Phase 3 Open-label Study to Evaluate the Response and Safety of Kuvan® in Subjects With Phenylketonuria: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 3 Open-label Study to Evaluate the Response and Safety of Kuvan® in Subjects With Phenylketonuria (NCT01732471), a na phase 3 study. The primary outcome is Percentage of Participants With Response to Kuvan® (Sapropterin Dihydrochloride) Treatment.

2. Clinical Question

This is a descriptive question about response in a treated group, not a randomized comparison of Kuvan® with another treatment or with no treatment. The endpoint can describe how many participants met a prespecified biochemical threshold at the stated assessment time. Without a comparator, it cannot by itself separate a treatment effect from other influences on measurements over time. The posted record also identifies safety outcomes, including adverse events and serious adverse events, as study objectives. Those outcomes address a different question from the primary biochemical response endpoint.

3. Trial Design

The registry identifies NCT01732471 as a completed Phase 3, open-label, non-comparative clinical study of Kuvan® (sapropterin dihydrochloride) in patients with phenylketonuria. The official title describes treatment after 6 weeks in patients aged 4 to 18 years with elevated blood phenylalanine levels. The primary outcome, however, is specified at Day 8. These statements describe different aspects of the record: the treatment period in the official title and the assessment time for the primary endpoint. The registry record does not provide further detail about visit scheduling or the relationship between those timings.

The study is listed as single-group, with no masking and allocation marked not applicable. No like-for-like control arm is described, so the design does not support a direct randomized comparison between treatment groups. The registry lists enrollment as 90. That entry does not establish how many participants contributed data to each outcome; outcome-specific analysis counts are not reported in the registry record.

The listed primary population is the overall ITT population. It includes participants with an efficacy assessment result from at least one visit other than the inclusion visit. The registry also names an overall safety population for adverse-event outcomes, but does not give further population rules or analysis counts. These population labels should not be treated as proof that all enrolled participants were included in every analysis.

The study start is recorded as 2012-11, primary completion as 2013-10, and overall status as completed. The sponsor is Merck KGaA, Darmstadt, Germany. No randomization scheme, protocol-specific statistical plan, sample-size justification, or interim-analysis plan is reported in the registry record. As a result, the design can be characterized from its recorded single-group structure and stated outcomes, but the rationale for specific design decisions cannot be established from this information.

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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Overall (ITT) population included all participants who had efficacy assessment result from at least 1 visit except for the inclusion visit.

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: Intention to Treat (ITT) population included all participants who had efficacy assessment result from at least 1 visit except for the inclusion visit.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Response to Kuvan® (Sapropterin Dihydrochloride) Treatment, measured over Day 8.

The primary endpoint is the percentage of participants who met the response definition at Day 8. A participant was classified as a responder if blood phenylalanine levels had fallen by greater than or equal to 30% compared with baseline. This converts a continuous laboratory measurement into a threshold-based outcome: each participant either meets the stated criterion or does not, and the group result is expressed as a percentage.

A threshold can make a biochemical response definition straightforward to communicate and apply. It also means that the endpoint does not describe the full range of individual changes. Participants with changes on either side of the cutoff are classified differently even if their measurements are close, while variation in the size of reductions among responders is not conveyed by the response percentage alone. The registry lists percent change in blood phenylalanine levels at Day 8 as a secondary outcome, which addresses change on a continuous scale rather than only whether the response threshold was met.

The endpoint is defined against each participant’s baseline, not against a separate untreated group. In general, a within-participant comparison describes change over time, while a concurrent control group helps distinguish treatment-associated change from other possible influences. Because this study is non-comparative, the primary outcome is descriptive of the recorded response in the study population and does not provide a controlled estimate of the difference attributable to treatment.

The registry specifies a 95% confidence interval as the dispersion measure for the primary percentage. In general, a confidence interval communicates the statistical uncertainty around an estimated response proportion. The registry record does not report the primary estimate or interval, so neither the observed response frequency nor its precision can be evaluated from the posted primary-result information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical information available in the registry record is limited. The primary outcome is a percentage of participants meeting a binary response definition, and the listed dispersion measure is a 95% confidence interval. The record does not report a response estimate, interval limits, analysis method, or analysis count. Statistical interpretation must therefore distinguish the endpoint’s stated definition from results that are not reported.

What does a response percentage summarize?

In general, a binary endpoint assigns each participant to a category according to a prespecified rule. In this trial, the rule was a reduction in blood phenylalanine levels of greater than or equal to 30% at Day 8 compared with baseline. The percentage summarizes the share of participants in the defined analysis population who met that rule. It does not show the size of each participant’s reduction, the distribution of measurements, or how close non-responders were to the cutoff. The registry’s secondary percent-change outcomes would describe change on a continuous scale, but their results are not reported in the registry record.

How should a confidence interval be understood?

General explanation: a confidence interval describes uncertainty around an estimate under a specified statistical procedure. For a response percentage, the interval reflects uncertainty in the estimated proportion, rather than the range of individual participant outcomes. A narrower interval generally indicates greater precision, while a wider interval indicates less precision. Its width depends on factors such as the amount of usable outcome information and the response distribution. The registry names a 95% confidence interval for the primary endpoint, but gives no estimate or interval values. Precision therefore cannot be assessed.

What does the single-group design allow?

The study is recorded as single-group, open-label, and non-comparative. General explanation: a single-group analysis can describe outcomes observed among participants receiving the study intervention. It cannot estimate a randomized between-group contrast because no concurrent control group is listed. Baseline provides a reference for calculating the stated change, but it is not a substitute for a control arm. Changes over time can be influenced by factors other than the intervention, so a before-and-after description has a different interpretation from a controlled comparison.

Open-label means masking is recorded as none. In general, knowing the assigned intervention can influence participant experience, clinical management, and some outcome assessments. The primary endpoint is based on blood measurements, but the registry record does not describe laboratory procedures, assessor roles, or any safeguards against measurement bias. Those details should not be assumed.

What is known about the analysis population?

The primary population is called overall ITT and includes all participants who had an efficacy assessment result from at least one visit except the inclusion visit. This wording identifies an eligibility rule for the analysis population, but the number meeting it is not reported in the registry record. It does not establish that every participant recorded under enrollment contributed a primary endpoint. The registry separately refers to an overall safety population for adverse-event outcomes; its exact inclusion rules and analysis count are not reported.

General explanation: missing outcome measurements can affect both the number of participants contributing to an estimate and the interpretation of that estimate. If the likelihood of missingness is related to response or participant characteristics, the observed participants may not represent everyone enrolled. The registry record does not describe missing-data handling, imputation, or sensitivity analyses, so it is not possible to evaluate how missing efficacy measurements were addressed.

What can the planning illustration establish?

The listed planning illustration is described as a 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 is not the trial’s own design plan, and its two-arm assumptions do not match the recorded single-group study. General explanation: a planning calculation asks how much information a proposed design might need to detect a chosen effect under stated assumptions. It is not an observed result and is not observed power. Because no primary effect estimate is reported in the registry record, the illustration’s dependence on the observed effect cannot be independently assessed from the record.

General explanation: over-dispersion matters when data vary more than a chosen statistical model expects, because a model that understates variability can produce overly narrow uncertainty intervals or misleading tests. The primary endpoint is a binary participant-level response, but the registry record does not report an over-dispersion assessment or a model. No claim about whether over-dispersion was relevant or handled is justified.

Finally, the registry records four outcome measures and no analyses. The statistical plan, multiplicity procedures, testing hierarchy, and any interim analyses are not reported in the registry record. Without those details and the numerical outcome results, readers cannot assess the analysis choices, reproduce the primary estimate, or determine how uncertainty was quantified in practice.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Kuvan®")
n      <- c(90)
events <- c(30)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Kuvan®  90  30  33.3  23.7  44.1  24.5  43.6  24.5  43.6

11. Multiplicity, Missing Data and Analysis Populations

The registry lists four outcome measures. The primary measure is the percentage of participants meeting the response definition at Day 8. Named secondary outcomes include percent change from baseline in blood phenylalanine levels at Day 8 in the overall population, percent change in the responder subpopulation, and the number of participants with adverse events and serious adverse events in the overall safety population. The record states that no analyses are recorded. It does not provide results for these measures in the information available for this analysis.

When a study evaluates multiple outcomes or performs multiple statistical tests, general statistical practice considers multiplicity: repeated testing can increase the chance of a result appearing notable by chance. Methods such as prespecified hierarchies or adjustments can address particular multiplicity concerns, but the registry record does not report a testing hierarchy, adjustment procedure, or statistical analysis plan. It is therefore not possible to determine whether or how multiplicity was handled. No inference about the primary endpoint’s testing context should be made from the outcome list alone.

The primary analysis population is defined as participants with an efficacy assessment result from at least one visit other than the inclusion visit. The record does not state how many participants met this definition, how missing measurements were handled, or whether sensitivity analyses were performed. The overall safety population is named for adverse-event outcomes, but its inclusion rules are not described. Enrollment is recorded as 90; this does not by itself establish the denominator used for the primary endpoint.

General explanation: missing data can affect an estimate if participants without measurements differ systematically from those with measurements. The direction and magnitude of any such effect depend on the unobserved outcomes and the reasons measurements are missing. Since the registry record does not describe missingness or its treatment, the robustness of the efficacy estimate cannot be assessed. Interim analyses and stopping rules are also not reported in the registry record.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: upper limb fracture (1.1%).

The registry reports 1 participant with a serious adverse event among 90 at risk. It also reports 23 participants with other adverse events among 90 at risk. These are separate registry safety counts, and the record does not provide further detail about how the “other” category was defined. The listed serious adverse-event term is upper limb fracture, reported as 1.1%.

These counts describe events recorded in the safety population; they do not establish that an event was caused by Kuvan®. In general, adverse-event counts are interpreted in the context of event definitions, observation time, severity, and a suitable comparison group. The registry record does not provide a comparator group or further details about event timing, exposure duration, or attribution. Although the official title describes treatment after 6 weeks, that alone does not provide participant-level event follow-up information.

The serious and other adverse-event counts should not be combined into a total: the record does not specify whether categories overlap or provide definitions that would justify such an operation. The death field is not populated with a count. A blank or unreported value is not evidence that no deaths occurred. The available figures therefore support only a descriptive account of the listed safety counts, not a comparative safety conclusion.

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

The record establishes that this was a completed, open-label, single-group Phase 3 study of Kuvan® in patients with phenylketonuria. Its primary endpoint asked what percentage of participants met a defined biochemical response threshold at Day 8. The population definition and threshold are specified, as are some adverse-event counts. These details make the intended descriptive questions understandable.

However, the primary response percentage and its 95% confidence interval are not reported in the registry record. Without them, readers cannot determine how many participants met the endpoint, how large the estimated response proportion was, or how precise it was. The enrollment entry is not a substitute for the missing endpoint result. Likewise, the registry’s outcome list does not provide the numerical secondary results.

The non-comparative design is also important. A baseline comparison can describe change from baseline, but it does not provide the same evidence as a concurrent control group. Without a comparator, observed change cannot be attributed uniquely to the intervention. This is a limitation of what the design can establish, regardless of whether participants experienced a measured change.

The reported serious and other adverse-event counts describe safety observations in the listed at-risk population. They do not establish causality, and the available record does not provide a comparison group or enough detail to characterize event timing and context. The listed upper limb fracture term is a reported serious-event term, not evidence on its own about treatment attribution.

Thus, the record is informative about study structure and endpoint definitions, but insufficient for a numerical interpretation of the primary response. It does not support a controlled treatment-effect estimate, and the safety information should be read as descriptive. Conclusions beyond those points would require results or methods that are not reported in the registry record.

14. Why This Trial Matters Statistically

This study illustrates why outcome definitions and outcome results must be read separately. The primary endpoint is specified in concrete terms: a participant qualifies as a responder if blood phenylalanine levels fall by greater than or equal to 30% at Day 8 compared with baseline. That definition makes the intended classification transparent. Yet a precise definition alone does not reveal how many participants met it or how uncertain the estimated percentage is. The registry record does not report the result or the stated 95% confidence interval.

The design also demonstrates the distinction between describing change and estimating a comparative effect. A single-group, open-label study can characterize outcomes recorded among treated participants, but it has no listed control group against which to estimate a randomized contrast. Baseline measurements provide a reference for the endpoint calculation, not a concurrent counterfactual. This distinction is central when interpreting studies that report a response threshold or change over time.

The record’s analysis-population definition matters too. The primary population requires an efficacy assessment from a visit other than the inclusion visit. Without a reported count or missing-data method, readers cannot tell how the population contributing to the endpoint relates to enrollment. The safety counts are reported with their at-risk denominators, but the record does not provide the context needed to compare event rates across treatments.

Finally, the statistical plan is not reported. The existence of multiple outcome measures raises general questions about testing choices and missing outcomes, but the record does not identify procedures for multiplicity or missing-data handling. These omissions do not prove that appropriate methods were absent; they limit what can be verified from the registry. The trial is therefore a useful example of how design, endpoint definitions, analysis populations, and completeness of reporting jointly determine the strength of statistical interpretation.

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 primary endpoint result is not reported in the registry record. In particular, the response percentage, response count, and confidence interval are unavailable. This prevents assessment of the magnitude and precision of the main outcome, even though its definition and analysis population are described.

The single-group design has no concurrent comparator, and the study is open-label. It can describe outcomes observed in the treated group but cannot establish a controlled contrast. Baseline is used in the response definition, but a within-participant comparison does not address all alternative explanations for change. The record does not provide further details on measurement procedures or masking of outcome assessment.

The registry records enrollment as 90, but outcome-specific denominators and analysis counts are not reported. The ITT population definition requires an efficacy result from at least one visit other than the inclusion visit; how missing results were handled is not reported in the registry record. The safety population’s inclusion rules are also not described. These gaps make it difficult to assess how representative the analyzed participants were of those enrolled.

Although the record lists secondary outcomes and four outcome measures, their numerical results and statistical methods are not reported in the registry record for this analysis. The multiplicity approach, analysis plan, and interim-analysis procedures are not reported in the registry record. The listed planning illustration uses a two-arm framework that does not match the recorded single-group design, and it is not the trial’s own design justification.

Safety information is limited to the listed counts and serious-event term. Details about event timing, duration of observation, attribution, and the meaning of the separate “other” category are not reported. The death field has no recorded count and cannot be interpreted as zero. These reporting limits constrain both efficacy and safety interpretation.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase 3 Open-label Study to Evaluate the Response and Safety of Kuvan® in Subjects With Phenylketonuria — NCT01732471.
• Registry record last updated 2014-07-28; status last verified 2014-07.
• Results first posted 2014-07-28.
• 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

NCT01732471 is recorded as a completed Phase 3, open-label, non-comparative, single-group study of Kuvan® (sapropterin dihydrochloride) in patients with phenylketonuria. The official title describes treatment after 6 weeks in patients aged 4 to 18 years with elevated blood phenylalanine levels. Enrollment is recorded as 90. The primary endpoint is the percentage meeting a Day 8 reduction threshold of greater than or equal to 30% compared with baseline, in an overall ITT population defined by having an efficacy assessment beyond the inclusion visit.

The primary response estimate and its 95% confidence interval are not reported in the registry record. Named secondary outcomes include percent change in blood phenylalanine levels at Day 8 and adverse-event counts. The registry reports 1 participant with a serious adverse event among 90 at risk and 23 with other adverse events among 90 at risk; upper limb fracture is listed as a serious term at 1.1%. Statistical-plan details, missing-data handling, and the primary numerical result are not reported in the registry record.