Tetrahydrobiopterin Treatment in Children With Idiopathic Cognitive Developmental Disorders: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Tetrahydrobiopterin Treatment in Children With Idiopathic Cognitive Developmental Disorders (NCT01141595), a na na study. The primary outcome is Preschool Language Scales.

2. Clinical Question

The study’s stated purpose was to develop biomarkers that might help screen children for central nervous system BH4 concentration and identify those who may benefit from supplementation. That purpose provides context, but the listed primary outcome is a language-scale score; the record does not report a numerical biomarker result or a statistical analysis linking a biomarker to language-score change. The available information therefore describes the question and measurement plan more clearly than it answers the question about change.

3. Trial Design

This was a completed, single-group study sponsored by The University of Texas Health Science Center, Houston. The registry lists an enrollment of 10 and identifies autism spectrum disorder as the condition. The study started in 2010-07, with primary completion in 2011-09. Its phase is listed as NA. Allocation is listed as NA, masking as none, and the model as single group.

Participants received sapropterin dihydrochloride, identified in the record as Kuvan®. The arm description instructed participants to take 20 mg/kg/day orally, dissolved in 4 - 8oz. of water or apple juice with breakfast. The primary outcome was measured at baseline, 8 weeks, and 16 weeks after treatment started. The specified primary comparison is each participant’s baseline raw score against the score at the end of the 16-week period.

A single-group design can describe what happened over time among participants receiving the intervention, but it does not provide a concurrent untreated or alternative-treatment group. Changes over time cannot, by themselves, distinguish an intervention effect from other explanations for change. The record does not describe random assignment, a control arm, or masking; it explicitly lists no masking.

The registry lists one outcome measure and reports no analyses. It does not report the number of participants who completed the primary assessment, a numerical outcome estimate, or an uncertainty measure. Thus, the record supports a description of the intended design and outcome, but not a quantitative assessment of the observed change or a comparative treatment effect.

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: No significant events

Overall Study

Analysis population for the primary outcome, as defined in the registry: The number of participants with data available that completed at least the 16 week assessment.

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 Preschool Language Scales, measured over 16 weeks.

The primary endpoint is change in the raw score of the Preschool Language Scales from baseline to the end of the 16-week period. Scores were measured at baseline, 8 weeks, and 16 weeks after treatment began; the stated endpoint is the change from baseline to the end of the study. The raw score ranges from 0 to 130, and higher scores indicate better performance.

A language-scale score is used to express performance in a defined measurement unit rather than relying only on a general impression of change. Using a baseline and a later assessment allows the study to describe how scores changed over the observation period for participants with the required data. The intermediate 8-week assessment is part of the measurement schedule, although the primary endpoint description focuses on baseline-to-16-week change.

The registry does not give the observed mean change, its standard deviation, or the number of participants included in this endpoint analysis. It also does not report how the scale was administered or whether any other language or developmental measures were collected. The endpoint description therefore clarifies what was intended to be measured, but it does not establish the size or precision of any change.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical information in this record is limited. It identifies a continuous primary outcome, describes the endpoint as a mean change, and names standard deviation as the measure of dispersion. It also states that the analysis was as treated and that no data were imputed. The registry reports no analyses and does not give a numerical outcome estimate. The explanations below describe these statistical ideas generally; they should not be mistaken for details of an analysis that the record does not report.

What does a mean change describe?

In general, a mean change summarizes the average difference between measurements taken at two times for the participants included in the analysis. Here, the described change is from baseline to the end of the 16-week period on the Preschool Language Scales raw score. A mean is a summary of the group; it does not show whether every participant changed in the same direction or by a similar amount. Individual participant values or a distribution of changes would be needed to describe that variation in detail, and these are not reported in the registry record.

The direction of a change must be interpreted using the scale’s meaning. The record says higher raw scores indicate better performance. But without the mean change, readers cannot tell whether the posted result reflects an increase or decrease, or how large the change was. The score range is 0 to 130; that describes the scale, not the observed result.

What does standard deviation tell readers?

In general, standard deviation describes how dispersed individual observations are around their mean. A smaller standard deviation indicates that the values are more clustered around the mean, while a larger one indicates greater spread. It is not itself a confidence interval and does not directly state how precisely a mean has been estimated. For a change outcome, the relevant dispersion would describe variation in participants’ changes if calculated for those changes. Although the registry names standard deviation, its value is not reported in the registry record.

Variation matters because a group average can conceal quite different individual patterns. Similar average changes can arise from relatively consistent participant changes or from a mix of larger and smaller changes. Without the estimate, the dispersion, and the analysis sample size, readers cannot assess the observed pattern or its precision.

Why is the single-group design important?

In general, repeated measurements in one group can describe within-group change over time. They do not create a concurrent comparison with what would have happened over the same period without the intervention or with another intervention. A before-and-after change can be affected by factors other than treatment, including general time-related changes and measurement variation. This means a single-group change should not be described as a treatment-versus-control effect. The record does not list a control group or a randomized comparison.

Having measurements at baseline, 8 weeks, and 16 weeks allows more than one observation over time, but the primary endpoint described in the record is the baseline-to-end change. The registry does not report a model for repeated measurements or an analysis of the intermediate observation. No statistical test or adjustment method is reported either.

What can a confidence interval add?

In general, a confidence interval communicates uncertainty around an estimate under a specified statistical method. It can help readers distinguish the estimated size of an effect from the range of values that remain compatible with the data and method. It is not a guarantee that the true value lies within the interval, and it does not remedy design limitations such as the absence of a comparator. The registry record does not report a confidence interval for the primary endpoint.

A p-value, in general, summarizes how compatible the observed data are with a specified statistical null model, given the assumptions of the test. It is not a measure of effect size, clinical importance, or the probability that a hypothesis is true. No p-value or test for the primary endpoint is reported in the registry record, so none can be interpreted.

How should the planning illustration be read?

The sample-size section is described as a planning illustration based on an observed effect, rather than the trial’s own design. Its stated assumptions include a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. For non-time-to-event outcomes, the illustration is expressed as participants per arm. These are hypothetical planning assumptions, not evidence that the study enrolled two arms or used those methods for its primary analysis.

Planning calculations answer a different question from analysis of observed trial results. They can illustrate what sample size might be needed under stated assumptions, but they do not show that a trial had a particular probability of detecting an effect. They are not observed power. The registry record does not report the study’s own sample-size justification or statistical plan, and it does not provide the numerical primary outcome estimate needed to assess the observed effect.

What does as-treated analysis mean generally?

In general, an as-treated analysis groups or analyzes participants according to the treatment they actually received, rather than necessarily according to an original randomized assignment. The record says the primary outcome analysis was as treated, but the study is listed as single-group and allocation is listed as NA. It does not provide further details about how participants were handled in the analysis. Since no numerical analysis is posted, the effect of this analysis approach on the result cannot be evaluated.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Kuvan®")
n   <- c(8)
m   <- c(7.6)
sp  <- c(8.4)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Kuvan®  8  7.600  8.400  0.577  14.623

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists one outcome measure, the Preschool Language Scales, and reports no analyses. It does not say whether the outcome was designated as primary in a broader statistical plan or whether other outcomes were analyzed but not posted. The record does not report a strategy for adjusting for multiple comparisons. With no analysis results or detailed statistical plan, it is not possible to determine whether multiplicity was considered or how it might affect interpretation.

The primary outcome description says there was no imputed data and that the analysis was as treated. In general, imputation is a statistical approach for handling missing values; not imputing means the record does not describe replacing missing outcome values with modeled or substituted values. The number of participants with data who completed at least the 16-week assessment is not reported in the registry record. Nor are the amount, reasons, or pattern of missing outcome data reported. This prevents readers from assessing how much information contributed to the endpoint or whether missingness could have affected the result.

The stated population for the outcome includes participants with data available who completed at least the 16-week assessment. The record does not explain how participants who lacked that assessment were handled beyond saying there was no imputed data and that the analysis was as treated. It also does not report a sensitivity analysis to examine how alternative assumptions about missing values might change an estimate.

These gaps matter because a change estimate describes the participants included in its calculation. If some participants lack endpoint data, the observed group may not represent everyone enrolled. This is a general concern, not evidence that missing data biased this study. The available record does not provide enough information to judge the extent or consequences of missingness.

12. 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.

Most frequent non-serious adverse event terms

The safety summary lists 10 participants at risk for serious adverse events and 0 participants with a serious adverse event in the Kuvan® group. It also lists 10 participants at risk for other adverse events and 2 participants with an other adverse event. These are counts as posted, not estimates of comparative risk: the study has no comparator group.

The record does not list any serious adverse event terms. It does not identify the nature, timing, severity, or relationship to treatment of the 2 other adverse events in the information. A count of participants with an event also does not indicate how many separate events occurred if a participant experienced more than one. The registry does not report that detail.

The death count is not reported in the registry record. This is distinct from a reported count of zero, so it should not be read as evidence that no deaths occurred. Likewise, the serious-event count describes what is posted for this group, but the small study and the absence of a comparator limit what can be concluded from the counts. These figures do not provide a complete safety profile or establish a causal relationship between treatment and any event.

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

This record describes a completed single-group study of sapropterin dihydrochloride in children with autism spectrum disorder. Its primary endpoint was change in Preschool Language Scales raw score from baseline to the end of 16 weeks. The registry gives the score range and direction, and specifies that the analysis used available data without imputation. It does not post the numerical change, its standard deviation, the endpoint analysis sample size, or a confidence interval. As a result, the posted information does not show the size or precision of the primary outcome change.

The absence of a reported result should not be treated as a result showing no change. It also does not establish that scores improved. The record simply does not provide the numerical endpoint findings needed to describe the observed direction or magnitude. The stated study purpose concerns developing biomarkers, but the listed primary outcome is a language-scale score; the record does not provide a numerical biomarker result or an analysis connecting biomarkers and score change.

Even with a reported before-and-after estimate, the single-group design would describe change over time rather than compare the intervention with a control. A change could not be attributed to treatment on the basis of this design alone. That is a general interpretive limitation of an uncontrolled before-and-after study, not a judgment about what happened to these participants.

The safety summary reports 0 serious adverse events among 10 participants at risk, and 2 participants with other adverse events among 10 at risk. The death count is not reported in the registry record. These counts are limited descriptions of the posted safety data and do not establish comparative safety or explain the nature of the reported events.

The planning illustration, where shown, is not an observed outcome or a measure of the trial’s actual ability to detect an effect. It uses hypothetical assumptions and should not be used to fill gaps in the registry’s outcome reporting. Overall, the record establishes what was intended to be measured and some features of study conduct, but it does not permit a quantitative conclusion about the primary outcome.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of the distinction between a clearly described endpoint and a result that can be quantitatively interpreted. The record defines the primary measure, the direction of better performance, the measurement schedule, and the intended baseline-to-end change. Yet it does not report the mean change, its standard deviation, or the number of participants contributing endpoint data. Without those elements, readers cannot assess the observed magnitude, variability, or precision.

The single-group design also highlights the difference between describing change and estimating a comparative effect. Repeated measurements can show how a group’s scores evolve over time, but without a comparator they do not show how those changes differ from what might have occurred under another condition. The design therefore shapes what the results could support even if outcome estimates were available.

Missing-data reporting is another important statistical issue. The record states that no data were imputed and identifies the analysis as as treated, but it does not report how many participants completed the endpoint assessment or describe missingness. Those details help readers understand which participants contributed to the estimate and how representative that group may be of the enrolled participants.

Finally, planning calculations and trial results answer different questions. A planning illustration can show hypothetical sample-size requirements under stated assumptions; it cannot substitute for an outcome estimate or be interpreted as observed power. This record makes those distinctions especially relevant because the numerical primary outcome is not posted. For statistical readers, the central lesson is to separate the study’s measurement plan, its design limitations, and its actual posted results. Here, the first two are described more fully than the third.

15. 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 most consequential limitation for interpreting the posted results is that the registry record does not report a numerical result for the primary endpoint. It specifies a mean change in Preschool Language Scales raw score but gives neither the mean nor its standard deviation. The number of participants included in that analysis is also not reported in the registry record, despite an enrollment of 10.

The single-group design means there is no concurrent control against which to compare change. The record lists no masking and does not describe random allocation. These design features limit interpretation of any within-group change as a treatment effect. The record does not report further details about how the intervention was implemented or participant adherence beyond the instruction to take the stated dose.

The primary outcome description identifies assessments at baseline, 8 weeks, and 16 weeks, but the endpoint focuses on baseline-to-end change. The record does not report individual score patterns, a repeated-measures analysis, or numerical findings at the intermediate assessment. It also does not provide a confidence interval, p-value, or statistical test for the endpoint.

Missing-data information is limited. The record says no data were imputed and describes the analysis as as treated, but it does not state how many participants completed the 16-week assessment, how many lacked outcome data, or why data were missing. The registry does not report a sensitivity analysis or enough information to assess the implications of missing observations.

The stated purpose involves biomarkers of central nervous system BH4 concentration, but no numerical biomarker findings or analysis relating biomarkers to the primary outcome are reported. Safety reporting is also limited to counts: the nature of the other adverse events and the death count are not reported in the registry record. Together, these gaps constrain interpretation of both the endpoint and the broader study purpose.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Tetrahydrobiopterin Treatment in Children With Idiopathic Cognitive Developmental Disorders — NCT01141595.
• Registry record last updated 2014-04-01; status last verified 2014-02.
• Results first posted 2014-02-24.
• 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.

19. Record Summary

This completed study examined sapropterin dihydrochloride, identified as Kuvan®, in children with autism spectrum disorder and idiopathic cognitive developmental disorders. The sponsor was The University of Texas Health Science Center, Houston. Enrollment was 10. The study started in 2010-07 and reached primary completion in 2011-09.

The design was single group, with no masking and allocation listed as NA. Participants were instructed to take 20 mg/kg/day orally in water or apple juice with breakfast. The primary outcome was change in Preschool Language Scales raw score from baseline to the end of 16 weeks; higher scores indicate better performance.

The registry record reports no analyses and does not give a numerical primary outcome result or the number included in the endpoint analysis. Safety counts list 0 serious adverse events and 2 participants with other adverse events among 10 at risk; the death count is not reported in the registry record. The record describes the study’s purpose and measurement plan, but leaves the primary outcome’s magnitude and precision unavailable.