Fluorodeoxyglucose Positron Emission Tomography (FDG PET) Findings in Patients With Phenylketonuria Before and After KUVAN Therapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Fluorodeoxyglucose Positron Emission Tomography (FDG PET) Findings in Patients With Phenylketonuria Before and After KUVAN Therapy (NCT00986973), a na na study. The primary outcome is Plasma Phenylalanine Level (mg/dl).

2. Clinical Question

The clinical question is exploratory: it asks whether measurements change over time during treatment in a small group, rather than whether treatment differs from a concurrent control. That distinction matters because a before-and-after pattern alone cannot separate a treatment-associated change from other changes over time. The record describes the intended assessment but does not report numerical findings with which to judge the direction, size, or precision of any change.

The study also lists cognitive tests as secondary outcomes: the Hopkins Verbal Learning Test (HVLT) Total Recall and Delayed Recall, Paced Auditory Serial Addition Task (PASAT), Symbol-Digit Modalities Test (SMTD), Wechsler Adult Intelligence Scale (WAIS-IV)-Digit Span, and Delis-Kaplan Executive Function System Verbal Fluency Subtest (D-KEFS). These measures indicate that the study included additional cognitive assessments, but their results are not reported in the registry record. The primary question should therefore be kept distinct from those secondary assessments.

3. Trial Design

The registry record classifies this as a single-group study with allocation listed as NA and masking listed as single. Its status is COMPLETED. The listed enrollment is 6, and the sponsor is Children's Hospital of Philadelphia. The study start is recorded as 2010-03 and primary completion as 2011-07. These registry entries describe the study record; they do not by themselves establish that numerical outcome results were reported.

All participants were assigned to receive Sapropterin (KUVAN), with measurements planned at baseline and at four months. The primary-outcome description says blood tests for plasma phenylalanine were collected before and four months after therapy. The arm description gives the treatment duration as four months. No parallel control arm, random allocation, or treatment comparison between groups is described. As a result, the design supports a within-participant description of change over time, subject to the availability and completeness of paired observations.

The registry describes single masking but does not identify who was masked. The specific masking procedure and whether outcome assessors or participants knew the treatment assignment are not reported in the registry record. Because the record describes a single-group treatment study, the meaning and practical scope of masking are not clear from the available description.

The record lists Phenylketonuria as the condition and the study title identifies FDG PET findings as the subject of interest. However, the stated primary endpoint is plasma phenylalanine level in mg/dl, not a numerical FDG PET measurement. The planned relationship between blood Phe, brain glucose metabolism, and any PET assessment is described in broad terms, while the specific imaging measures and their results are not reported in the registry record.

One participant was withdrawn because of poor compliance with KUVAN therapy. The record does not state how many participants completed the four-month assessment, whether the withdrawn participant contributed baseline data, or how incomplete observations were handled. The analysis population and analysis method are not reported in the registry record. Those omissions limit interpretation of both the intended paired comparison and the sample represented by any eventual estimate.

The record lists 7 outcome measures and 7 analyses. It names six secondary cognitive tests in addition to the primary outcome. The specific statistical tests, covariate adjustments, and rules for selecting among analyses are not reported in the registry record. A planning illustration based on an observed effect is described as hypothetical, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Those assumptions do not describe the actual single-group design, and the illustration is not a report of observed study power or the trial's own design justification.

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: Six adults (4 male and 2 females) were interested in participating in the study, each signed informed consent forms and were screened for eligibility. All six were enrolled.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: 1 subject was withdrawn from the study due to poor compliance with KUVAN therapy.

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 Plasma Phenylalanine Level (mg/dl), measured over Measurements were obtained at the beginning and conclusion of each study period (baseline and 4 months).

The primary endpoint is plasma phenylalanine level, measured in mg/dl. The registry identifies the summary measure as a mean with standard deviation and gives the assessment times as the beginning and conclusion of each study period, described as baseline and four months. The endpoint description says blood tests for Phe were collected before and four months after Sapropterin therapy.

Plasma Phe is a blood measurement. The registry record describes it as the primary means of evaluating brain glucose metabolism and states a hypothesis that treatment would decrease Phe levels. These statements describe the study's rationale and intended interpretation; they do not make the blood measurement a direct measure of brain glucose metabolism. The specific FDG PET endpoint, method for quantifying PET findings, and relationship between PET measurements and plasma Phe are not reported in the registry record.

For a before-and-after study, the clinically relevant summary would generally include the measurements at each time and the within-participant change, with a measure of uncertainty. General statistical explanation: using paired measurements preserves the fact that each participant contributes observations at both times; the analysis can then focus on each participant's change rather than treating the observations as independent. The registry record does not report the baseline mean, four-month mean, standard deviations, number of paired measurements, or estimated change.

The endpoint description also contains two different dose notations: 20/mk/kg/day in the arm description and 20/mg/kg/day in the primary-outcome description. The registry record does not clarify which notation is intended. No interpretation of the measured endpoint should depend on resolving that discrepancy by assumption.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

General statistical explanation: continuous outcomes, such as a concentration measured on a numeric scale, are often described using a mean and standard deviation. The mean represents the central level across observations, while the standard deviation describes how dispersed those observations are. The registry identifies plasma Phe as a continuous endpoint summarized by a mean and standard deviation. The corresponding numerical summaries are not reported in the registry record.

What does a before-and-after comparison estimate?

In a single-group before-and-after study, the intended comparison is between measurements taken from the same participants at different times. A paired analysis uses each participant's observations together and estimates the average within-participant change. This differs from comparing two unrelated groups, because each person's baseline value is linked to their follow-up value. The registry describes baseline and four-month Phe measurements, but the estimated paired change and the number of complete pairs are not reported in the registry record.

General statistical explanation: pairing can account for stable differences between participants because the comparison is made within each person. The resulting uncertainty depends on how much the individual changes vary, not only on the variation in measurements at either time considered separately. That is why baseline and follow-up means and standard deviations alone would not necessarily be enough to reconstruct the uncertainty of a paired change. The registry record does not report the analysis details needed to assess this issue.

How should uncertainty be read?

General statistical explanation: a confidence interval expresses uncertainty around an estimate under a specified statistical model and analysis. A narrow interval indicates more precise estimation than a wide interval, while the interval's position indicates which values remain compatible with the data and assumptions. A p-value addresses compatibility with a specified null hypothesis under the test assumptions; it does not measure the size or importance of an effect. Neither a confidence interval nor a p-value is reported for the primary endpoint in the registry record.

Because the numerical endpoint results are absent, there is no estimate to describe as precise or imprecise. It is also not possible to assess whether any apparent change would be driven by one participant, how variable participant-level changes were, or whether the data contain unusual values. Those questions require the underlying observations or suitable summary results, which are not reported in the registry record.

What does the design allow?

The design is a single group receiving therapy, with measurements planned before and after treatment. A concurrent control group is not listed, and allocation is NA. General statistical explanation: random allocation and a concurrent comparison can help distinguish differences associated with treatment from differences that may arise because of time, measurement, or other factors. In a single-group study, a change after baseline cannot by itself establish what would have happened over the same period without treatment. This design constraint applies even if a before-and-after estimate is available.

The registry lists single masking but does not identify who was masked or describe the masking procedure. The specific role of masking in outcome measurement is therefore not reported in the registry record. For an objectively measured laboratory outcome, measurement procedures and laboratory handling may still matter; their details are not reported in the registry record. This general point does not establish that measurement bias occurred.

What is over-dispersion, and does it apply?

General statistical explanation: over-dispersion refers to variability greater than a statistical model expects. It is particularly relevant for outcomes analyzed as counts or proportions under models with restrictive assumptions. Plasma Phe is described as a continuous outcome summarized by a mean and standard deviation, and no over-dispersion assessment is reported in the registry record. The term should not be treated as a finding in this study.

How should the planning illustration be distinguished from the study?

The record describes a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The illustration is described as participants per arm for non-time-to-event outcomes. These are planning assumptions, not evidence that the trial enrolled two arms or used those assumptions in its primary analysis. The actual study is described as single group, and the numerical planning outputs are not reported in the registry record.

General statistical explanation: a sample-size calculation asks how many observations a hypothetical design would need under stated assumptions about the effect to detect, variability, significance level, and power. A calculation using an observed effect is especially dependent on the observed estimate, which can be unstable in a small pilot. A planning illustration does not show the probability that the completed study detected an effect and is not observed power. The registry does not report the trial's own sample-size justification, target precision, or prespecified effect used for its design.

The planning description assumes equal allocation between two arms, but the recorded trial has a single-group structure. It is therefore a hypothetical planning framework rather than a direct description of the enrolled design. Without the numerical illustration and its inputs, no numerical sample-size conclusion can be drawn. The registry record also does not report whether any such illustration was used when the study was planned.

What is not available about the statistical analysis?

The registry lists 7 outcome measures and 7 analyses, but does not provide the statistical test used for the primary endpoint, an adjustment strategy, or a detailed analysis plan. It does not report whether assumptions were checked, how outliers were handled, whether the analysis used a transformed scale, or how missing observations were treated. These details are not reported in the registry record and should not be inferred from the description of a mean and standard deviation.

The primary-outcome description says the goal was to estimate change in blood glucose metabolism and refers to plasma Phe as the measurement. The precise statistical estimand—the exact quantity intended to be estimated, such as a mean within-person change among a defined analysis population—is not reported in the registry record. The distinction matters because different choices about participants and missing measurements can yield different interpretations.

For the cognitive outcomes, the record names six measures but does not report their scoring procedures, direction of favorable change, or statistical methods. General statistical explanation: test scores may have different scales and distributions, so they should not be treated as interchangeable simply because they are all numeric. Without the scoring and analysis details, comparisons across those outcomes cannot be interpreted from the registry description alone.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 7 outcome measures and 7 analyses. It names plasma Phe as the primary outcome and lists six secondary cognitive assessments: HVLT Total Recall, HVLT Delayed Recall, PASAT, SMTD, WAIS-IV-Digit Span, and the D-KEFS Verbal Fluency Subtest. The statistical results for these outcomes are not reported in the registry record.

General statistical explanation: when researchers test multiple outcomes, the chance of obtaining at least one apparently notable result by chance can increase, depending on the tests and their relationships. A multiplicity plan may define which outcome is primary, adjust significance thresholds, or treat secondary analyses as exploratory. The registry record does not report a multiplicity adjustment, a hierarchy among secondary outcomes, or a prespecified procedure for interpreting multiple tests. It is therefore not possible to assess how multiple testing was handled.

The record reports that 1 subject was withdrawn because of poor compliance with KUVAN therapy. The number with available baseline and four-month Phe values, and the number included in each cognitive analysis, are not reported in the registry record. The record does not state whether the primary analysis included all enrolled participants, only those with follow-up data, or another analysis population.

Missing-data methods are not reported in the registry record. In particular, it does not say whether missing follow-up observations were excluded, imputed, or handled through a model that could use partial records. The reason given for the withdrawal is poor compliance, but the record does not report whether any other measurements were missing or why. The consequences of missingness for the estimated change therefore cannot be assessed.

General statistical explanation: missing observations can affect an estimate when the likelihood of missingness is related to participants' characteristics, treatment experience, or unobserved outcomes. This is a general concern, not a finding about this study. The registry record does not contain enough information to determine whether the withdrawn participant's measurements were included or whether missingness could have influenced the results.

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 lists the Sapropterin (KUVAN) Therapy group with 6 participants at risk for serious adverse events and 0 participants affected by serious adverse events. It also lists 6 participants at risk for other adverse events and 0 affected by other adverse events. The death field is null, and death results are not reported in the registry record. No top serious adverse-event terms are listed.

These figures describe the recorded event counts for the group. The at-risk values indicate the group size recorded for those safety categories; they do not establish how long each participant was observed or whether every participant completed the planned follow-up. The record reports that 1 subject was withdrawn because of poor compliance, but does not state how that participant's safety follow-up was handled.

General statistical explanation: observing no recorded events in a small group does not establish that the underlying risk is zero. Safety estimates are more informative when the observation period, event definitions, follow-up completeness, and method of collecting events are clear. Those details are not reported in the registry record. The figures should therefore be read as the registry's recorded counts, not as proof that no event could occur.

The serious and other adverse-event counts should not be interpreted as a comparison between treatments, because the record describes a single treatment group and no control group. The record also does not provide event timing, severity beyond the serious classification, relatedness to treatment, or participant-level descriptions. No conclusion about comparative safety can be drawn from these counts alone.

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

The record describes a completed pilot study of Sapropterin (KUVAN) in patients with PKU, with a planned comparison of plasma Phe at baseline and four months. The listed enrollment is 6, and 1 subject was withdrawn because of poor compliance. It identifies the primary measure and several secondary cognitive assessments. Those details show what the study set out to examine and how the basic comparison was framed.

The record does not report the numerical primary or secondary results. Baseline and follow-up means, standard deviations, changes, confidence intervals, and p-values are not reported in the registry record. Therefore, the available information does not establish whether plasma Phe changed, in which direction it changed, or how precisely any change was estimated. The cognitive outcomes likewise cannot be described as improving, worsening, or remaining stable based on the record information.

The study's aim refers to brain glucose metabolism and FDG PET findings, but the specified primary endpoint is plasma Phe. The detailed PET measurements and their results are not reported in the registry record. A blood Phe measurement should not be equated with a direct numerical PET result without an explicit measurement and analysis linking the two.

The single-group before-and-after design has no listed concurrent control. General statistical explanation: a change measured over time in participants receiving treatment does not, on its own, show what would have happened without treatment. The design can describe observed within-participant change if paired data and analysis are available, but cannot directly isolate a treatment effect from other influences over time.

The study should not be read as evidence for or against treatment benefit based only on its aim, design, or hypothesis. Its numerical findings are not reported in the registry record, and its small enrollment and withdrawal make the missing analysis details especially important. The defensible interpretation is limited to the study's stated question, structure, and recorded safety counts, while leaving efficacy and precision undetermined.

13. Why This Trial Matters Statistically

This pilot is statistically informative as an example of the difference between a study question and a reported result. The record describes an intended before-and-after assessment of plasma Phe during four months of Sapropterin therapy, but numerical outcome estimates are not reported in the registry record. Without those estimates, readers cannot judge direction, magnitude, or precision. A detailed design description cannot substitute for the outcome data needed to answer the primary question.

The single-group structure also illustrates why the comparison being made matters. Measurements at baseline and follow-up are linked within participants, but there is no concurrent control group listed. General statistical explanation: within-participant comparisons can describe change over time, while a controlled comparison is needed to assess how that change differs from what would occur under another condition. The distinction is important when interpreting any before-and-after result.

The record reports a withdrawal for poor compliance and a small enrollment. These details make reporting of the analysis population and paired observations important, yet those details are not reported in the registry record. Transparent reporting of the number measured at each time, the number included in the analysis, and the handling of missing data would help readers understand how representative an estimate is of the enrolled participants.

The study also links a blood marker to an aim involving brain glucose metabolism and FDG PET. This makes clear endpoint definitions important: the primary measure is plasma Phe, while specific PET measures and results are not reported in the registry record. Statistical interpretation depends on knowing exactly what was measured, at what time, and what quantity was estimated.

Finally, the record's hypothetical planning assumptions should be separated from the actual single-group study. Planning calculations do not establish that a completed study had adequate precision, and they are not observed power. The record does not report its own design justification. These features make the study a useful case for reading registry descriptions cautiously and distinguishing objectives, methods, safety counts, and quantitative results.

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 of the available record is that numerical efficacy findings are not reported in the registry record. There are no reported baseline or follow-up means, standard deviations, estimated changes, confidence intervals, or p-values for the primary endpoint. Numerical findings for the cognitive outcomes are also not reported. Without these, the direction, magnitude, and precision of change cannot be assessed.

The study has a single-group design with no concurrent control listed. Any measured change over time would not by itself distinguish a therapy-associated change from other time-related influences. The registry record also lists allocation as NA, so no randomized comparison is described. These design characteristics restrict causal interpretation independently of the size of any observed change.

The listed enrollment is 6, and 1 subject was withdrawn because of poor compliance. The number with complete paired measurements, the analysis population, and the handling of missing data are not reported in the registry record. The record does not say whether withdrawal occurred before or after any specific measurement or how it affected the endpoint analysis.

The study's stated interest includes FDG PET findings and brain glucose metabolism, while the primary endpoint is plasma Phe. Specific imaging outcomes, measurement procedures, and results are not reported in the registry record. The primary-outcome description also uses the dose notation 20/mg/kg/day, while the arm description uses 20/mk/kg/day; the record does not clarify this difference.

Masking is listed as single, but who was masked and how masking was implemented are not reported in the registry record. Statistical methods, multiplicity procedures, and a sample-size justification are also not reported. The record's planning illustration uses assumptions for a hypothetical two-arm comparison, whereas the described trial is single group. These omissions limit evaluation of the analysis plan, precision, and reproducibility.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Fluorodeoxyglucose Positron Emission Tomography (FDG PET) Findings in Patients With Phenylketonuria Before and After KUVAN Therapy — NCT00986973.
• Registry record last updated 2015-06-08; status last verified 2015-05.
• Results first posted 2015-05-12.
• 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

NCT00986973 is a completed pilot study of Sapropterin (KUVAN) therapy in patients with phenylketonuria. The registry lists enrollment of 6, a single-group design, allocation NA, and single masking. The study start is recorded as 2010-03 and primary completion as 2011-07.

The primary outcome is plasma phenylalanine level in mg/dl, summarized as a mean with standard deviation and assessed at baseline and four months. The arm description gives a treatment duration of four months and a dose notation of 20/mk/kg/day; the primary-outcome description gives 20/mg/kg/day. One subject was withdrawn because of poor compliance.

The record names six secondary cognitive assessments and lists 7 outcome measures and 7 analyses. It records 0 participants with serious adverse events and 0 with other adverse events among 6 at risk in each category; deaths are not reported in the registry record. Numerical efficacy results, the detailed statistical analysis, the analysis population, missing-data procedures, and the sample-size justification are not reported in the registry record.