Berotralstat Treatment in Children With Hereditary Angioedema: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Berotralstat Treatment in Children With Hereditary Angioedema (NCT05453968), a non-randomized phase 3 study. The primary outcome is Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUC0-last) of Berotralstat.

2. Clinical Question

3. Trial Design

This is a Phase 3 study of berotralstat prophylaxis in children with hereditary angioedema. The registry records a non-randomized allocation, no masking, and a single-group model. Enrollment is listed as 29. The study began on 2022-10-25, and primary completion is listed as 2024-09-11. Its status is active, not recruiting.

Dosing is organized into four body-weight cohorts. Participants weighing at least 40 kg received 150 mg capsules; those weighing 32 to < 40 kg received 108 mg granules; those weighing 24 to < 32 kg received 96 mg granules; and those weighing 12 to < 24 kg received 78 mg granules. Each regimen was oral and once daily, for up to 144 weeks. Dose modifications were permitted because of weight changes, pharmacokinetic results, or safety.

The cohort descriptions are dosing categories, not randomized treatment assignments. Because there is no randomized comparator, differences between cohorts cannot be read as causal contrasts between dose levels: the groups are defined by body weight, and the record does not describe them as exchangeable comparison groups. Nor does the design establish a comparison against no prophylaxis or another treatment.

The primary endpoint is a Week 2 pharmacokinetic measure. The registry also lists safety and attack-related outcomes, including treatment-emergent adverse events, adjusted hereditary angioedema attacks and attack symptoms. The registry record does not report a separate statistical analysis plan or explain how the later attack-related outcomes are intended to support dose selection.

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: Participants were enrolled into a 12-week standard of care (SOC) period prior to initiating berotralstat. Participants were assigned to one of 4 cohorts based on body weight. Results contained herein are based on an interim analysis with data cutoff date of 11 September 2024 which was determined by the protocol defined event.

Pre-treatment SOC Period (12 Weeks)

Treatment Period-Part 1 (Weeks 1-12)

Treatment Period-Part 2 (Weeks 13-48)

Reasons for not completing this period:

Treatment Period-Part 3 (Weeks 49-144)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) population included participants in the safety population with at least 1 evaluable and quantifiable post dose PK sample obtained. Number of participants analyzed refers to the participants who were evaluable for this outcome measure. Per protocol, fewer serial PK samples were drawn in Cohort 4 participants to remain within acceptable ranges of blood draw volumes; hence, Cohort 4 participants were not included in the analysis of this PK parameter.

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: Safety population included all participants who received at least 1 dose of berotralstat.

6. Primary Endpoint

The registry lists the primary outcome as Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUC0-last) of Berotralstat, measured over Week 2.

The primary endpoint is the area under the plasma concentration-time curve from time 0 to the last measurable concentration (AUC0-last) of berotralstat, assessed at Week 2. It represents the area beneath a plot of measured plasma concentration against time, ending at the last concentration that can be measured. In general, an area-under-the-curve measure is used to describe drug exposure over a specified sampling interval; it is not itself a count of attacks or a direct measure of symptom change.

The registry specifies a geometric mean and geometric coefficient of variation for this endpoint, with units of nanogram* hour per milliliter (ng*h/mL). A geometric mean is a summary suited to measurements that are interpreted multiplicatively or are right-skewed; the geometric coefficient of variation describes relative spread on a multiplicative scale. These are general statistical interpretations of the chosen summaries, not additional findings about this study.

The record gives the endpoint definition, timeframe, unit, and summary approach, but does not report an AUC0-last estimate or its geometric coefficient of variation. It therefore does not permit readers to assess the observed exposure level or the precision of that estimate. The registry describes the pharmacokinetic population as safety-population participants with at least 1 evaluable and quantifiable post-dose pharmacokinetic sample; the number analyzed for this endpoint is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does AUC0-last measure?

AUC0-last is an exposure summary. Concentration measurements are considered over time, and the area under their concentration-time curve is calculated through the last measurable observation. In general, this compresses a series of measurements into a summary of exposure across the observed interval. It does not describe every concentration at every time, and it is not equivalent to a clinical outcome such as an attack count. The registry defines the endpoint and states that it is assessed at Week 2, but does not report the resulting estimate.

Why report a geometric mean?

The registry specifies a geometric mean for AUC0-last. In general, geometric summaries are useful when the scientific interpretation is multiplicative, or when values are positively skewed and a few large observations could pull an arithmetic mean upward. The geometric coefficient of variation is a measure of relative variability associated with a geometric summary. It should not be confused with a standard deviation or with a confidence interval. The registry record does not report the geometric coefficient of variation for the primary endpoint, so the degree of observed relative variability is unknown from this record.

What would a confidence interval add?

In general, a confidence interval expresses uncertainty around an estimated quantity under the assumptions of the analysis. Its width reflects both the observed data and the method used to estimate uncertainty. A confidence interval would help readers judge how precisely the mean exposure was estimated; it would not, by itself, show that a particular exposure level is clinically beneficial or establish a causal treatment effect. No confidence interval for AUC0-last is reported in the registry record.

How should the cohort structure be understood?

The study is identified as non-randomized, unmasked, and single-group. The four cohorts are defined by body-weight ranges and corresponding berotralstat regimens. They are not randomized arms. In general, randomization helps balance measured and unmeasured characteristics across comparison groups, whereas a cohort structure based on participant characteristics can retain differences that affect outcomes. Here, weight is part of the cohort definition, and the registry permits dose modifications for weight changes, pharmacokinetic results, or safety. The cohort listings therefore describe treatment experience within dosing categories; they do not provide a like-for-like estimate of what would have happened under a different dose.

For a non-randomized study, descriptive estimates can still characterize measured drug exposure and observed safety events. Interpretation depends on knowing which participants contributed data, when measurements were taken, and how incomplete observations were handled. The registry provides a definition of the pharmacokinetic population: participants in the safety population with at least 1 evaluable and quantifiable post-dose pharmacokinetic sample. It does not report the number analyzed for AUC0-last or detail the handling of missing or unevaluable samples.

What do the adverse-event counts convey?

Counts of participants with events are descriptive safety summaries. In general, a count depends on the population observed and the period of observation; counts alone do not convey exposure time, event severity beyond the listed classification, or the probability of an event under a controlled comparison. The registry separates serious events from other adverse events and lists pre-treatment and treatment-cohort periods. Those periods and cohort sizes should be kept distinct when reading the counts. A zero in a group means no event was listed for that group; it does not establish that the underlying risk is zero.

The record lists serious-event terms of Accident and Upper limb fracture, each with 14.3%. It does not explain the denominator or provide enough context in the listed terms to reinterpret these percentages as rates or comparative risks. The group-level counts remain the clearest way to read the serious-event entries. No deaths are listed for the reported groups.

What do the planning assumptions mean?

The registry record includes assumptions for planning illustrations based on an observed effect: a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It says that the effect to detect is a stated fraction of the observed effect, and that time-to-event illustrations use a total event count under the Schoenfeld approach while other illustrations give participants per arm. Such calculations are planning illustrations, not evidence that the trial had a particular probability of detecting an effect. They are not observed power, and the record does not present an analysis comparing randomized arms in this single-group, non-randomized study.

In general, a planning calculation depends on assumptions about the target effect, variability, allocation, analysis method, and error rate. Changing those assumptions changes the planning result. The registry’s assumptions do not substitute for the study’s own design justification or statistical analysis plan. The sample-size justification and the trial’s own statistical plan are not reported in the registry record.

The registry lists 18 outcome measures and 0 analysis records. That distinction matters: listing outcomes describes what the study intended to assess, while analysis records would give details of statistical methods and results. The absence of analysis records leaves uncertainty about estimation methods beyond the summary specified for the primary endpoint, adjustment for repeated or multiple outcomes, and the handling of incomplete data.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 18 outcome measures, including the primary pharmacokinetic endpoint and secondary safety and hereditary angioedema outcomes. It does not report a multiplicity strategy. When a study assesses multiple outcomes, testing each one can increase the chance of at least one apparently notable result arising by chance; general approaches include prespecifying a primary outcome, controlling an overall error rate, or treating secondary results as exploratory. Which approach was planned or used is not reported in the registry record.

The registry has 0 analysis records. It therefore does not give a statistical analysis plan describing tests, confidence intervals, model choices, covariate handling, or any adjustment for multiple outcomes. The primary endpoint’s geometric-mean summary is specified, but its estimate and uncertainty are not reported. No separate inferential analysis for the secondary outcomes is described.

Missing-data handling is also not reported in the registry record. The pharmacokinetic population requires at least 1 evaluable and quantifiable post-dose sample, but the number meeting that criterion and the treatment of participants without evaluable measurements are not stated. The record does not explain how missing attack diaries, incomplete follow-up, or other unavailable outcome data were handled. Enrollment should therefore not be assumed to equal the analysis population for every outcome.

These omissions limit assessment of whether the reported or planned analyses preserve the intended interpretation of each outcome. They do not establish that missing data or multiplicity were mishandled; rather, the registry record does not provide the information needed to assess those methods.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

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: accident (14.3%), upper limb fracture (14.3%).

The registry separates serious adverse events from other adverse events and reports a pre-treatment period separately from the treatment cohorts. In the pre-treatment period, 0 serious adverse events are listed among 29 participants at risk, while 18 participants are listed with other adverse events. During treatment, the highest-weight cohort has 1 serious adverse event among 7 participants at risk and 6 with other adverse events. The 32 to < 40 kg cohort has 0 serious events among 9 at risk and 7 with other adverse events; the 24 to < 32 kg cohort has 0 serious events among 9 at risk and 9 with other adverse events; and the 12 to < 24 kg cohort has 0 serious events among 4 at risk and 3 with other adverse events. No deaths are listed.

These are participant counts, not rates adjusted for time at risk. The treatment duration could be up to 144 weeks, but the registry does not provide person-time or a detailed account of each participant’s observation period. The cohort counts should not be combined into an overall treatment rate or compared as though the cohorts were randomized. Their weight-defined membership and differing cohort sizes limit direct comparisons.

The registry lists Accident and Upper limb fracture among the top serious-event terms, each at 14.3%. That listing does not establish a causal relationship to berotralstat. The counts describe what the safety record lists; they do not establish comparative safety or rule out events not observed in the recorded groups.

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

This study addresses a pharmacokinetic and safety question for berotralstat prophylaxis in children with hereditary angioedema aged 2 to < 12 years. The registry identifies the intended primary measure as Week 2 AUC0-last and specifies a geometric-mean summary with geometric coefficient of variation. It also describes weight-based dose cohorts and lists attack-related secondary outcomes.

The registry record does not report the primary endpoint estimate, its variability, or a confidence interval. It therefore cannot show the observed drug exposure or how precisely it was estimated. The listed secondary outcomes are not accompanied by results or analysis details in the record. The design and outcome definitions alone do not establish a clinical effect.

The study is non-randomized, unmasked, and single-group. The body-weight cohorts are dosing categories, not randomized controls. Accordingly, the cohort listings do not provide a controlled comparison of one regimen against another, and safety counts should be read descriptively. They cannot establish that berotralstat caused or prevented any listed event.

The record also does not provide the number analyzed for the primary endpoint, the approach to missing data, the multiplicity strategy, or the trial’s statistical analysis plan. Those omissions leave important uncertainty about the precision and interpretation of any outcome analysis. The planning assumptions in the registry describe illustrations based on an observed effect; they are not observed power and are not evidence of a treatment effect.

In short, the record documents the design, weight-based regimens, intended pharmacokinetic endpoint, and selected safety counts. It does not report the primary result or provide enough comparative evidence to draw conclusions about effectiveness or comparative safety.

13. Why This Trial Matters Statistically

Pharmacokinetic studies in children can characterize drug exposure across a population for which dosing is organized by body weight. This study records four weight-based berotralstat regimens and identifies a Week 2 AUC0-last measure as its primary endpoint. Statistically, the endpoint is distinct from the attack-related outcomes: it summarizes measured plasma exposure, while the secondary outcomes concern attacks, symptoms, treatment of attacks, and adverse events.

The cohort structure also makes the distinction between description and comparison especially important. Weight defines the cohorts, and dose modifications were permitted for weight changes, pharmacokinetic results, or safety. A statistical summary within a cohort can describe the observations in that group, but it cannot alone estimate what the same participants would have experienced under another regimen. The non-randomized, single-group design therefore sets limits on causal interpretation.

The registry lists 18 outcome measures, but 0 analysis records. That contrast highlights a general lesson in trial reporting: an outcome list tells readers what was intended to be measured, while analysis results and methods are needed to judge the estimates, uncertainty, and handling of incomplete observations. The absence of the primary estimate is particularly consequential because the endpoint is the stated pharmacokinetic focus.

The posted safety counts provide a descriptive record, but without detailed time-at-risk information or a randomized comparator they cannot be converted into a controlled safety comparison. The record’s planning assumptions likewise should not be mistaken for observed evidence. Together, these features make careful separation of the study’s aims, its design, and its reported findings essential when interpreting pediatric pharmacokinetic research.

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 most important limitation for interpretation is that the registry record does not report the primary AUC0-last result. It also does not report the geometric coefficient of variation or a confidence interval, so readers cannot assess the magnitude or precision of the primary estimate. The number analyzed for this endpoint is not reported in the registry record.

The design is non-randomized, unmasked, and single-group. The weight-based cohorts are not like-for-like controls, and body weight determines cohort membership. Dose modifications were permitted because of weight changes, pharmacokinetic results, or safety. These features prevent simple causal comparisons between cohort outcomes or regimens.

The registry lists safety counts, but does not provide person-time or a detailed account of the observation duration for each participant. Treatment was described as lasting up to 144 weeks, which does not establish that every participant was observed for that duration. The listed counts therefore should not be treated as time-adjusted rates.

Although the record names attack-related secondary outcomes, their results and analysis details are not reported. The statistical analysis plan, missing-data methods, and multiplicity approach are also not reported in the registry record. Enrollment of 29 should not be interpreted as the analyzed population for every endpoint. These reporting gaps limit assessment of completeness, precision, and the intended inferential framework without establishing that the study’s conduct or analyses were deficient.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Berotralstat Treatment in Children With Hereditary Angioedema — NCT05453968.
• Registry record last updated 2026-02-25; status last verified 2026-02.
• Results first posted 2026-02-25.
• 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.

18. Record Summary

The registry describes NCT05453968, a Phase 3 study sponsored by BioCryst Pharmaceuticals, evaluating berotralstat prophylaxis in children with hereditary angioedema aged 2 to < 12 years. It is listed as non-randomized, unmasked, and single-group, with enrollment of 29 and status active, not recruiting.

Four oral, once-daily regimens are defined by body-weight cohort, with dose modifications permitted for weight changes, pharmacokinetic results, or safety. The primary endpoint is Week 2 AUC0-last, summarized as a geometric mean with geometric coefficient of variation. The record also lists safety and attack-related outcomes.

The primary endpoint result, its uncertainty, and analysis details are not reported in the registry record. Safety counts are descriptive and do not constitute a randomized comparison.