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 Study of Phenoptin in Subjects With Phenylketonuria Who Participated in Protocols PKU-004 or PKU-006 (NCT00332189), a non-randomized phase 3 study. The primary outcome is Tabulation of the Incidence and Frequency of All AEs and SAEs That Occur Throughout the Study..
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00332189 |
| Phase | Phase 3 |
| Condition | Phenylketonuria |
| Allocation | Non-Randomized |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 111 |
| Arms in the primary outcome | n/a |
| Lead sponsor | BioMarin Pharmaceutical |
| Results posted | Yes |
2. Clinical Question
Population
People with phenylketonuria who had participated in Protocols PKU-004 or PKU-006 were eligible for this extension study. The registry lists an enrollment of 111 and describes the safety population as the total patient population. Further eligibility details and participant characteristics are not reported in the registry record.
Intervention
The intervention was sapropterin dihydrochloride, identified in the study title as Phenoptin. The stated objective was to evaluate safety during long-term treatment. The registry does not report the dose, dosing schedule, adherence, or whether treatment exposure was the same for all participants.
Comparator
There was no randomized comparator. The study is described as non-randomized, open-label, and single-group. It therefore does not provide a concurrent control group for estimating how event rates would compare under another treatment or no treatment.
Primary question
The primary outcome concerns the incidence and frequency of adverse events and serious adverse events over the study period. The registry also describes safety assessment through clinically significant changes in vital signs, physical examination findings, and laboratory test results. It does not report numerical results for those clinical assessments. Blood phenylalanine levels are listed as a secondary outcome, but no result is posted in the registry record.
3. Trial Design
This completed study is described in its official title as a Phase 3b, multicenter, open-label extension study. The registry lists its phase as Phase 3. Participants had phenylketonuria and had participated in Protocols PKU-004 or PKU-006. The listed intervention was sapropterin dihydrochloride, also called Phenoptin in the study title.
The design was non-randomized and single-group, with no masking. Those features are important when interpreting the safety findings: the posted counts describe events among people receiving study treatment, but the design does not establish a randomized comparison with a control group. The registry lists an enrollment of 111 and a completed status. The study start is recorded as 2006-07, and primary completion as 2009-08.
The primary outcome is a tabulation of the incidence and frequency of all adverse events and serious adverse events throughout the study. The timeframe is baseline through final visit, with a maximum of 30 months. Adverse events were collected at month 3 and month 6, then at 6 month intervals. The record also describes safety evaluation through clinically significant changes in vital signs, physical examination findings, and laboratory results. It does not specify the treatment duration each participant completed or give a detailed visit schedule beyond the adverse-event collection points.
The stated study objective was safety evaluation in people with phenylketonuria who had taken part in earlier Phase 3 studies with Phenoptin. The exact protocol rationale, sample-size justification, detailed eligibility criteria, and statistical analysis plan are not reported in the registry record. The record identifies a secondary outcome concerning blood phenylalanine levels, but provides no numerical outcome result for it.
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: The last assessment obtained in PKU-004 or PKU-006 could be used to determine eligibility for this study provided assessment was conducted fewer than six weeks prior to PKU-008 Day 1.
Overall Study
| Stage | Total Patient Population |
|---|---|
| STARTED | 111 |
| COMPLETED | 90 |
| NOT COMPLETED | 21 |
Reasons for not completing this period:
| Reason | Total Patient Population |
|---|---|
| Adverse Event | 3 |
| Uncooperative/Noncompliant | 3 |
| Withdrawal by Subject | 9 |
| Lack of Efficacy | 4 |
| Moved out of country | 2 |
Analysis population for the primary outcome, as defined in the registry: Percentage of total population who experienced an AE or SAE presented here. For full list of SAEs, and AEs experienced with a frequency of greater than 5%, see the Reported Adverse Event section.
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.
| Characteristic | Unit | Total Patient Population |
|---|---|---|
| Participants analysed | 111 | |
| Age Continuous | years | 16.4 (SD 10.2) |
| Age, Customized: >=4 to <8 | participants | 20 |
| Age, Customized: >=8 to <12 | participants | 24 |
| Age, Customized: >=12 to <18 | participants | 28 |
| Age, Customized: >=18 | participants | 39 |
| Sex: Female, Male: Female | Participants | 44 |
| Sex: Female, Male: Male | Participants | 67 |
| Race/Ethnicity, Customized: Caucasian | participants | 108 |
| Race/Ethnicity, Customized: Asian/Asian Pacific Islander | participants | 1 |
| Race/Ethnicity, Customized: Hispanic | participants | 1 |
| Race/Ethnicity, Customized: Other | participants | 1 |
| Region of Enrollment: North America | participants | 54 |
| Region of Enrollment: Europe | participants | 57 |
6. Primary Endpoint
The registry lists the primary outcome as Tabulation of the Incidence and Frequency of All AEs and SAEs That Occur Throughout the Study., measured over Baseline through Final Visit (a Maximum of 30 months) with AEs collected at month 3 and 6 then at 6 month intervals.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | percentage of subjects reporting events |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is described as tabulation of the incidence and frequency of all adverse events and serious adverse events during the study. The stated unit is the percentage of subjects reporting events. The timeframe runs from baseline through final visit, for a maximum of 30 months. Events were collected at month 3 and month 6, followed by collection at 6 month intervals.
Safety endpoints of this kind are used to describe what adverse experiences were reported during exposure and how often participants experienced them. They can identify event types that warrant attention and provide a structured account of the observed safety experience. The registry description also includes clinically significant changes in vital signs, physical examination findings, and laboratory test results as aspects of safety assessment. Numerical findings for those assessments are not reported in the registry record.
The posted safety summary gives counts for the total patient population: 7 are listed under serious events and 93 under other adverse events, with 111 at risk in each category. The registry does not provide an overall percentage for either count in the primary outcome description. Those counts should therefore be read as descriptive event summaries, not as a comparison between treatment strategies. The record also lists blood phenylalanine levels as a secondary outcome, but no result is reported.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry’s adverse-event summary describes safety events in a single-group, open-label extension study. It lists 7 participants under serious events and 93 under other adverse events; 111 are listed at risk for each category. These are descriptive counts. The record does not provide a concurrent control group, so the figures cannot estimate a treatment difference relative to another therapy or to no treatment.
The serious-event terms listed include Gastrooesophageal reflux disease, Testicular mass, Tonsillectomy, Dysmenorrhoea, Road traffic accident, and Hand Fracture. Each term is accompanied by a posted frequency of 0.9%. These terms identify events reported in the registry; they do not, by themselves, establish that treatment caused the event. The record does not provide further event-level detail such as timing, duration, outcome, or an assessment of relationship to treatment for these terms.
The primary outcome is framed as incidence and frequency of adverse events and serious adverse events over baseline through final visit, with a maximum of 30 months. Adverse events were collected at month 3 and month 6 and then at 6 month intervals. The posted counts do not show how long each participant was followed or how much treatment exposure each person had. Accordingly, they are not exposure-adjusted rates and do not account for differences in time under observation.
No confidence intervals, hypothesis tests, adjusted estimates, or other inferential analyses are reported in the registry record. This means the precision of the event estimates cannot be assessed from the posted summary alone. A confidence interval, in general, describes a range of estimates compatible with the observed data under a specified statistical method; without one, readers should avoid treating a count or posted percentage as a precise estimate of the underlying event frequency.
The study’s open-label, non-randomized design also limits causal interpretation. Participants and investigators were not masked, and there was no randomized allocation to a comparison group. Observed events may reflect the underlying condition, other circumstances, treatment, or a combination of factors; the posted data do not separate those possibilities. The registry’s safety objective is therefore best understood as descriptive monitoring during extension treatment, not as a test of comparative safety.
The record lists blood phenylalanine levels as a secondary outcome, but no numerical result is reported. It also does not give numerical results for the described vital-sign, physical-examination, or laboratory assessments. No statistical analyses are listed. Consequently, the registry record supports a limited reading: it reports adverse-event counts and selected serious-event terms, while leaving comparative effects, uncertainty estimates, and several other safety measurements unavailable.
9. Statistical Methods Explained
The registry describes a non-randomized, open-label, single-group study and reports descriptive safety counts. No statistical analyses are listed. The following explains, in general terms, how this type of information is commonly interpreted and what the posted record does and does not allow readers to conclude.
What does an event count represent?
An event count records how many participants are reported in a category. The registry lists 7 under serious events and 93 under other adverse events, with 111 at risk in each category. The listed unit for the primary endpoint is the percentage of subjects reporting events, but the summary does not provide an overall percentage for those counts. The counts should be quoted as posted rather than converted into percentages or combined.
Counts are descriptive: they characterize what was reported among the study population. They are not, by themselves, estimates of a treatment effect. A treatment effect requires a defined contrast, such as a comparison between treatment groups or between observed and expected outcomes under a specified model. This study has no randomized comparison group in the registry description. Therefore, the counts cannot show whether event occurrence was higher or lower than it would have been under another treatment or without the study intervention.
Why distinguish serious events from other events?
Seriousness and frequency describe different aspects of adverse events. Seriousness classifies events according to regulatory criteria, while frequency describes how often events are reported. A serious event does not necessarily occur often, and an event that is not classified as serious may still be relevant to a safety assessment. The registry presents separate counts for serious events and other adverse events. The categories should not be added together: the record does not establish that the categories are mutually exclusive at the participant level, and a participant may have experienced more than one event.
The listed serious-event terms each have a posted frequency of 0.9%. These frequencies should be read as registry-reported values. They do not identify whether events were considered related to treatment, and the record does not provide event-level narratives or a causal assessment for each term.
What does a confidence interval add?
In general, a confidence interval communicates uncertainty around an estimate. It reflects both the observed data and the assumptions of the statistical method used to construct it. A narrow interval indicates greater precision under those assumptions; a wide interval indicates less precision. The registry record does not report confidence intervals for the adverse-event counts or the listed term frequencies. It is therefore not possible to judge their statistical precision from the posted summary alone.
Even when a confidence interval is available, it does not correct for the absence of a control group or remove possible biases in an open-label study. It quantifies uncertainty under a model; it does not turn an uncontrolled observation into a randomized comparison. In this study, design limitations and missing inferential results are separate issues.
Why does follow-up time matter?
The primary outcome timeframe is baseline through final visit, with a maximum of 30 months. Event collection is described at month 3 and month 6 and then at 6 month intervals. In general, participants with longer exposure or follow-up have more opportunity for an event to be observed. A participant-level count does not adjust for such differences in observation time. An exposure-adjusted rate would require suitable information about time at risk, which is not reported in the registry record.
The stated collection schedule indicates when adverse events were collected, but it does not establish that every participant completed the same follow-up or had the same treatment exposure. The record does not provide participant-level follow-up duration, person-time, or a breakdown of events by time period. The maximum timeframe should not be interpreted as the observed follow-up duration for every participant.
What can the design say about causation?
Randomization is a general method for making treatment groups comparable on average, including for factors that may not be measured. This study is explicitly non-randomized and single-group, so that protection against confounding is not available through a randomized contrast. Open-label treatment also means the study was not masked. These features do not invalidate descriptive reporting, but they constrain what conclusions can be drawn about why events occurred.
When an event is observed during treatment, timing alone does not establish that the treatment caused it. Events may be associated with the underlying condition, other exposures, or unrelated circumstances. The registry does not report a causal analysis or event-relatedness breakdown that would distinguish these explanations. The listed serious-event terms therefore describe reports during the study rather than demonstrated treatment effects.
How should planning calculations be treated?
In general, sample-size calculations are planning tools that depend on assumptions about an outcome, a comparison, significance level, allocation, and the effect to be detected. They do not represent observed evidence or the probability that a completed study has demonstrated an effect. The stated planning assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and effects defined as fractions of an observed effect. Such assumptions do not describe this trial’s single-group, non-randomized design as a comparative experiment. The registry does not report the trial’s own sample-size justification, and no inferential analysis is listed.
10. Multiplicity, Missing Data and Analysis Populations
Multiplicity concerns arise when a study conducts multiple statistical tests or evaluates multiple outcomes in ways that increase the chance of a misleading positive finding. The registry identifies a primary safety outcome and a secondary outcome concerning blood phenylalanine levels. It does not report a multiplicity adjustment, a hierarchy for interpreting outcomes, or a statistical analysis plan. No statistical analyses are listed, so there are no posted hypothesis-test results for which a multiplicity strategy can be assessed.
Missing-data methods are also not reported in the registry record. The study description gives a maximum timeframe of 30 months and an adverse-event collection schedule, but does not state how incomplete visits, withdrawals, missing measurements, or participants with different follow-up durations were handled. It would be inappropriate to assume that every enrolled participant contributed complete data at every planned assessment.
The analysis population is described for the primary safety summary as the total patient population, and the adverse-event listing reports 111 at risk in each category. The registry does not give a separate definition of the population used for each outcome, nor does it explain exclusions or the handling of participants who discontinued treatment. It also does not report a population definition for the secondary blood phenylalanine outcome.
These omissions limit assessment of whether the posted counts reflect all enrolled participants, only those with particular follow-up, or another analysis set. They also prevent evaluation of whether missingness could have affected the observed event summaries. The record’s counts can be described as posted, but the underlying missing-data and analysis-population procedures are not reported in the registry record.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Total Patient Population | 7 | 111 | 6.3% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Total Patient Population | 93 of 111 |
Most frequent serious adverse event terms
| Event term | Organ system | Total Patient Population |
|---|---|---|
| Gastrooesophageal reflux disease | Gastrointestinal disorders | 1 of 111 |
| Testicular mass | Reproductive system and breast disorders | 1 of 111 |
| Tonsillectomy | Surgical and medical procedures | 1 of 111 |
| Dysmenorrhoea | Reproductive system and breast disorders | 1 of 111 |
| Road traffic accident | Injury, poisoning and procedural complications | 1 of 111 |
| Hand Fracture | Injury, poisoning and procedural complications | 1 of 111 |
| Surgery | Surgical and medical procedures | 1 of 111 |
| Lymphadenectomy | Surgical and medical procedures | 1 of 111 |
| Joint dislocation | Injury, poisoning and procedural complications | 1 of 111 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Total Patient Population |
|---|---|---|
| Upper respiratory tract infection | Infections and infestations | 22 of 111 |
| Cough | Respiratory, thoracic and mediastinal disorders | 21 of 111 |
| Nasopharyngitis | Infections and infestations | 20 of 111 |
| Vomiting | Gastrointestinal disorders | 20 of 111 |
| Pyrexia | General disorders | 18 of 111 |
| Headache | Nervous system disorders | 13 of 111 |
| Diarrhoea | Gastrointestinal disorders | 10 of 111 |
| Pharyngolaryngeal pain | Respiratory, thoracic and mediastinal disorders | 10 of 111 |
| Influenza | Infections and infestations | 9 of 111 |
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | 9 of 111 |
Serious events with the highest arm-level rate: gastrooesophageal reflux disease (0.9%), testicular mass (0.9%), tonsillectomy (0.9%), dysmenorrhoea (0.9%), road traffic accident (0.9%).
The registry lists 7 under serious events and 93 under other adverse events, with 111 at risk in each category. These are counts in the total patient population, not a randomized comparison. The record’s primary outcome is framed as the percentage of subjects reporting events, but it does not post an overall percentage for either count in the summary.
The serious-event terms listed are Gastrooesophageal reflux disease, Testicular mass, Tonsillectomy, Dysmenorrhoea, Road traffic accident, and Hand Fracture. Each is reported with a frequency of 0.9%. These are registry-listed terms and frequencies; they should not be interpreted as proof that treatment caused an event. The record does not provide event-level detail or a treatment-relatedness assessment for these terms.
Counts of participants and counts of events are not necessarily interchangeable: a participant can experience more than one event. The record does not clarify whether participants represented in the serious-event count also appear in the other-adverse-event count, so the categories should not be added. It also does not provide exposure-adjusted rates, confidence intervals, or a comparison group. The figures describe reported safety experience during follow-up, with a maximum timeframe of 30 months, rather than a comparative risk estimate.
12. What the Result Does, and Does Not, Mean
The posted results mean that the registry recorded adverse events during a completed, open-label extension study of sapropterin dihydrochloride in people with phenylketonuria who had participated in Protocols PKU-004 or PKU-006. The safety summary lists 7 under serious events and 93 under other adverse events, with 111 at risk in each category. It also lists selected serious-event terms, each with a reported frequency of 0.9%.
These figures do not establish that the study intervention caused any particular event. They do not show whether the event counts would have been different under another treatment or without treatment, because the registry describes a single-group, non-randomized study without a concurrent control group. Nor do the counts account for differences in each participant’s time under observation. The study timeframe extends from baseline to final visit, with a maximum of 30 months, but the registry does not report individual follow-up duration.
The figures also do not provide a complete quantitative account of all safety assessments mentioned in the outcome description. The record refers to clinically significant changes in vital signs, physical examination findings, and laboratory results, but numerical results for those assessments are not reported. Blood phenylalanine levels are listed as a secondary outcome, but no numerical result is reported for that outcome.
No confidence intervals, hypothesis tests, adjusted analyses, or other statistical analyses are listed. Thus, the posted counts and term frequencies cannot be used to assess statistical precision or comparative effects. In general, an uncontrolled safety summary can document events observed during study participation, but it cannot separate treatment effects from other possible explanations. The registry record supports a descriptive account of reported events, not a conclusion about comparative safety, causality, or clinical benefit.
13. Why This Trial Matters Statistically
This study illustrates an important statistical distinction between documenting events and estimating a treatment effect. A single-group extension study can describe adverse events occurring during follow-up and can contribute safety information for participants who continued from earlier protocols. Such descriptions may be useful for characterizing the experience reported in the study population. They do not provide the same evidence as a randomized comparison.
The non-randomized, open-label design is central to interpretation. Without a concurrent randomized comparator, the observed counts cannot be contrasted with outcomes under another treatment strategy. Without masking, awareness of treatment and study participation may also affect how events are reported or assessed. These are design considerations, not reasons to disregard the descriptive counts.
The record also shows why event counts need context. The listed serious and other adverse-event counts are not exposure-adjusted, and the maximum follow-up timeframe does not tell readers how long each participant was observed. The record gives a collection schedule but does not report individual follow-up, event timing, or a detailed breakdown of treatment exposure. Those omissions make it difficult to characterize how event occurrence varied over time.
Finally, the registry lists clinical assessments and blood phenylalanine as outcomes without numerical results for them, and it lists no statistical analyses. This separates the stated scope of the study from the information available for quantitative interpretation. The trial is statistically informative as an example of descriptive safety reporting, while its design and reporting do not support comparative or causal conclusions.
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 is the absence of a randomized control group. The study is non-randomized, open-label, and single-group, so its safety counts cannot estimate a comparative treatment effect. Events recorded during treatment may have multiple possible explanations, and the registry does not report an analysis that attributes them to treatment.
The registry does not report individual follow-up duration, treatment exposure, or exposure-adjusted event rates. Although the timeframe allows a maximum of 30 months and gives the adverse-event collection schedule, it does not establish how much observation time each participant contributed. Differences in follow-up can affect the opportunity to observe an event.
Event detail is limited. The record gives aggregate counts and selected serious-event terms, but does not provide timing, duration, outcomes, recurrence, or treatment-relatedness assessments for the listed terms. The record also does not clarify whether the serious-event and other-adverse-event categories overlap at the participant level. The categories should not be combined to infer a total.
Numerical results for the described vital-sign, physical-examination, and laboratory assessments are not reported in the registry record. Blood phenylalanine levels are listed as a secondary outcome, but no result is reported. No confidence intervals, hypothesis tests, adjusted estimates, or statistical analyses are listed. The analysis populations, handling of missing data, detailed eligibility criteria, and trial-specific sample-size justification are also not reported in the registry record. These gaps limit assessment of precision, completeness, and the representativeness of the posted summaries.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Study of Phenoptin in Subjects With Phenylketonuria Who Participated in Protocols PKU-004 or PKU-006 — NCT00332189.
- Registry record last updated 2012-11-16; status last verified 2012-10.
- Results first posted 2012-11-16.
- 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.
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18. Record Summary
The registry describes a completed, Phase 3-listed, multicenter, open-label extension study, identified in its official title as Phase 3b. It enrolled 111 people with phenylketonuria who had participated in Protocols PKU-004 or PKU-006. The design was non-randomized and single-group; the listed intervention was sapropterin dihydrochloride.
The primary outcome concerned the incidence and frequency of adverse events and serious adverse events from baseline through final visit, for a maximum of 30 months. The safety summary lists 7 under serious events and 93 under other adverse events, with 111 at risk in each category. Six serious-event terms are listed, each with a frequency of 0.9%.
The registry lists blood phenylalanine levels as a secondary outcome but reports no numerical result for it. No statistical analyses are listed. The record does not report a randomized comparator, confidence intervals, detailed missing-data methods, or numerical findings for the additional clinical safety assessments.