Study of the Safety and Tolerability of HPN-100 Compared to Sodium Phenylbutyrate in Children With Urea Cycle Disorders: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of the Safety and Tolerability of HPN-100 Compared to Sodium Phenylbutyrate in Children With Urea Cycle Disorders (NCT00947544), a na phase 2 study. The primary outcome is Rate of Adverse Events During the Switchover Part of the Study Rate of Adverse Events (Number of Participants Showing Adverse Events).

2. Clinical Question

The central question is therefore a safety question in a pediatric population: what adverse events were recorded during the short treatment sequence, and what information does the record offer about safety during the extension? The primary outcome is a count of participants with adverse events, rather than a measure of how often events occurred per unit of time or how severe symptoms were. Those distinctions matter when interpreting safety summaries.

The study also listed ammonia-control and pharmacokinetic outcomes, including blood ammonia measures and measures related to ammonia metabolism and drug exposure. Their inclusion indicates that the study planned to describe more than adverse events. However, the registry record does not provide numerical results for those secondary outcomes in the registry record. The clinical question can therefore be characterized from the protocol description, but the posted numerical evidence does not support a complete appraisal of all planned outcomes.

3. Trial Design

This was a phase 2, open-label, fixed-sequence, single-group study. Participants received one week of NaPBA followed by one week of HPN-100 during the switch-over part. The registry describes no masking and no randomized allocation. The record lists 17 participants enrolled, and identifies children 6–17 years of age with urea cycle disorders as the study population.

A fixed sequence means that treatment order was set: NaPBA came first and HPN-100 followed. The same participants could therefore contribute measurements under both treatments, but treatment and period are linked. Any difference between measurements could reflect treatment, time, order, or changes during participation; the design does not isolate these explanations in the way random assignment can. Open-label status also means treatment identity was not masked, which can matter for outcomes involving reporting or clinical judgment.

The study included a long-term safety extension described as 12 month. According to the study summary, after review of the first ten participants who completed the switch-over part, the data and safety monitoring board approved enrollment of up to an additional 20 participants into the extension. The record does not state how many participants ultimately entered or completed that extension, or how many contributed to each reported safety summary.

The registry lists Amgen as sponsor and the study status as completed. The listed study dates run from 2010-03 for study start to 2011-08 for primary completion. These registry entries place the study in context but do not establish how every protocol activity was conducted. Further details such as the full eligibility criteria, the precise analysis populations, and the statistical analysis plan are not reported in the registry record.

Although the study objective uses comparative language, the design is not a randomized comparison. The regimen and sequence are described, but the allocation field is not applicable and the study model is single group. The primary safety information should consequently be read as descriptive evidence from this study, not as an estimate from a randomized head-to-head trial.

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.

Switch-Over Period (2 Weeks)

Safety-Extension Period (12 Months)

Reasons for not completing this period:

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Rate of Adverse Events During the Switchover Part of the Study Rate of Adverse Events (Number of Participants Showing Adverse Events), measured over 1 week on each treatment for a total of 2 week..

The primary outcome is described as the rate of adverse events during the switch-over part, specified as the number of participants showing adverse events. The stated timeframe is one week on each treatment for a total of two week. In practical terms, this endpoint counts participants who experienced an event; it does not, by itself, describe the number of separate events per participant, the duration of events, or their severity.

Counting participants with an adverse event is a common way to summarize safety in a clinical study. It gives a simple account of how many people were affected during the defined observation period. It can be useful for identifying whether events were recorded and for describing the overall safety experience in a group. For a switch-over study, however, treatment-specific interpretation requires clear reporting of the events attributed to each treatment and the participants contributing to each treatment period.

The registry lists safety and pharmacokinetic evaluation as the primary objective, but the available primary outcome description does not provide a full treatment-by-treatment result. The adverse-event summary lists HPN-100 participants at risk and participants affected, but an equivalent NaPBA primary-outcome summary is not reported in the registry record. Nor are confidence intervals, a statistical comparison, or a detailed event definition reported in the registry record. Without these elements, the endpoint description clarifies what was intended to be counted, but does not establish a precise comparative estimate.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a single-group, open-label, fixed-sequence study. These design terms shape what statistical conclusions are possible. In a single-group study, participants do not enter separate randomized treatment groups. In this study, the same treatment order was specified for the switch-over period: NaPBA followed by HPN-100. Because treatment order was not randomized, the design cannot ensure that other influences on measurements are balanced between treatment periods.

What does a fixed sequence mean for comparison?

When the same participants receive treatments in sequence, their measurements can be compared within person. This can reduce the influence of stable differences between participants, such as characteristics that do not change over the short observation period. But a within-person comparison still depends on the conditions of measurement. Period effects, changes over time, carryover from the earlier treatment, or changes in clinical status can affect measurements. The registry record does not report details of a washout period, an assessment of carryover, or an analysis that addresses period effects. Those details should not be assumed.

Open-label means the treatments were not masked. General statistical consideration: knowledge of treatment can affect the reporting or assessment of outcomes, particularly when outcome definitions involve judgment or participant reports. This does not show that bias occurred in this study. The record's design information simply means that masking cannot be relied on to prevent such influence.

How should event counts be read?

The primary outcome is a number of participants with adverse events. A participant count is different from an event count: one participant may have multiple events, while a participant-level summary generally records whether that person had at least one qualifying event. The record's adverse-event fields describe participants at risk and participants affected. The listed HPN-100 figures are 17 at risk, 3 with serious adverse events, and 4 with other adverse events. The registry does not explain in the registry record whether the serious and other categories are mutually exclusive or how repeated events were handled.

A proportion or rate can summarize the frequency of an outcome, but a meaningful comparison requires a defined numerator, denominator, and observation period. The primary timeframe is stated as one week on each treatment for a total of two week. The registry does not provide complete treatment-specific participant counts for both periods, nor a complete primary-outcome comparison. Event percentages listed for serious terms should be read as the posted percentages, not treated as independently verifiable estimates with a known denominator unless the denominator is stated.

What can a confidence interval add?

General statistical explanation: a confidence interval presents a range of values compatible with the observed data under a specified statistical model. It conveys estimation uncertainty, rather than proving that a result is true or false. A narrow interval generally indicates greater precision than a wide interval. The registry record does not report confidence intervals for the adverse-event counts or a treatment comparison, so the precision of a comparative safety estimate cannot be assessed from the listed figures.

A hypothesis test, when reported, addresses whether data are inconsistent with a specified null hypothesis under its assumptions. A p-value is not a measure of clinical importance, and it does not describe the probability that a treatment is safe or effective. No primary-outcome p-value or statistical test is reported in the registry record. The absence of a reported test should not be interpreted as evidence that no analysis was performed; it means the registry record does not present one.

What do the sample-size illustrations represent?

Any sample-size illustrations associated with the posted results are planning calculations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Such calculations are hypothetical planning illustrations, not results from the study's actual design. They do not represent observed power, and they do not show that the trial was designed with those assumptions. The record does not report the trial's sample-size justification, so its planned enrollment rationale cannot be inferred from an illustration.

The study itself is listed as a single-group, fixed-sequence study, whereas the illustration assumptions describe equal allocation between two arms. That distinction is essential: an illustrative calculation under a different design does not convert the study into a randomized two-arm trial. The illustrations are not observed evidence and do not resolve the lack of a reported comparative estimate.

For time-to-event calculations, the stated convention is to give the total number of events; for other calculations, the convention is participants per arm. This is a general presentation distinction, not evidence that this study had a time-to-event primary endpoint. The primary endpoint in the registry is a participant count for adverse events. No sample-size illustration can replace reporting the actual endpoint definition, analysis population, result, and uncertainty.

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("HPN-100", "NaPBA")
n      <- c(11, 11)
events <- c(4, 2)
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  HPN-100  11  4  36.4  10.9  69.2  15.2  64.6  15.2  65.1
ARM  NaPBA  11  2  18.2  2.3  51.8  5.1  47.7  5.5  48.4

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 11 outcome measures, including the primary adverse-event outcome and secondary outcomes concerning hyperammonemic events, blood ammonia control, ammonia values, and pharmacokinetic measures. When a study examines multiple outcomes, the chance of at least one apparently notable result can increase if each is tested separately. General statistical methods can address this through prespecified outcome priorities or adjustments for multiple testing, but the registry record does not report a multiplicity strategy or a statistical analysis plan.

The record lists zero analyses. That registry entry does not establish that no analyses were conducted; it means analyses are not listed in the record. The methods used for each outcome, any adjustment for multiple comparisons, and the distinction between planned and exploratory analyses are not reported in the registry record. Numerical results for most of the listed outcomes are also not available in the registry record.

Missing-data methods are not reported in the registry record. The record does not specify how missing measurements, early discontinuations, incomplete treatment periods, or participants who did not enter or complete the extension were handled. It also does not identify a detailed analysis population for the primary outcome. The population field is empty, and the number contributing to each outcome is not reported in the registry record.

These omissions limit interpretation because outcome counts depend on who was observed and how incomplete observations were treated. They also prevent assessment of whether all outcomes were analyzed as planned. The study summary notes an extension enrollment decision following review of the first ten switch-over completers, but does not provide a statistical interim-analysis plan or explain whether that review changed outcome analyses. Such details are 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: hyperammonemia (11.8%), gastroenteritis (5.9%), aggression (5.9%).

The serious adverse-event summary lists HPN-100 with 17 participants at risk and 3 participants affected. The record separately lists 4 participants affected by other adverse events. These are participant counts, not necessarily the total number of event episodes. The registry also identifies hyperammonemia at 11.8%, gastroenteritis at 5.9%, and Aggression at 5.9% among the top serious adverse-event terms.

The percentages should be read as registry-reported values. The event-specific denominator and whether each term represents a unique participant are not reported in the registry record. A participant can experience more than one event, so the percentages for different terms should not be summed to estimate the number of participants affected. The record does not provide a corresponding complete serious-event summary for NaPBA, preventing a treatment-by-treatment comparison from these figures.

Serious adverse events are a safety classification, not a judgment that an event was caused by study treatment. The record does not provide event-level narratives, timing, attribution, or resolution details. These counts therefore describe what was recorded, but do not establish cause, comparative risk, or the likelihood of an event outside this study. The long-term extension was intended to assess safety, but its participant totals and detailed event results are not reported in the registry record.

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

The record supports a description of the study design and selected safety counts. It documents a phase 2, open-label study in children with urea cycle disorders, using a fixed sequence of NaPBA followed by HPN-100. For HPN-100, the safety summary reports 17 participants at risk, 3 participants affected by serious adverse events, and 4 affected by other adverse events. Several serious-event terms and their registry percentages are also listed.

These observations do not establish that HPN-100 caused the events, nor do they quantify a causal difference between HPN-100 and NaPBA. The sequence was fixed rather than randomized, and the record does not provide a complete treatment-specific primary-outcome comparison. Without that comparison, a reader cannot estimate how the recorded adverse-event experience differed by treatment from the registry figures.

The results also do not establish that no other adverse events occurred. The available safety summary is not a complete event-level report, and event timing, participant overlap across terms, and event-specific denominators are not stated. Likewise, the record's list of secondary outcome titles does not tell the reader what the observed ammonia or pharmacokinetic results were. Their numerical findings are not reported in the registry record.

General statistical interpretation: a study's observed counts are subject to sampling uncertainty, especially when the number of participants is limited. Confidence intervals or other uncertainty estimates can help show how imprecise an estimate may be, but none are reported for the primary safety comparison. The study can therefore be read as a descriptive safety investigation, not as a definitive estimate of comparative safety or evidence of treatment effect.

The study summary says a longer-term extension was planned and that additional enrollment was approved after review of the first ten switch-over completers. This describes the extension's purpose and enrollment decision, but does not provide its final enrollment, follow-up completeness, or results. The intended duration alone cannot establish what was observed during that extension.

14. Why This Trial Matters Statistically

Statistically, the study illustrates the distinction between a planned comparison and the design that actually supports it. The protocol description compares HPN-100 with NaPBA, but participants received the drugs in a fixed order, without masking or randomized allocation. This sequence permits descriptive observations under both treatments, yet it does not separate treatment effects from order and period influences as a randomized comparison aims to do.

It also demonstrates why endpoint definitions and outcome reporting matter. The primary endpoint is described as a count of participants showing adverse events over the switch-over period. That is a useful safety summary, but interpretation depends on treatment-specific denominators, event definitions, analysis populations, and uncertainty estimates. The registry record gives selected HPN-100 safety counts, but not a complete primary comparison or confidence intervals.

The study planned a range of additional outcomes, including ammonia control and pharmacokinetic measures. A list of planned outcomes can clarify the scientific scope, but cannot substitute for reported numerical results. The gap between listed outcomes and reported analyses is important for readers assessing which questions can be answered from a registry record.

Finally, the extension highlights a separate issue: evidence from short-term switch-over observation and evidence from longer-term follow-up answer different questions. A plan for an extension does not itself provide long-term safety findings. Reporting the number followed, their observation time, outcome definitions, and missing-data handling would be necessary to assess that evidence. The study therefore offers a useful example of how design, reporting completeness, and statistical precision jointly determine what can be concluded from clinical trial data.

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 main limitation for interpretation is the nonrandomized, fixed treatment order. NaPBA was given before HPN-100, so changes between periods may reflect treatment, time, order, or other changes during participation. The open-label design also leaves outcomes potentially susceptible to knowledge of treatment, although the registry record does not establish that this affected results.

The enrollment was 17, and the record does not state the number analyzed for each endpoint. It does not report a full primary-outcome comparison between NaPBA and HPN-100, confidence intervals, a statistical test, or a detailed analysis plan. This makes it difficult to assess the precision and robustness of any comparative interpretation. The adverse-event summary gives HPN-100 counts, but the corresponding complete NaPBA figures are not reported in the registry record.

Further safety details are also absent: event-level timing, attribution, outcomes, and the relationship between serious and other event categories are not specified. The denominators underlying the listed serious-event percentages are not stated. The long-term extension's final enrollment, follow-up, completion, and results are not reported in the registry record, despite its inclusion in the study description.

For secondary outcomes, the record identifies planned measures but does not report their numerical results in the registry record. Multiplicity handling, missing-data methods, analysis populations, and the sample-size justification are not reported. The registry also does not specify an interim-analysis plan; the described monitoring-board review should not be taken as evidence of a formal statistical interim analysis. These limitations mean the available record permits a narrow descriptive reading, rather than a complete evaluation of comparative safety, ammonia outcomes, or long-term results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of the Safety and Tolerability of HPN-100 Compared to Sodium Phenylbutyrate in Children With Urea Cycle Disorders — NCT00947544.
• Registry record last updated 2024-07-11; status last verified 2024-06.
• Results first posted 2013-12-25.
• 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

This completed phase 2 study enrolled 17 children 6–17 years of age with urea cycle disorders. It used an open-label, single-group, fixed sequence: one week of NaPBA followed by one week of HPN-100, with a long-term safety extension described as 12 month. The primary outcome was the number of participants with adverse events during the switch-over period.

The HPN-100 safety summary lists 17 participants at risk, 3 with serious adverse events, and 4 with other adverse events. The listed serious-event terms include hyperammonemia at 11.8%, gastroenteritis at 5.9%, and Aggression at 5.9%. The registry record does not report a complete primary-outcome comparison, uncertainty estimates, detailed extension results, or numerical results for the listed secondary outcomes.

Because treatment order was fixed and the study was open-label, the record supports descriptive interpretation rather than a randomized causal comparison. Details on analysis populations, missing data, multiplicity, and the statistical analysis plan are not reported in the registry record.