A Study of Icatibant for Acute Attacks of Hereditary Angioedema in Japanese Participants: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Icatibant for Acute Attacks of Hereditary Angioedema in Japanese Participants (NCT03888755), a na phase 3 study. The primary outcome is Time to Onset of Symptom Relief (TOSR).

2. Clinical Question

The study objective also included evaluation of pharmacokinetics and safety. Listed secondary outcomes cover symptom scores, investigator and participant assessments, and additional measures of symptom improvement or relief. The registry lists 18 outcome measures, but does not report analysis results for them. Consequently, the clinical question can be described from the planned measures, but the posted registry information does not establish the observed timing or degree of symptom change.

3. Trial Design

This was a Phase 3, open-label study of icatibant in Japanese participants with acute attacks of HAE. The registry records a single-group model, no masking, and allocation as NA. It lists Shire as the sponsor and the study status as completed. The recorded study start date is 2015-03-18, and the primary completion date is 2016-02-12.

The registry lists enrollment of 8. That figure is not necessarily the number treated or the number included in each endpoint analysis: the primary endpoint population is described as all participants treated with icatibant, and the number treated is not separately reported in the registry record. The arm description allows treatment with a 30 milligram subcutaneous injection, with up to 3 injections, or 90 mg, at least 6 hours apart. Because the arm description is truncated, the stated condition for possible additional injections cannot be fully assessed.

There was no concurrent comparator arm, so the design does not support a randomized between-group treatment contrast. Open-label status means the study description does not include masking of participants or investigators. The record does not report whether any outcome assessment procedures were independently blinded or whether other steps were used to limit assessment bias.

The primary outcome was time to onset of symptom relief, expressed in hours and summarized by a median with a 95% confidence interval. The endpoint was followed from baseline up to 120 hours post-treatment. The registry record does not report the primary endpoint's numerical result, a participant flow accounting, or the number contributing to the primary analysis. A statistical analysis plan and sample-size justification are not reported in the registry record.

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: A total of 8 Japanese participants were enrolled and included in the study treatment.

Overall Study

Analysis population for the primary outcome, as defined in the registry: The treated population included all participants treated with icatibant

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: The treated population included all participants treated with icatibant.

6. Primary Endpoint

The registry lists the primary outcome as Time to Onset of Symptom Relief (TOSR), measured over Baseline up to 120 hours post-treatment.

The primary endpoint, time to onset of symptom relief (TOSR), measures elapsed time from treatment until a specified reduction in symptoms. Relief was defined as a 50 percent reduction from the pretreatment score in the composite VAS: a 3-symptom score for non-laryngeal attacks and a 5-symptom score for laryngeal attacks. The described symptom components include skin swelling, skin pain, and abdominal pain; the laryngeal composite also includes difficulty swallowing and voice change.

Each VAS is described as a 100 millimeter horizontal line anchored by no symptom and worst possible symptom. The composite score averages the relevant symptom VAS measurements. A time-to-event endpoint retains information about when a defined symptom threshold is reached, rather than reducing the outcome to a score at only one follow-up time. In general, this kind of measure is useful when the timing of improvement is clinically and analytically relevant, but its interpretation depends on a clear threshold, adequate follow-up, and transparent handling of participants who do not reach the threshold during observation.

The registry specifies assessment from baseline up to 120 hours post-treatment and reports the intended summary as a median with a 95% confidence interval. The median and its interval are not reported in the registry record. Nor does the record provide the number of participants reaching the relief threshold or details about handling observations without a recorded event.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The methods described in the registry record establish the intended endpoint and summary format, but do not provide enough information to reconstruct the analysis. The following explains the statistical ideas relevant to the design and endpoint in general, while distinguishing them from methods specifically documented for this study.

What does a median time-to-event result mean?

In general, a time-to-event endpoint records the time until a defined event occurs. Here, the event is reaching the specified reduction in composite VAS score. The median is the time by which half of the analyzed participants have experienced the defined event, when the data and analysis allow that median to be estimated. A median can be less influenced by unusually long times than a mean, but it does not describe every participant's experience or the full shape of the time distribution.

The registry identifies the median as the intended summary, but does not report its value. It also does not state the number of participants who reached the threshold, whether any participants had no recorded relief by the end of follow-up, or how such observations were handled. Without those details, the time-to-event calculation cannot be independently understood from the registry record.

What does the confidence interval add?

In general, a confidence interval communicates uncertainty around an estimated quantity. A narrower interval indicates greater statistical precision under the assumptions of the analysis; a wider interval indicates less precision. It is not a range guaranteed to contain the true value for an individual participant, and it does not measure clinical importance. The registry specifies a 95% confidence interval for the median TOSR but does not report its limits. Precision therefore cannot be evaluated from the posted information.

Why does the endpoint definition matter?

A time-to-relief result depends on the event rule. The registry defines relief as a 50 percent reduction from the pretreatment composite VAS score and describes separate symptom composites for non-laryngeal and laryngeal attacks. A threshold based on a change from baseline can depend on the baseline score, and a composite score can conceal differing patterns among its individual symptoms. These are general considerations; the record does not report baseline score distributions or symptom-level results that would show how they affected this study.

The VAS description gives endpoints of no symptom and worst possible symptom on a 100 millimeter line. The composite is an average of the relevant symptom measurements. In general, averaging several symptom ratings creates a single measure that may be easier to summarize, but it can obscure whether the component symptoms changed similarly. The registry does not report component-specific primary outcome results.

What can an uncontrolled design estimate?

A single-group study can describe outcomes observed among participants receiving the intervention, subject to the completeness and quality of measurement. In general, it cannot by itself estimate what would have happened to comparable participants under a different treatment or no treatment. A randomized comparator helps distinguish treatment-associated changes from time trends and other influences. Since this study has no separate control group, a causal contrast is not reported.

Open-label status means treatment assignment was not masked according to the registry. For a participant-reported symptom scale, expectations and awareness may affect reported scores in general. That possibility does not demonstrate bias in this study; the registry does not report whether additional procedures were used to reduce it.

What statistical plan is documented?

The registry gives the endpoint, unit, summary measure, confidence-interval level, and follow-up window. It does not report a full statistical analysis plan, a model for the time-to-event data, assumptions used to estimate the median, or procedures for censoring and missing observations. The number of posted analyses is 0. Accordingly, these methods should not be inferred from the endpoint description alone.

The record also does not report interim analyses, subgroup analysis plans, or a sample-size justification. These omissions matter because analysis choices can affect how an estimate is calculated and how uncertainty is quantified. The registry's description of the treated population does not substitute for a full account of who was included in each analysis.

How should planning illustrations be read?

In general, a sample-size calculation is a planning exercise based on assumptions about the effect to detect, variability, significance level, allocation, and analysis method. The registry's planning note describes an illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It says time-to-event illustrations use a total event count and other illustrations use participants per arm. These are planning assumptions, not features of this single-group trial's observed analysis.

Such illustrations are not observed power and do not show that a result is statistically convincing. The record does not state that these assumptions were the trial's design assumptions, and the primary outcome estimate needed to assess an illustration based on an observed effect is not reported in the registry record. No planning count or result should therefore be treated as an observed trial finding.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 18 outcome measures, including the primary TOSR endpoint and secondary measures of symptom relief, symptom scores, and global assessment. It also reports 0 analyses. A list of multiple outcomes raises a general multiplicity question: when many hypotheses are tested, the chance of at least one apparently notable result can increase unless the analysis plan accounts for that issue. The registry record does not report whether any multiplicity adjustment or hierarchy of testing was planned.

Missing-data methods are also not reported. For the primary time-to-event endpoint, relevant details would include what happened when symptom assessments were absent, when a participant did not reach the relief threshold during follow-up, or when follow-up ended before the event could be observed. These are general considerations, not evidence that any such circumstances occurred. The record does not provide participant-level completeness, reasons for missing observations, or sensitivity analyses.

The primary endpoint population is described as all participants treated with icatibant. The registry lists enrollment of 8, but does not report the number treated, the number included in each outcome analysis, or whether an additional analysis population was used. A full account of analysis populations and exclusions is not reported in the registry record.

The record does not describe interim analyses, a prespecified statistical analysis plan, or how outcome reporting was prioritized. These absences limit assessment of whether the reported endpoint definitions and analysis choices were set before results were known. Since no endpoint analyses are posted, it is not possible to assess multiplicity adjustments, missing-data handling, or analysis-population choices from results.

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 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports safety counts for the icatibant group. It lists 8 participants at risk for serious adverse events and 0 affected, and 8 at risk for other adverse events and 3 affected. Deaths are reported as 0. No serious adverse-event terms are listed.

These are counts recorded for the study, not comparative risk estimates. The trial has no separate control group, so the counts cannot show whether event occurrence differed from what would have been observed under another treatment or condition. The record does not provide event descriptions for the other adverse-event category, timing, severity, duration, or participant-level detail. It also does not report whether the other adverse-event count includes events of particular types or how events were attributed.

In general, a zero count in a small study does not establish that an event cannot occur; it means no affected participants were recorded in that category in this registry entry. Conversely, a count in the other adverse-event category does not alone establish seriousness, causation, or a rate applicable to a wider population. The safety figures should be read as limited descriptive information from the registry record.

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

The record establishes that a Phase 3, open-label, single-group study was conducted to evaluate icatibant for acute attacks of HAE in Japanese participants. It defines the primary endpoint as time to a prespecified reduction in composite VAS score and identifies the intended summary as a median with a 95% confidence interval. It also reports a limited set of safety counts.

The record does not report the primary endpoint estimate, the confidence interval limits, or numerical results for the listed secondary outcomes. It therefore cannot establish from the posted results how long participants took to meet the symptom-relief threshold, how variable those times were, or whether the outcome differed between treatment conditions. No such comparison was included in the single-group design.

In general, a defined endpoint and a completed study do not by themselves supply evidence about the size or precision of an observed effect. Those interpretations require results, the number analyzed, and a description of the statistical methods. Here, the registry reports 0 analyses and does not provide the outcome estimates needed for that evaluation.

The safety counts indicate that 0 participants were recorded as affected by serious adverse events, 3 were recorded in the other adverse-event category, and deaths were 0. Those observations are descriptive and do not establish comparative safety or causation. The registry does not report event-level details that would clarify the other adverse-event entries.

Thus, the record is informative about the study question, intervention description, endpoint definition, design, and selected safety counts. It is not sufficient to judge the magnitude or precision of symptom relief, to compare icatibant with another treatment, or to draw a general conclusion about treatment effects. Such claims would go beyond the results reported in the registry record.

13. Why This Trial Matters Statistically

This trial is statistically notable for the contrast between a well-defined time-to-event endpoint and the absence of a posted endpoint estimate. The registry specifies what counted as symptom relief, identifies the symptom composites, gives the follow-up window, and names the intended summary and uncertainty measure. These details clarify the question the analysis was meant to answer, but they cannot substitute for the median and confidence interval themselves.

The single-group design also illustrates a distinction between describing outcomes and estimating comparative effects. A single-group study can record what happened after treatment among treated participants. In general, a control group is needed to support a direct estimate of how outcomes differ under alternative conditions, especially when the outcome may change over time. Without that comparison, observed changes cannot be separated from other possible influences using the trial design alone.

The study's outcome list spans participant-reported symptoms, investigator assessments, and other measures. Multiple outcomes can capture different aspects of a clinical question, but they also make transparent analysis planning important. The registry record does not report a multiplicity strategy, a detailed statistical plan, or analyses for the listed measures. That absence limits the ability to assess how the outcomes were interpreted collectively.

The record also demonstrates why analysis populations and missing-data procedures matter for time-to-event outcomes. A median depends on the event information available and on how observations without a recorded event are handled. The registry describes the treated population but does not report the number analyzed or the handling of incomplete follow-up. These details are necessary for judging both the estimate and its precision.

Finally, safety counts from a study of this size are descriptive, and the absence of a comparator makes them unsuitable for direct comparative claims. The statistical importance of the record lies in defining the intended questions while leaving key estimates and methods unreported.

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 trial-specific limitation is the absence of the primary endpoint result. The registry gives the definition of TOSR and its intended summary but does not report the median or the 95% confidence interval. No primary-outcome estimate can therefore be interpreted from this entry.

The design is single-group and open-label, with no randomized comparator. This prevents a direct between-group estimate and leaves any observed change open to influences that the design cannot separate. Participant-reported VAS scores may also be sensitive to awareness of treatment in general, although the record does not report evidence that this affected the results.

The listed enrollment is 8, while the number treated and the number included in each analysis are not reported. The primary endpoint population is described as all participants treated with icatibant, but participant flow and exclusions are not given. Missing-data handling, censoring rules, baseline score distributions, and the numbers reaching the endpoint are also not reported in the registry record.

The intervention description is truncated after beginning to state the condition for additional injections. Although it specifies a 30 milligram subcutaneous injection and a maximum of 3 injections, or 90 mg, at least 6 hours apart, the complete dosing condition cannot be assessed from the registry text.

Finally, the record does not report a statistical analysis plan, a sample-size justification, interim analyses, multiplicity procedures, or analysis details for the 18 listed outcomes. It reports 0 analyses. These gaps limit assessment of the results and their robustness, beyond the design constraints already described.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study of Icatibant for Acute Attacks of Hereditary Angioedema in Japanese Participants — NCT03888755.
• Registry record last updated 2021-06-03; status last verified 2021-05.
• Results first posted 2019-08-08.
• 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 record describes a completed Phase 3, open-label, single-group study of icatibant for acute attacks of hereditary angioedema in Japanese participants. Enrollment is listed as 8. The primary endpoint is time to onset of symptom relief, defined by a 50 percent reduction in a composite VAS score and intended to be summarized by a median with a 95% confidence interval over baseline up to 120 hours post-treatment.

The primary endpoint result and secondary outcome analyses are not reported in the registry record; the record lists 18 outcome measures and 0 analyses. Safety entries report 0 serious adverse-event cases, 3 participants affected in the other adverse-event category, and 0 deaths. The single-group design does not provide a randomized comparison, and analysis-population, missing-data, and statistical-plan details are not reported.