Effect of Kuvan on Neurocognitive Function, Blood Phenylalanine Level, Safety, and Pharmacokinetics in Children With PKU: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effect of Kuvan on Neurocognitive Function, Blood Phenylalanine Level, Safety, and Pharmacokinetics in Children With PKU (NCT00838435), a na phase 3 study. The primary outcome is Full-Scale Intelligence Quotient (FSIQ) Score.

2. Clinical Question

In practical statistical terms, the record describes monitoring of neurocognitive scores in a treated group, alongside safety and other outcomes. Without a concurrent control group, any change in scores cannot be separated statistically from other influences that may operate over time, including normal development, repeated testing, or changes in participants’ circumstances. Those are general considerations for interpreting an uncontrolled study, not findings about these participants. The registry record does not report an estimate that would establish how FSIQ changed during the study or how that change compares with what would have occurred without treatment.

3. Trial Design

This is a Phase 3, multicenter, open-label, single-group study of sapropterin dihydrochloride in children with phenylketonuria. The registry lists enrollment of 95 participants and identifies BioMarin Pharmaceutical as the sponsor. The study status is completed. Its start is recorded as 2009-02 and its primary completion as 2018-09-14.

The intervention description specifies oral sapropterin dihydrochloride at 20 mg/kg once daily with food. The dose is dissolved in water or apple juice, based on the participant’s age and ability. The record describes an age range of 0-6 years. It does not report a separate control arm, and its allocation entry is not applicable. Masking is listed as none, consistent with the open-label description: treatment assignment was not concealed through blinding in the design recorded.

The primary measure is FSIQ, with assessments through 84 months. Other listed outcomes include adverse events, growth measurements, Bayley-III neurocognitive scores, and pharmacokinetic measures. The record also describes evaluation of blood phenylalanine concentration and growth in its study summary. The intervention description does not establish a treatment duration for every participant, and an individual follow-up schedule is not reported in the registry record.

Because all participants belong to a single treatment group, the design can describe outcomes observed during study participation but cannot estimate a randomized treatment contrast against an untreated or active comparator group. Open-label conduct also means expectations and knowledge of treatment may influence some assessments or reporting, depending on the outcome and its measurement. These are design considerations, not evidence that any particular measurement was biased. The registry record does not report a protocol-level statistical plan, sample-size justification, interim-analysis plan, or details of any analysis model.

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.

Part 1 (4 Weeks)

PK Sub-Study 2 (4 Weeks)

Reasons for not completing this period:

Safety/Efficacy Sub-Study 1 (6 Months)

Reasons for not completing this period:

Part 2 (7 Years)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Efficacy population is based on all subjects from the enrolled population who have at least 2 WPPSI/ WISC assessments.

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.

Population: Safety Population consist of all subjects who received any study drug in the Full Analysis Set(FAS).

6. Primary Endpoint

The registry lists the primary outcome as Full-Scale Intelligence Quotient (FSIQ) Score, measured over Assessments through 84 months..

The primary endpoint is Full-Scale Intelligence Quotient (FSIQ), a score derived from selected subtests in age-appropriate Wechsler intelligence assessments. The record specifies the WPPSI-III for children >30 months and ≤6 years, and the WISC-IV for children >6 years old. It states that the outcome is the FSIQ score from WPPSI-III and/or WISC-IV testing. The stated score range is 40 to 160, with higher scores associated with higher intelligence quotient.

FSIQ is used as a measure of neurocognitive function. A standardized score can summarize performance across selected assessment tasks in a form intended to be interpretable across children assessed with the relevant age-appropriate instrument. The record does not provide further detail on how scores from the two instruments were combined or handled in the analysis, so no additional assumptions about comparability or scoring should be made.

The primary-outcome timeframe is assessments through 84 months. That identifies the period covered by the outcome but does not, by itself, specify a single assessment visit or a particular change-from-baseline contrast. The registry record does not report the FSIQ result, the number of participants contributing to that result, or the statistical method used to summarize measurements over time. Consequently, the endpoint’s definition can be described, but its observed level, change, variability, and precision cannot be assessed from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical interpretation of this study begins with its design. A single-group study follows outcomes in one treatment group without a separate comparator. It can describe the measurements collected in that group, but it does not estimate a randomized difference between treatment and control. A change over time within participants may reflect treatment as well as development, repeated measurement, changes in care or circumstances, and other influences. This is a general limitation of uncontrolled longitudinal data, not a claim that any one influence explains the outcomes in this study.

What does the primary measure represent?

FSIQ is a continuous score derived from selected subtests of age-appropriate Wechsler assessments, according to the registry description. The record identifies the WPPSI-III for children >30 months and ≤6 years and the WISC-IV for children >6 years. It states that higher scores are associated with higher intelligence quotient and gives a score range of 40 to 160. A continuous outcome can be summarized by a mean to describe its average level and a standard deviation to describe variation among measurements around that mean. The registry lists the primary parameter as a mean and dispersion as a standard deviation, but the observed values are not reported in the registry record.

A mean is a summary of the measurements included in a particular analysis; it does not show the full distribution or how individual participants’ scores changed. A standard deviation describes variability in the observed scores, not the precision of the estimated mean. A confidence interval, when reported, would express uncertainty around an estimate under the assumptions of the analysis. No confidence interval for FSIQ is reported in the registry record, so precision cannot be evaluated from this entry.

Why does the absence of a comparator matter?

In a randomized comparison, allocation helps make the groups comparable on average, allowing an outcome contrast to estimate the effect of assignment under the study’s assumptions. This trial is not a randomized comparison: allocation is listed as not applicable, masking as none, and the model as single group. An observed mean or change in the treated group would therefore be descriptive. It would not isolate the effect of treatment from time trends or other differences that could influence outcomes.

Within-person repeated measurements can be useful for describing trajectories, but they do not substitute for a control group. General statistical methods for repeated observations account for correlation among measurements from the same participant, since those observations are not independent. The registry record does not report which model, if any, was used to account for repeated assessments, whether the primary analysis targeted a particular visit, or how score observations across the assessment period were combined.

What do the safety counts convey?

The record gives a safety population and counts for participants with serious adverse events, participants with other adverse events, and deaths. These counts are descriptive summaries. In a single-group study, they do not provide an excess-risk estimate against a comparator. A causal interpretation also depends on event definitions, timing, adjudication, exposure, and other clinical context; details beyond the listed counts and terms are not reported in the registry record. The serious-event percentages listed for selected terms should be read as the record’s descriptions, not as a controlled treatment contrast.

How should planning illustrations be understood?

The record describes a planning illustration based on a fraction of an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It states that time-to-event illustrations use a total number of events and other illustrations use participants per arm. This is a general planning framework, not a description of this single-group trial’s observed sample or proof of its ability to detect an effect. Planning sample sizes are prospective illustrations under their assumptions; they are not observed power. The numerical inputs and resulting planning values are not reported in the registry record for this interpretation, and the illustration should not be confused with the trial’s design or results.

What statistical details remain uncertain?

The registry record does not report the primary FSIQ estimate, its variability, a confidence interval, or an inferential test. It does not report the detailed analysis model, any adjustment for baseline characteristics, the handling of repeated measurements, or the approach to missing observations. It also does not report whether analyses were adjusted for multiple outcomes or repeated testing. These omissions prevent an assessment of model assumptions and the robustness of any statistical conclusions. General statistical principles can explain why those details matter, but they cannot replace study-specific information absent from the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The record lists multiple outcomes, including FSIQ, adverse events, growth measurements, Bayley-III scores, and pharmacokinetic measures. Considering several outcomes can raise multiplicity concerns: the more statistical questions examined, the more important it is to understand which were prespecified as primary, how testing was organized, and whether any adjustment or interpretation strategy was used. The record identifies FSIQ as the primary outcome and lists one analysis for that measure, but a broader multiplicity plan is not reported in the registry record. No adjustment method or hierarchy for secondary outcomes is reported.

Missing data are especially relevant when outcomes are assessed over time. If participants miss assessments or leave the study, the analyzed observations may not represent all enrolled participants. The registry defines the efficacy population as enrolled participants who have at least 2 WPPSI or WISC assessments. The number meeting that criterion is not reported in the registry record. The record does not describe reasons for missing assessments, the extent or pattern of missingness, or whether missing scores were imputed or handled with a particular statistical model.

The safety population is separately identified in the safety information. The record does not explain in detail how safety-population membership was determined or whether every participant contributed the same duration of observation. The primary-outcome efficacy population and safety population therefore should not be assumed to be interchangeable. Their sizes or overlap beyond the stated safety count are not reported in the registry record.

These gaps matter because population definitions and missing-data methods can affect the interpretation of estimated means and event summaries. Without the analysis details and outcome results, it is not possible to judge whether missingness could have influenced the primary endpoint or whether multiplicity affected conclusions.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: constipation (2.1%), gastroenteritis (2.1%), convulsion (2.1%), phenylketonuria (1.1%), colitis ulcerative (1.1%).

The registry lists a safety population of 95 participants. Within that population, 12 participants are recorded as having serious adverse events, 90 as having other adverse events, and deaths as 0. These are counts, not estimates from a comparison with another group. The registry also lists constipation, gastroenteritis, convulsion, phenylketonuria, colitis ulcerative, and diarrhoea among the serious-event terms, with percentages of 2.1%, 2.1%, 2.1%, 1.1%, 1.1%, and 1.1%, respectively.

Serious adverse events and other adverse events are separate categories in the record. The counts do not show that events were caused by the intervention, and they do not establish how the frequency would differ under another treatment or without treatment. A single-group safety summary can describe events recorded during the study, but causal attribution requires clinical assessment and a suitable comparison, neither of which can be inferred from these counts alone.

The registry record does not provide additional detail on the duration of exposure for each participant, event timing, event adjudication, or the relationship of each event to treatment. The listed percentages should be read as reported for the named terms, not as a basis for estimating comparative risk. The zero deaths entry is a count in this safety population; it is not evidence about risk beyond the study’s recorded observation.

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

This study record describes a Phase 3, open-label, single-group evaluation of sapropterin dihydrochloride in young children with PKU. It identifies FSIQ as the primary outcome and specifies age-appropriate Wechsler assessments, with an assessment timeframe through 84 months. It also identifies safety, growth, neurocognitive, and pharmacokinetic outcomes. These design and measurement details clarify what the study set out to evaluate.

The record does not report the numerical primary-outcome result. It therefore cannot establish from the information presented whether FSIQ was higher, lower, or unchanged during the study, nor how precise any estimate was. Even if a before-and-after result were available, a single-group design would not establish what would have happened to a comparable group without the intervention. Changes over time cannot be attributed uniquely to treatment by this design alone.

The safety entries report adverse-event counts and selected serious-event terms, including a count of 0 deaths. Those observations describe what is recorded for the safety population; without a comparator and further event details, they do not establish comparative safety or causation. The record does not report the numerical results for the other listed outcomes in the registry record for this analysis.

Statistical interpretation also depends on the analysis population, handling of missing measurements, and methods used for repeated scores and multiple outcomes. Some population definitions are stated, but the detailed methods and the primary endpoint results are not reported in the registry record. As a result, the record supports a description of the trial structure, outcome definitions, and selected safety counts, but not a conclusion about the magnitude, precision, or causal meaning of a neurocognitive effect.

13. Why This Trial Matters Statistically

This trial is statistically notable for the combination of a long assessment timeframe and a single-group, open-label design. The primary outcome is a standardized neurocognitive score measured with age-appropriate Wechsler instruments, and the record specifies assessments through 84 months. Such an outcome can be important to characterize in a study of young children, but repeated measurement over time brings analytical questions about within-participant correlation, timing of assessments, and how scores from different age-appropriate tests are summarized. The registry record does not report the methods used to address those questions.

The single-group design makes the distinction between description and causal comparison particularly important. Outcome measurements can describe participants’ experience during the study, but without a comparator they do not isolate the contribution of treatment from developmental change or other time-related influences. This is a general design limitation, not a judgment about the quality of any particular assessment.

The record also makes clear that the primary outcome has an explicitly defined efficacy population, while safety is reported for a safety population. These distinctions matter because the participants contributing to an outcome analysis may not be the same as those included in a safety summary. The registry record does not report how many participants met the primary-outcome population definition.

Finally, the presence of several listed outcome domains makes transparency about outcome hierarchy, missing data, and multiplicity relevant to interpretation. Those statistical details are not reported in the registry record. Since the primary FSIQ result is also not reported, readers can learn how the endpoint was defined and what design was used, but cannot assess its observed magnitude or precision.

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 main limitation for interpreting the primary endpoint is that its numerical result is not reported in the registry record. The mean FSIQ, standard deviation, change estimate, confidence interval, and p-value are not reported. This prevents assessment of the observed score pattern and its statistical precision.

The single-group design provides no concurrent comparator. Consequently, the study record cannot support a randomized between-group estimate, and any within-group change would not separate treatment-associated change from other influences over time. Open-label conduct is also relevant: masking is listed as none. The record does not report whether assessors were masked or what steps were used to limit measurement influences.

The endpoint is defined using the WPPSI-III and/or WISC-IV, with instrument selection based on age. The registry record does not explain how scores across instruments were combined or how observations at different assessment times were analyzed. It does not report the statistical model, missing-data method, reasons for missing assessments, or the number of participants meeting the stated efficacy-population definition.

There are multiple listed outcomes, but a multiplicity strategy is not reported in the registry record. The detailed analysis plan, sample-size justification, and interim-analysis plan are also not reported. Safety counts are descriptive and lack a comparator; further details such as event timing, treatment relationship, and exposure duration are not reported. These limitations restrict conclusions to the design and the recorded safety summaries, rather than a causal assessment of efficacy or comparative safety.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Effect of Kuvan on Neurocognitive Function, Blood Phenylalanine Level, Safety, and Pharmacokinetics in Children With PKU — NCT00838435.
• Registry record last updated 2020-12-22; status last verified 2020-12.
• Results first posted 2020-12-22.
• 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 identifies a completed Phase 3, multicenter, open-label, single-group study of sapropterin dihydrochloride in children aged 0-6 years with PKU. Enrollment is listed as 95. The intervention is described as 20 mg/kg orally once daily with food, dissolved in water or apple juice according to age and ability.

FSIQ is the primary outcome, assessed with age-appropriate Wechsler instruments through 84 months. The record defines an efficacy population based on having at least 2 WPPSI or WISC assessments. Numerical primary-outcome results and detailed analysis methods are not reported in the registry record.

The safety population is listed as 95, with 12 participants recorded with serious adverse events, 90 with other adverse events, and 0 deaths. These are descriptive counts in a study without a comparator group and do not establish causation or comparative risk.