Kuvan® in Phenylketonuria Patients Less Than 4 Years Old: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Kuvan® in Phenylketonuria Patients Less Than 4 Years Old (NCT01376908), a randomized phase 3 study. The primary outcome is Dietary Phenylalanine (Phe) Tolerance at Week 26.

2. Clinical Question

The clinical question is about dietary tolerance under a defined blood phenylalanine target, rather than a direct comparison of blood phenylalanine concentrations alone. The registry reports mean tolerance in milligrams per kilogram per day and describes the primary analysis population as all randomized subjects at the start of the study, analyzed according to assigned group. The primary endpoint is therefore a group-level summary at a specified follow-up time. The clinical question also sits within a broader evaluation: the study was designed to assess efficacy, safety, and population pharmacokinetics, and its listed secondary outcomes include blood phenylalanine levels, developmental measures, growth, and adverse events. Those additional outcomes address different aspects of treatment and cannot be treated as interchangeable measures of the primary endpoint.

3. Trial Design

The registry describes NCT01376908 as a Phase IIIb, multicentre, randomized, controlled, open-label, parallel-group study of sapropterin dihydrochloride (Kuvan®) in people with phenylketonuria younger than 4 years. BioMarin Pharmaceutical is listed as the sponsor. The study is marked completed, with 56 enrolled. The recorded study start is 2011-06, and the primary completion is 2014-07.

Participants were allocated to Kuvan® plus a phenylalanine-restricted diet or a phenylalanine-restricted diet alone. The registry describes once-daily tablets for the combination group. Because masking is listed as none, the study was open-label: participants and study personnel were not masked to the assigned intervention, as far as the registry design record states. The registry identifies parallel allocation, meaning the arms are compared as separate groups rather than as treatment periods experienced by each participant.

The primary endpoint was dietary phenylalanine tolerance at Week 26, expressed as a mean in milligrams per kilogram per day. The stated intention-to-treat population consisted of all randomized subjects at the start of the study, analyzed according to allocated group. The record lists 27 participants in the Kuvan® plus diet arm and 29 in the diet-alone arm for this endpoint. The registry also lists secondary outcomes addressing mean blood phenylalanine levels, dietary tolerance, adverse events, developmental milestones, Bayley III assessments, growth, hypophenylalanemia, and tolerance during an extension period.

Further details of randomization procedures, allocation concealment, treatment adherence, protocol deviations, and the original sample-size justification are not reported in the registry record. The record identifies the study as randomized but does not provide those additional design details.

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: Out of 109 subjects screened for the study, 77 pharmacogenetics (PGx) informed consent forms were signed and 73 samples were analyzed which were used as analysis population for outcome measure 11 "Number of samples with phenylalanine hydroxylase (PAH) gene mutations".

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intention-to-treat (ITT) population consisted of all the randomized subjects at the start of the study and were analyzed according to the group allocated.

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 consisted of all the randomized subjects at the start of the study and were analyzed according to the group allocated.

6. Primary Endpoint

The registry lists the primary outcome as Dietary Phenylalanine (Phe) Tolerance at Week 26, measured over Week 26.

The primary endpoint is dietary phenylalanine tolerance at Week 26, measured in milligrams per kilogram per day. The registry defines tolerance as the amount of dietary phenylalanine prescribed while blood phenylalanine remains within the selected therapeutic target range: 120 to less than 360 micromoles per liter. It is a measure of how much phenylalanine from the diet is allowed under that specified biochemical target, rather than simply a measurement of the blood concentration itself.

The endpoint is useful for the stated study question because it combines a dietary quantity with a condition on blood phenylalanine. Reporting tolerance as a mean permits a comparison of the average prescribed dietary amount between the randomized groups at the specified follow-up. It does not, by itself, describe the distribution of individual participants’ tolerance values, how many participants remained within the target range at every assessment, or the clinical importance of a particular difference. The registry reports standard errors alongside the group means, which describe precision of the estimated means rather than the spread of individual outcomes.

The registry identifies the primary analysis population as all randomized participants at the start of the study, analyzed according to allocated group. Details about missing Week 26 measurements and how any such observations were handled are not reported in the registry record.

7. Results Posted in the Registry

• Phe-restricted Diet: mean 50.10 versus 80.60 on control; difference -30.50 (95% CI -42.28 to -18.72), standardized effect d = -1.35; z-test p = <0.001.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Number of Subjects With Hypophenylalanemia

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Phe-restricted Diet: 33.3% (9/27) versus 37.0% (10/27) on control; risk difference -3.7 percentage points (95% CI -29.2 to 21.8), risk ratio 0.90 (0.44–1.86); unadjusted two-proportion z-test p = 0.776.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Phe-restricted Diet and the control. The interval gives the range of effects that remain compatible with the data.

Population PK Parameter: Area Under the Plasma Concentration Curve, Time 0 to Infinity (AUC [0-infinity])

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Population PK Analysis Set: Age Group 2 (1 to 2 Years): mean 215.74 versus 234.89 on control; difference -19.15 (95% CI -74.69 to 36.39), standardized effect d = -0.25; z-test p = 0.499.
  • Population PK Analysis Set: Age Group 2 (>= 2 Years): mean 206.22 versus 234.89 on control; difference -28.67 (95% CI -93.95 to 36.61), standardized effect d = -0.29; z-test p = 0.389.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Population PK Analysis Set: Age Group 2 (1 to 2 Years) and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Population PK Analysis Set: Age Group 2 (>= 2 Years) and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes cover several different domains: blood phenylalanine, dietary tolerance, adverse events, developmental milestones and assessments, growth, hypophenylalanemia, and dietary tolerance during an extension period. The posted secondary summaries represented in the record include a binary hypophenylalanemia outcome and pharmacokinetic area under the plasma concentration curve by age group. These outcomes do not measure the same construct as the primary Week 26 dietary tolerance endpoint, so they offer context rather than a direct replication of the primary comparison.

The registry lists 16 posted secondary outcomes, but it does not provide a complete set of reported analyses for them. This limits any assessment of whether the secondary findings form a consistent overall pattern. The primary result concerns a defined dietary measure at Week 26; secondary outcomes may describe biochemical status, safety, development, growth, or drug exposure. A result in one domain cannot automatically establish a result in another.

Secondary comparisons are also less definitive when they are unadjusted and when many outcomes are considered. General statistical explanation: testing multiple outcomes creates more opportunities for apparently notable results to arise by chance, even if each individual test uses a conventional threshold. A multiplicity strategy can address that issue, but the registry record does not report an adjustment plan. The secondary findings are therefore best treated as descriptive or exploratory evidence unless a fuller analysis plan establishes otherwise.

The record does not report analyses for the listed secondary comparisons. Their posted estimates can be read as summaries of the available data, but they do not establish confirmatory conclusions about those outcomes. Interpretation should consider the size and uncertainty of each estimate, the outcome’s definition, and the number of analyses considered, rather than relying only on whether an individual unadjusted p-value appears small.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Mean Blood Phe Levels
• Change From Baseline in Dietary Phe Tolerance After 26 Weeks
• Number of Subjects With Any TEAEs, AEs Related to Kuvan, Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation
• Number of Subjects With Normal Neuromotor Developmental Milestones Assessed Using Denver Developmental Scale (DDS)
• Neurodevelopmental Status Assessed Using Bayley III Scales of Infant and Toddler Development
• Growth Parameters Standard Deviation Scores (SDS)
• Number of Subjects With Hypophenylalanemia
• Dietary Phe Tolerance During Extension Period

9. Statistical Interpretation

10. Statistical Methods Explained

What does a mean describe?

A mean is a measure of the center of a set of observations. For the primary endpoint, each group’s reported mean summarizes dietary phenylalanine tolerance in that arm at Week 26. A group mean is not a description of every participant: individual measurements can lie above or below it, and the mean alone does not show whether values are tightly clustered or widely spread.

The registry reports standard errors of 4.2 for the combination arm and 4.3 for the diet-alone arm. A standard error describes the estimated precision of a sample mean; it is not the standard deviation of individual participants’ values. The distinction matters because a standard error becomes smaller as an estimate becomes more precise, while the underlying participant-to-participant variability can remain substantial. The endpoint record does not provide the standard deviation for these primary group means.

How should the mean difference be read?

A mean difference compares the two group means on the original measurement scale. The posted comparison is expressed as diet alone minus Kuvan® plus diet. Its estimate is −30.5 mg/kg/day, with a 95% confidence interval from −42.28 to −18.72. A negative value means the diet-alone mean is lower than the combination-arm mean under that contrast definition. Expressing the contrast in the endpoint’s original units preserves a direct interpretation in milligrams per kilogram per day.

The contrast is not a separate measurement from the group means; it is their between-group comparison as reported by the registry analysis. The registry lists the analysis population as all randomized subjects at the start of the study, analyzed according to allocated group. This is an intention-to-treat description. It does not reveal how missing outcome data, protocol deviations, or measurements outside the expected schedule were handled.

What does a confidence interval contribute?

General statistical explanation: a confidence interval represents uncertainty in an estimated quantity under the statistical method used. A narrower interval indicates greater precision than a wider interval, all else being equal. A 95% confidence interval is not a range containing 95% of individual responses, and it should not be interpreted as assigning a 95% probability to the fixed, unknown effect. The registry reports interval limits for the primary contrast, but the exact interval-construction method is not reported in the registry record.

For a difference, zero represents no group difference on the measurement scale. The posted primary interval does not include zero. That observation is consistent with the reported unadjusted p-value of < 0.001 under the analysis used. Neither the interval nor the p-value tells readers whether the size of the difference is important in practice; that judgment requires context beyond a statistical test and is not established by the registry figures alone.

What does an unadjusted p-value mean?

General statistical explanation: a p-value is calculated under a specified null hypothesis and model. It describes how unusual data at least as incompatible with the null as the observed data would be if the null and model assumptions held. It is not the chance that a result occurred “by chance,” the chance that treatment has no effect, or a measure of the probability that the conclusion is correct. A small p-value does not show that the estimate is free of bias or that the analysis assumptions are appropriate.

The primary comparison’s reported p-value is unadjusted. The registry does not report a multiplicity adjustment for the primary and secondary outcomes. When many outcomes or comparisons are examined, the chance of at least one small p-value can increase, which is why the prespecified status of outcomes and any adjustment strategy matter. The registry names the primary endpoint, but the analysis plan and multiplicity procedures are not reported in the registry record.

Why is the design relevant to interpretation?

Random allocation aims to make treatment groups comparable on average, including for characteristics that are not measured, although it does not ensure perfect balance in a particular study. A controlled, parallel-group comparison therefore supports a different interpretation from an uncontrolled before-and-after result. The registry identifies randomization and a control arm, but details such as the sequence-generation method and allocation concealment are not reported in the registry record.

Open-label status means treatment assignment was not masked. General statistical explanation: knowledge of assignment can influence participant behavior, clinical management, or outcome assessment, particularly when outcomes include decisions or judgments. The registry does not report the extent to which such influence occurred in this trial. The endpoint’s definition includes prescribed dietary amount, so the absence of masking is a relevant design feature without establishing that any bias actually occurred.

What can the secondary analyses add?

The registry lists secondary outcomes spanning blood phenylalanine, dietary tolerance, safety, developmental assessments, growth, and pharmacokinetics. These outcomes can provide complementary descriptions, but each addresses a distinct question and may use different analysis populations or measurement scales. The record includes secondary summaries for hypophenylalanemia and pharmacokinetic area under the curve by age group; it does not list reported analyses for those comparisons. The statistical methods for these secondary results, including any adjustments for multiple testing, are not reported in the registry record.

General statistical explanation: a binary outcome, such as whether an event occurred, is often summarized as a count or proportion, whereas a continuous outcome is summarized using a mean or another measure of location and spread. A risk difference compares proportions in absolute terms; a mean difference compares averages in the outcome’s units. These measures answer different questions and should not be directly combined into a single estimate. In the pharmacokinetic summaries, the standard deviation describes observed variability in the sample, unlike the standard error reported for the primary means.

General statistical explanation: when data are sparse or a sample is small, estimates for event proportions and between-group contrasts can be imprecise. Confidence intervals help display that uncertainty. Over-dispersion is a situation in which observed variability exceeds what a statistical model assumes; if ignored, standard errors and tests can be misleading. The registry does not report whether over-dispersion was assessed or whether any particular model was used for the secondary outcomes.

11. Confidence Intervals and Precision

The primary mean difference is −30.5 mg/kg/day, with a 95% confidence interval from −42.28 to −18.72. The interval gives a range of values compatible with the observed data under the method used. For the stated diet-alone-minus-combination contrast, the interval remains below zero, indicating that the estimated contrast is not especially close to a zero difference within this interval. The registry’s unadjusted p-value is < 0.001, consistent with the interval’s placement.

The interval is not a range for individual participants’ dietary tolerance. It concerns the group contrast. The reported standard errors, 4.2 and 4.3, likewise describe precision of the arm means rather than the spread of individual values. The primary record does not provide the underlying outcome distribution, so the degree of individual variability cannot be inferred from the means and standard errors alone.

Precision is also relevant to secondary results. The posted hypophenylalanemia risk-difference interval extends on both sides of zero, and the pharmacokinetic mean-difference intervals also include values on both sides of zero. Those intervals are compatible with differing directions of the group contrast and indicate uncertainty in those secondary comparisons. Their interpretation should not be reduced to whether a p-value crosses a threshold: the range of plausible contrasts and the outcome’s meaning both matter.

The registry record does not identify the confidence-interval construction method for these outcomes. The intervals should therefore be understood as the estimates posted in the record, without assuming a particular model or adjustment procedure beyond what is explicitly reported.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are illustrations based on the observed effect, not the trial’s original design calculation. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. For the outcomes represented in these comparisons, the figures are participants per arm, not total events. Time-to-event planning results, if present, would instead give total events; that is not the format of these displayed planning estimates.

The 80% power column means the planned chance of detecting an effect of the specified size under the listed assumptions, if that effect is the true effect and the assumptions hold. The 90% power column uses a higher target probability of detecting that effect, so its required participant count is larger for the same effect assumption. These are planning quantities, not guarantees about what a future study will find. This is not observed power.

Rows planning for 100%, 75%, and 50% of the observed effect explore progressively smaller target effects. Smaller effects are harder to distinguish from random variation and therefore require more participants to achieve the same power target, all else being equal. The planning counts can change sharply when the assumed effect is reduced, especially when the observed estimate is uncertain or when the outcome is uncommon.

The registry does not report the trial’s original sample-size justification or its original assumptions. These planning illustrations should not be read as evidence that the completed trial was designed using the same target effect, significance level, allocation, or approximation. They are a way to understand how sample-size requirements depend on an assumed effect and power target, not a reconstruction of the study’s protocol.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -30.500; pooled standard deviation σ = 22.525.
2. n = 2 × (1.96 + 0.842)² × 22.525² / -30.500² = 8.6, rounded up to 9 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -30.5                      # observed difference in means
sigma <- 22.5245380599651                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(1376908)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 9 (80% power), 12 (90% power)
 75% of observed effect: n per arm = 16 (80% power), 21 (90% power)
 50% of observed effect: n per arm = 35 (80% power), 46 (90% power)
power.t.test: 9.6 
Simulated power at n = 9 per arm: 0.768 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

The registry distinguishes a primary endpoint from a broad set of secondary outcomes, but the statistical analysis plan is not reported in the registry record. In particular, the record does not state whether secondary outcomes were prespecified in a formal hierarchy, whether any outcomes were designated as exploratory, or whether multiplicity adjustments were planned or applied. The primary p-value is identified as unadjusted, and the listed secondary analyses do not include reported analyses.

Multiplicity matters because a study can examine multiple outcomes, time points, measures, or subgroup comparisons. General statistical explanation: each additional test creates another opportunity for a low p-value even when the underlying hypotheses are all null. An adjustment or a prespecified testing sequence can control the interpretation of that family of tests, but no such procedure should be assumed where the registry record does not report one. Secondary results should consequently be read with attention to their uncertainty and their place among the other outcomes.

The primary analysis population is described as all randomized subjects at the start of the study, analyzed according to allocated group. The registry does not report how many participants contributed Week 26 measurements in each arm beyond the endpoint group sizes, whether those counts reflect every randomized participant, or how missing endpoint data were handled. It also does not report reasons for missingness, imputation procedures, or sensitivity analyses. Those omissions prevent a full assessment of how incomplete data might affect the estimated group difference.

Allocation is identified as randomized, but details about random sequence generation, concealment, stratification, and any adjustments for baseline characteristics are not reported in the registry record. The record also does not state whether analyses followed a prespecified statistical model or how protocol deviations were treated. These are not reasons to discard the posted estimates; they are limits on how completely the analysis can be evaluated from the registry record alone.

15. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: gastroenteritis (3.7%), rash (3.7%), overdose (3.7%), stomatitis (3.7%), bronchiolitis (3.7%).

The registry’s serious adverse event summary lists 3 affected participants in the Kuvan® plus diet group and 1 in the diet-alone group. It lists 27 participants at risk in each group for this safety summary. The most frequently listed serious-event terms each have a posted frequency of 3.7%: gastroenteritis, rash, overdose, stomatitis, bronchiolitis, and bronchopneumonia. These terms should be read as the registry’s listed event categories, not as proof that an event was caused by the assigned intervention.

The registry also reports 26 participants with other adverse events in each group, with 27 at risk in each group for that summary. The safety denominators differ from the primary endpoint group sizes, which are 27 and 29; the reason for that difference is not reported in the registry record. Death counts are not reported in the registry record.

These summaries count participants with events; they do not fully describe event severity, timing, duration, recurrence, or clinical course. The figures alone also cannot establish comparative safety, particularly when event counts are limited and the record does not provide a detailed statistical safety analysis. They should be interpreted as descriptive registry results.

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

The primary result is a comparison of mean dietary phenylalanine tolerance at Week 26 among randomized children younger than 4 years with phenylketonuria. The posted means are higher in the Kuvan® plus diet group than in the diet-alone group, and the registry’s contrast and confidence interval quantify that difference on the endpoint’s scale. This is a statement about the reported group averages under the endpoint definition, not a conclusion about every participant.

The endpoint depends on a prescribed amount of dietary phenylalanine while keeping blood phenylalanine within the selected target range. It should not be substituted for a direct claim about long-term development, growth, safety, or all measures of blood phenylalanine. Those are separate outcomes. The registry’s list of developmental and other secondary outcomes indicates that the study considered broader questions, but the primary result does not answer them by itself.

The open-label design and the prescribing element of the endpoint are relevant when interpreting the comparison. Randomization is a strength of the design, while the lack of masking means treatment assignment was known. The registry record does not describe whether dietary decisions or outcome assessments were protected from influence related to that knowledge. This limitation does not show that the estimate is biased; it means the record does not allow that possibility to be fully evaluated.

The reported p-value and confidence interval describe statistical evidence and uncertainty under the analysis used. They do not determine the clinical importance of the difference, establish the likely experience of a particular child, or guarantee that the same estimate would occur in another population. The registry record does not provide a threshold for a clinically important difference in dietary tolerance.

The findings are specific to the population, comparison, endpoint, and Week 26 assessment recorded. The registry information does not establish outcomes beyond the stated follow-up, effects in older people, or the balance of benefits and harms for an individual. Those questions require broader evidence and clinical context; the registry result alone is not a basis for treatment advice.

17. Why This Trial Matters Statistically

This trial is statistically informative because it combines random allocation with a controlled comparison in a young population and reports a continuous primary endpoint with an estimated between-group difference and confidence interval. The endpoint is expressed in practical measurement units, making the group contrast more interpretable than a test result alone. The registry also identifies an intention-to-treat population, which clarifies the stated basis for the primary analysis.

The study illustrates why an estimate, its uncertainty, and its design need to be considered together. The reported p-value indicates evidence against a null difference under the analysis used, while the confidence interval shows the range of contrasts compatible with the data and method. Neither quantity alone describes individual variability, clinical importance, or potential design limitations. The outcome’s definition and the open-label design are particularly relevant because the endpoint includes a prescribed dietary amount.

The registry also demonstrates the limits of reading multiple outcomes as a single story. Secondary endpoints span safety, biochemical measures, development, growth, and pharmacokinetics. Those domains may be useful complements to the primary endpoint, but missing analysis details and unreported multiplicity procedures reduce the strength of broad conclusions from secondary comparisons. A statistically notable primary finding does not automatically resolve these other questions.

Finally, the record allows readers to distinguish observed trial results from planning illustrations. The planning figures show how assumed effect size and power targets influence participant requirements; they are not observed power and do not reveal the original design calculation. That distinction is important when interpreting a completed trial and considering what its estimates can support.

18. 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 open-label design is a limitation for interpreting an endpoint that includes the amount of dietary phenylalanine prescribed. The registry does not report whether dietary decisions, outcome assessment, or participant behavior were protected from influence related to knowledge of assignment. Randomization helps structure the comparison but does not remove all possible measurement or management differences.

The primary outcome is measured at Week 26 and summarizes group means. The registry does not provide participant-level distributions, a clinically important difference threshold, or enough information to assess how consistently participants remained within the target range. Nor does the primary result alone establish longer-term patterns or outcomes in other age groups.

Important analysis details are absent from the registry record. The method used to construct confidence intervals, the original sample-size justification, handling of missing data, protocol deviations, and the multiplicity strategy are not reported. The record also does not explain why the safety-summary denominators differ from the primary endpoint group sizes. Those gaps limit independent evaluation of the analysis and the completeness of follow-up.

The registry lists many secondary outcomes, but reported analyses are not available for those comparisons. This restricts assessment of the wider efficacy, safety, developmental, and pharmacokinetic pattern. The study’s enrollment was 56, and the results are specific to its randomized groups and outcome definitions; the record does not establish how precisely the findings generalize beyond the enrolled population.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Kuvan® in Phenylketonuria Patients Less Than 4 Years Old — NCT01376908.
• Registry record last updated 2017-09-15; status last verified 2017-08.
• Results first posted 2016-05-12.
• 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.

22. Record Summary

NCT01376908 is a completed Phase IIIb, multicentre, randomized, open-label, parallel-group study sponsored by BioMarin Pharmaceutical. It enrolled 56 infants and children younger than 4 years with phenylketonuria. The recorded study start is 2011-06, and primary completion is 2014-07.

The primary endpoint was mean dietary phenylalanine tolerance at Week 26, defined by the amount prescribed while blood phenylalanine remained within the selected target range. The registry reports a mean of 80.6 mg/kg/day for Kuvan® plus a phenylalanine-restricted diet and 50.1 mg/kg/day for diet alone. The posted diet-alone-minus-combination mean difference is −30.5 mg/kg/day, with a 95% confidence interval from −42.28 to −18.72 and an unadjusted p-value of < 0.001.

The registry also lists secondary outcomes across biochemical, safety, developmental, growth, and pharmacokinetic domains. Details of missing-data handling, multiplicity procedures, and the original sample-size justification are not reported in the registry record.