timing of measurement. Without a concurrent randomized comparison, a change observed between periods cannot be attributed uniquely to the added vitamin C or to BH4. This is a design limitation rather than a flaw that can be corrected simply by presenting a more detailed descriptive summary.
The record’s analysis population raises another interpretive issue. It says that participants who finished the trial were analyzed, but does not report how many finished or how many contributed measurements at each time. A reader therefore cannot assess the completeness of follow-up or the consequences of analyzing completers.
Finally, a pilot study can be informative about the planned outcome and treatment sequence, while still leaving uncertainty about effects and harms. Here, the registry record does not report primary-outcome estimates, inferential statistics, or a detailed analysis plan. The statistical value of the record is thus chiefly in clarifying what was intended and identifying what remains unreported, rather than in quantifying a treatment effect.
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 the registry record does not report numerical results for the primary albuminuria outcome. It also does not report estimates or uncertainty for the secondary outcomes. Consequently, the magnitude, direction, and precision of the measured outcomes cannot be evaluated from the record.
The design is open-label and single-group, with no randomized control comparison. The sequence places BH4 before BH4 plus vitamin C, so treatment phase and time are intertwined. The registry does not report a method for separating treatment effects from other changes over time, nor does it report an analysis of possible carryover between periods.
The primary analysis is described as including participants who finished the trial, but the record does not state how many finished, how many had measurements at each time point, or how missing measurements were handled. This prevents assessment of follow-up completeness and the possible effect of missing data. The record also does not report a statistical analysis plan, sample-size justification, or interim analyses.
The adverse-event entry reports counts without event terms for serious events and does not report the death count. It does not distinguish events by treatment period. The summary therefore offers limited detail for assessing safety, and the design provides no control group for comparison. These limitations do not show that an outcome or event did or did not occur beyond what the record lists; they define what can be concluded from the available registry information.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Tetrahydrobiopterin in Patients With Chronic Kidney Disease (CKD) and Albuminuria — NCT00625820.
- Registry record last updated 2016-10-18; status last verified 2016-08.
- Results first posted 2016-10-18.
- 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.
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18. Record Summary
This completed Phase 2 open-label pilot study enrolled 17 participants with chronic kidney disease and albuminuria. It was registered as a single-group study with no masking and no randomized allocation. The planned sequence was 6R-BH4 400mg twice daily for 6 weeks, followed by 6R-BH4 plus vitamin C 500mg twice daily for another 6 weeks.
The primary outcome was albuminuria measured using the urine albumin-to-creatinine ratio, with assessments described at 6 and 12 weeks. Secondary outcomes were systolic blood pressure and estimated glomerular filtration rate at those time points. The record says that participants who finished the trial were analyzed for the primary outcome, but does not report the number of completers.
The registry record does not report numerical efficacy results or a detailed statistical analysis plan. Its safety entry lists 0 serious adverse events among 17 at risk and 1 other adverse event among 17 at risk; deaths are not reported.