This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for A Pilot Study on Diurnal Variation (NCT01806051), a non-randomized na study. The primary outcome is Changes in Plasma Phe and Tyrosine Levels.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01806051 |
| Phase | NA |
| Condition | Phenylketonuria (PKU) |
| Allocation | Non-Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 6 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Dr. Linda Randolph |
| Results posted | Yes |
2. Clinical Question
Population
People with phenylketonuria (PKU) and healthy individuals without PKU. The control group could include a relative of a PKU participant, but a family relationship was not required.
Intervention
PKU participants were to receive Kuvan once daily. Their planned assessments included a 24-hour blood assessment before starting Kuvan, plasma phenylalanine and tyrosine draws at later study visits, and another 24-hour assessment.
Comparator
The non-PKU control group was to undergo a 24-hour blood assessment. This was a nonrandomized comparison: the groups differed by PKU status and were not assigned to Kuvan or a placebo in a randomized way.
Primary question
The primary outcome was intended to evaluate patterns of change in plasma phenylalanine (Phe) and tyrosine from baseline to the 4-week visit for each arm. The registry record reports that participants withdrew before any data were collected, so it contains no observed changes or comparison of patterns.
The study’s stated motivation was to gather information about diurnal variation, meaning changes that occur during the day, in Phe and tyrosine levels among people with PKU and people without PKU. The design description combines repeated assessment of PKU participants with a separate assessment of healthy controls. It therefore asks both about within-person patterns over time and about measurements in two populations, but it does not establish a randomized treatment comparison.
Although the title and intervention identify Kuvan, the primary question recorded is about patterns of change in laboratory levels, not a treatment-effect contrast between randomized groups. Because no data were collected, the registry record cannot answer whether levels changed, how they varied over a day, or whether patterns differed between the groups.
3. Trial Design
This was a prospective pilot study with a planned enrollment of 6. The registry classifies allocation as nonrandomized, masking as none, and the model as parallel. The listed phase is NA. The record gives a start date of 2013-03, a primary completion date of 2014-05, and a status of terminated. The sponsor is Dr. Linda Randolph.
The study description calls the design self-controlled: PKU participants were to have assessments before and after beginning once-daily Kuvan. At the second study visit, before Kuvan commenced, they were scheduled for a 24-hour blood assessment. Plasma Phe and tyrosine draws were planned at visits 3, 4, and 5, followed by another 24-hour blood assessment at visit 6. The control group consisted of healthy non-PKU individuals, who were to have a 24-hour blood assessment at visit 2. A control participant could be related to a PKU participant, but did not have to be.
These planned schedules do not make the arms interchangeable. PKU status defines the groups, allocation was not randomized, and the control group’s described schedule is not the same as the repeated assessments planned for PKU participants. Any observed difference between groups would therefore need careful interpretation in light of their different populations and assessment plans.
The record reports that participants withdrew before any data were collected. Thus, the planned enrollment and study procedures describe intended conduct, not a completed set of observations. The registry record does not report why the study was terminated, how many participants entered each arm, or whether any protocol procedures were completed before withdrawal.
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
| Stage | All Participants |
|---|---|
| STARTED | 6 |
| COMPLETED | 0 |
| NOT COMPLETED | 6 |
Reasons for not completing this period:
| Reason | All Participants |
|---|---|
| Withdrawal by Subject | 6 |
Analysis population for the primary outcome, as defined in the registry: Participants withdrew before any data were collected.
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: Participants withdrew before baseline characteristics were collected.
| Characteristic | Unit | All Participants |
|---|---|---|
| Participants analysed | 0 | |
| Age, Categorical: <=18 years | Participants | — |
| Age, Categorical: Between 18 and 65 years | Participants | — |
| Age, Categorical: >=65 years | Participants | — |
| Sex: Female, Male: Female | Participants | — |
| Sex: Female, Male: Male | Participants | — |
6. Primary Endpoint
The registry lists the primary outcome as Changes in Plasma Phe and Tyrosine Levels, measured over Baseline and 4 weeks.
| Element | Registry entry |
|---|---|
| Result type | N/A |
| Measure of spread | not applicable |
| Unit | not stated |
| Endpoint classification | not reduced to a single comparison |
The primary outcome was titled “Changes in Plasma Phe and Tyrosine Levels.” It was intended to evaluate patterns of change in plasma phenylalanine and tyrosine between baseline and the 4-week visit for each arm. These are laboratory measures central to the study’s stated interest in daily variation among PKU and non-PKU participants.
Repeated measurements can be useful when the scientific question concerns how a biomarker varies over time, rather than only its value at one visit. A 24-hour assessment can describe changes across a day, while measurements at later visits can be used to examine change over the study period. This is a general explanation of why the planned assessment schedule could address the question; it does not establish what the measurements would have shown.
The registry record gives no unit, numerical outcome, summary statistic, or estimate of change. It also states that participants withdrew before any data were collected. Therefore, the endpoint is defined as a planned measure, not a reported result. There is no observed baseline value, 4-week value, within-person change, or estimate of diurnal pattern to interpret. The endpoint description refers to both arms, while the detailed control-group schedule lists a 24-hour blood assessment at visit 2; the registry record does not clarify a further control-group visit schedule.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The central interpretive fact is that this pilot study produced no collected outcome data according to the registry record. Its primary outcome is described, but no Phe or tyrosine values, changes, estimates, confidence intervals, or tests are reported. The record lists zero analyses. Consequently, the study does not provide an empirical estimate of diurnal variation in either group or an estimate of change between baseline and 4 weeks.
The planned enrollment was 6, but enrollment is not a substitute for analyzed observations. The outcome population is described as participants who withdrew before any data were collected. The registry does not report the number of participants assigned to each arm, the number who withdrew, or reasons for withdrawal. Without observations, no estimate can be judged for its magnitude or precision, and no conclusion about statistical compatibility with different possible effects can be drawn.
There is also no treatment-effect contrast to interpret. The allocation was nonrandomized, there was no masking, and the two arms represented different populations: PKU participants scheduled to receive Kuvan and healthy people without PKU. The comparator was not a randomized placebo or untreated group matched by assignment. Even if measurements had been collected, an arm difference would not by itself isolate an effect of Kuvan from differences associated with PKU status or other differences between the groups. This is a general issue of interpretation for nonrandomized comparisons, not a finding about this study’s results.
The planned self-controlled assessments in PKU participants could in principle have been used to compare measurements within participants over time. A within-person comparison controls for characteristics that remain stable within a participant, as a general statistical principle. It does not automatically control for changes over time or other factors that vary between visits. In this record, however, there are no measurements from which to make even that within-person comparison.
The adverse-event record lists zero participants at risk and zero participants affected by serious and other events in each group. The death fields are not reported in the registry record. Since the record also states that participants withdrew before any data were collected, these entries should not be read as a safety evaluation based on exposure and observation. They describe the registry’s event reporting, not evidence that an intervention was free of adverse events.
The registry status is terminated, and the primary completion date is 2014-05. The reason for termination is not reported in the registry record. No statistical analysis plan, interim analysis, sample-size justification, or analysis population definition is reported. Overall, the posted information supports a description of intended methods and the absence of reported outcome findings, but not a conclusion about the magnitude, direction, or precision of any biological or treatment effect.
9. Statistical Methods Explained
Design and estimand. A statistical analysis starts by specifying the quantity it aims to estimate, often called the estimand. Here, the registry describes the primary aim as evaluating patterns of change in plasma Phe and tyrosine from baseline to 4 weeks for each arm. That is a broad outcome description: it does not specify a single numerical contrast, such as a difference in average change between groups. The record does not report a more detailed estimand or analysis plan.
The design is listed as parallel and nonrandomized, with no masking. “Parallel” generally means that distinct groups are followed under their respective study assignments or conditions. Nonrandomized allocation means group membership is not established by random assignment. In this study, the groups were also defined by PKU status: PKU participants were scheduled to receive Kuvan, while healthy non-PKU controls were scheduled for a 24-hour assessment. As a general principle, such group differences can make a direct between-group comparison harder to interpret as a treatment effect because group status and intervention are not separated by randomization.
Repeated measurement. The PKU-arm schedule included a baseline 24-hour assessment before Kuvan, plasma draws at visits 3, 4, and 5, and a later 24-hour assessment at visit 6. Repeated observations can represent within-person change and may help describe time patterns. A statistical method for repeated measurements must account for the fact that observations from the same person are generally related rather than independent. The registry record does not specify whether the intended analysis would use a repeated-measures model, compare selected time points, or use another approach.
Diurnal variation refers to changes that occur across the day. A 24-hour set of measurements can be informative about such a pattern if the timing and values are recorded. The registry describes 24-hour assessments but does not report the sampling times, assay procedures, or a planned way of summarizing the daily curve. Those details are not reported in the registry record. No actual curve or sequence of measurements is available because participants withdrew before any data were collected.
Uncertainty and precision. A confidence interval is a statistical range around an estimate that conveys uncertainty under the assumptions of the analysis. Narrower intervals generally indicate greater precision, while wider intervals indicate less precision. No estimate or confidence interval is reported for this study. With no collected endpoint data, there is no study-specific precision to assess and no basis for describing the range of effects compatible with the observations.
A p-value, when reported, describes how unusual data at least as inconsistent with a specified null hypothesis would be under that hypothesis and the statistical model. It is not a measure of effect size or the probability that a hypothesis is true. The registry lists no analyses and reports no p-value. Thus, no hypothesis test can be interpreted from the posted results.
Distribution and model choice. Statistical models should reflect the structure and distribution of the outcome. For example, over-dispersion occurs when observed variability exceeds that expected under a model’s assumptions; if ignored, uncertainty estimates can be misleading. This is a general statistical consideration, not a reported feature of the present data. The registry record does not report a model, distributional checks, handling of within-person correlation, or any assessment of over-dispersion. Since no observations were collected, those choices cannot be evaluated against the study’s data.
Planning illustrations. The stated planning framework describes two-sided significance level 0.05, equal allocation between two arms, and a normal approximation. It describes illustrations based on detecting a stated fraction of an observed effect; for time-to-event outcomes, the stated convention is total events, while other outcomes use participants per arm. These are planning conventions, not evidence that the trial used those assumptions to select its planned enrollment. The registry record does not report the trial’s own sample-size justification. It also reports no outcome analysis from which an observed effect could be assessed. Any sample-size illustration should therefore be understood as a planning illustration, not as observed power or as a result of the trial.
Power is a design quantity describing the chance that a planned test would reject a specified null hypothesis under a chosen alternative and model. It depends on assumptions about the effect, variability, sample size, and analysis. A post hoc calculation using an observed effect is not an observed property of the trial, and it cannot replace examination of the estimate and its uncertainty. In this record, there are no reported endpoint observations or analyses to support an outcome-based assessment. The planned enrollment of 6 should not be treated as a completed analysis sample.
Analysis transparency. The registry reports zero analyses and does not state an analysis population, missing-data method, multiplicity procedure, or interim-analysis plan. These omissions prevent evaluation of how the intended primary question would have been translated into a statistical estimate. They do not imply that a particular method was or was not used outside the information recorded; such details are not reported in the registry record.
10. Multiplicity, Missing Data and Analysis Populations
The registry describes one primary outcome measure, covering patterns of change in two laboratory measures—Phe and tyrosine—between baseline and 4 weeks for each arm. It does not report a plan for handling the multiple measures, time points, or arm-specific assessments. A multiplicity procedure is a general way to address the increased chance of false-positive findings when several statistical claims are tested. Whether such a procedure was needed, and how it would have been applied, cannot be determined from the registry record. No analyses or test results are reported.
Missing data are a central feature of the outcome record: participants withdrew before any data were collected. This means the posted results contain no endpoint measurements from which to estimate the planned changes. The reason for withdrawal, number of participants who withdrew, and any distinction between withdrawal and other forms of noncompletion are not reported in the registry record. There is no described imputation method, sensitivity analysis, or missing-data assumption.
An analysis population identifies which participants and measurements contribute to a particular analysis—for example, all enrolled participants or only those with specified follow-up data. The registry does not define an analysis population beyond its statement that participants withdrew before data collection. There are no reported outcome analyses to show which population was used.
The registry record also does not report interim analyses or rules for stopping early. The termination status alone does not establish why the study ended or whether a planned statistical stopping rule was involved. Those details are not reported in the registry record.
11. What the Result Does, and Does Not, Mean
The record documents a planned pilot investigation of daily variation in plasma Phe and tyrosine among PKU participants and healthy non-PKU controls. It also documents a once-daily Kuvan intervention planned for the PKU arm, a nonrandomized parallel design, and a baseline-to-4-week primary outcome description. These registry entries describe the study’s intended question and procedures.
The record does not document an observed change in either laboratory measure. Participants withdrew before any data were collected, and no analyses are reported. Therefore, no direction or size of change can be attributed to the study, and no claim about the presence or absence of a diurnal pattern can be made from its posted results. There is also no estimate with which to judge precision.
The design does not provide a randomized comparison of Kuvan against a control condition. The arms were different populations, and allocation was nonrandomized. As a general principle, this means a between-arm contrast would not automatically identify an effect of treatment. In this particular record, no such contrast is reported in any case.
The absence of reported adverse events should also be interpreted in context. Both groups are listed with zero participants at risk and zero affected by serious or other events, while participants are reported to have withdrawn before data collection. The registry’s event entries cannot establish a safety profile based on ongoing exposure and follow-up. Death information is not reported in the registry record.
Finally, the listed planning assumptions are not evidence that the study had adequate power, nor do they establish a sample-size rationale for the planned enrollment. Planning illustrations are conditional on their assumptions; they are not observed results. The defensible conclusion is limited to the documented design and the lack of collected outcome data, not to whether Kuvan changed Phe or tyrosine or whether either group had a particular daily pattern.
12. Why This Trial Matters Statistically
This trial matters statistically because it illustrates the distinction between a planned endpoint and an analyzed result. The registry defines a question about Phe and tyrosine patterns across baseline and 4 weeks, but the outcome population is described as participants who withdrew before any data were collected. Without observations, statistical methods cannot produce an estimate, quantify uncertainty, or test the planned question.
It also highlights why study design affects what comparisons mean. The record labels the study self-controlled, but it also describes a parallel, nonrandomized arrangement with PKU participants receiving Kuvan and non-PKU controls undergoing a 24-hour assessment. These structures answer different kinds of questions: repeated observations within an individual can describe change over time, while comparisons between groups require attention to how the groups differ. Randomization can help balance group characteristics in a treatment comparison; it was not used.
The planned daily assessments raise further methodological questions about timing, repeated measurements, and the relationship between values from the same participant. Those are important considerations for a study of diurnal patterns in general. Yet the registry does not report a statistical analysis plan, and no collected measurements are available to show how these issues were addressed.
Finally, planning calculations should remain distinct from trial findings. The stated framework describes assumptions for sample-size illustrations, but the registry does not report a trial-specific sample-size justification, and there are no outcome analyses. This distinction helps prevent a planning quantity from being mistaken for evidence about the study’s results or precision.
13. Limitations
- The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
- Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
The most consequential limitation is that the registry reports that participants withdrew before any data were collected. The primary outcome therefore has no observed measurements, and the record lists no analyses. The study cannot provide an estimate of Phe or tyrosine change or of diurnal variation.
The registry does not report the number of participants in each arm, the reasons for withdrawal, or the extent to which any planned procedures were completed. Although planned enrollment was 6, that figure does not establish the number analyzed. The status is terminated, but the reason for termination is not reported in the registry record.
The design also limits interpretation of any hypothetical between-group comparison. Allocation was nonrandomized, masking was absent, and PKU participants and healthy non-PKU controls differed by population as well as by their planned intervention and assessment schedules. The control-group description lists a 24-hour assessment at visit 2, while the primary outcome refers to baseline and 4 weeks for each arm. The registry record does not clarify the control-group follow-up schedule.
Important statistical details are not reported: the analysis model, an analysis population, methods for missing data, multiplicity handling, interim analyses, and a trial-specific sample-size justification. The registry also gives no sampling times or assay details for the 24-hour assessments. These limitations constrain assessment of the planned methods in addition to the absence of results.
The adverse-event listings show zero participants at risk and zero affected in each group, but the record reports withdrawal before data collection. These entries do not constitute a safety assessment with documented exposure and follow-up. Death information is not reported in the registry record.
14. Related Tutorials
15. Related Statistical Calculators
16. Sources
- ClinicalTrials.gov: A Pilot Study on Diurnal Variation — NCT01806051.
- Registry record last updated 2016-04-20; status last verified 2016-03.
- Results first posted 2016-04-20.
- 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.
Continue through the Clinical Biostats statistical pathway
Use this trial's endpoint as a starting point for deeper study of effect measures, confidence intervals, and sample-size planning.
17. Record Summary
This is a terminated, prospective pilot study of diurnal variation in plasma phenylalanine and tyrosine among PKU participants and healthy non-PKU controls. The registry lists planned enrollment of 6, nonrandomized allocation, no masking, a parallel model, and Kuvan once daily for the PKU arm. The primary outcome was intended to evaluate changes from baseline to 4 weeks for each arm.
The PKU group was scheduled for a baseline 24-hour blood assessment before Kuvan, later plasma draws, and another 24-hour assessment. Controls were scheduled for a 24-hour blood assessment. Participants withdrew before any data were collected, and the registry reports no analyses. No endpoint results or estimates are available. The reason for termination, withdrawal details, and statistical analysis plan are not reported in the registry record.