Study of C1 Inhibitor (Human) for the Prevention of Angioedema Attacks and Treatment of Breakthrough Attacks in Japanese Subjects With Hereditary Angioedema (HAE): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of C1 Inhibitor (Human) for the Prevention of Angioedema Attacks and Treatment of Breakthrough Attacks in Japanese Subjects With Hereditary Angioedema (HAE) (NCT02865720), a non-randomized phase 3 study. The primary outcome is Number of Participants With Treatment-emergent Adverse Events (TEAEs).

2. Clinical Question

3. Trial Design

This was a Phase 3, open-label, single-period study with a parallel model and non-randomized allocation. The registry lists CINRYZE 500 U and CINRYZE 1000 U as drug interventions. Its arm descriptions assign 500 U by intravenous infusion twice weekly for 12 weeks to participants 2 to 5 years of age, and 1000 U by intravenous infusion twice weekly for 12 weeks to participants 6 years of age and older.

Eight participants were enrolled. The registry record gives a study start date of 2016-09-08, a primary completion date of 2017-06-23, and a status of completed. The intervention descriptions and age-based dosing are part of the record; the number of participants in each age or dose group is not reported in the registry record.

Open-label means participants and study personnel were not masked to treatment assignment, as reflected in the record’s masking information. Non-randomized allocation means the registry does not describe chance assignment to the dose groups. The groups therefore should not be treated as interchangeable comparison groups: age and other differences could be associated with dose assignment as well as with observed outcomes. The record itself flags that the arms are not a like-for-like control comparison.

The study’s stated purpose was to determine whether intravenous investigational treatment was safe and well tolerated in Japanese participants with HAE, including prevention of attacks and treatment of breakthrough attacks. The primary endpoint listed in the registry concerns TEAEs. The registry lists 20 outcome measures, but the analysis count is 0. A detailed protocol, statistical analysis plan, sample-size justification, and account of interim analyses 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 participants were screened and enrolled. Investigational product administrations were planned according to participants' age; 500 units (U) for participants 2 to 5 years and 1000 U for participants 6 years and older. However, as no participants under the age of 6 years were enrolled, only the higher dose of 1000 U was administered.

Overall Study

Analysis population for the primary outcome, as defined in the registry: ITT-S set included participants who received any amount of investigational product.

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: Intent-to-treat safety (ITT-S) set included participants who received any amount of investigational product.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment-emergent Adverse Events (TEAEs), measured over From start of study drug administration up to Week 12.

The primary endpoint is the number of participants with treatment-emergent adverse events (TEAEs), reported as a participant count. It covers the period from the start of study drug administration up to Week 12. The registry defines a TEAE as an adverse event that began during treatment and up to 7 days after the last dose, or an event present at baseline that worsened in frequency or severity during that period. An adverse event is an untoward medical occurrence after administration of an investigational product and need not have a causal relationship with treatment.

Counting participants with at least one event is a way to summarize how many people experienced an event, rather than how many event episodes occurred. This can make a safety summary easier to interpret at the participant level, but it does not describe event duration, recurrence, severity, or causal attribution by itself. Those details require separate results.

The endpoint is relevant to the stated safety and tolerability purpose of the study. However, the numerical result for the primary endpoint is not reported in the registry record. The posted record therefore does not show how many participants met this endpoint, nor does it provide an estimate with which to assess its precision.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry presents a participant-count endpoint: the number of participants with TEAEs. A participant-count outcome records whether a participant experienced the defined event or events during the endpoint period. It is distinct from a count of every event episode, because one participant may experience more than one event while still contributing once to a count of participants affected. The primary outcome description does not give the observed count in the registry record.

What does an adverse-event count describe?

As a general statistical explanation, an adverse-event count is descriptive unless the analysis also specifies a comparison and a method for estimating uncertainty. A count can summarize what was observed in the study group, but it does not by itself establish whether an event was caused by treatment. Here, the registry’s definition says an adverse event does not necessarily have a causal relationship with treatment. Causal attribution requires clinical and design information beyond a simple count.

The TEAE window includes events that start during treatment and up to 7 days after the last dose, as well as events present at baseline that worsen in frequency or severity during that window. This definition makes the outcome dependent on both the event criteria and the period of observation. It also means that the primary endpoint should not be casually equated with every adverse event occurring at any time. The record specifies the timeframe as from the start of study drug administration up to Week 12, while the event definition includes the stated post-dose window.

Why does the study design matter?

As a general statistical point, random allocation helps make treatment groups comparable on average, including on characteristics that are not measured. This study used non-randomized allocation, with dose descriptions tied to age. The registry expressly cautions that the arms are not a like-for-like control comparison. Thus, a difference between groups, if one were reported, could reflect differences in age or other characteristics rather than a dose effect alone. The record does not provide a randomized estimate of a treatment contrast.

Open-label status is also relevant to interpretation. As a general consideration, knowledge of treatment assignment can affect reporting, observation, and assessment of events, especially when outcomes involve judgment. This does not demonstrate that reporting was biased in this study; it identifies a potential source of uncertainty in an unmasked design. The registry does not report any blinding procedures.

How should precision be understood?

As a general statistical explanation, a confidence interval summarizes the uncertainty around an estimated effect or rate under the analysis assumptions. A wider interval indicates less precision, while a narrower interval indicates more precision. The registry record does not report a primary endpoint estimate or a confidence interval, so precision for that endpoint cannot be assessed from the posted record. The enrollment of 8 also means the study can contribute only limited information about less common outcomes.

The calculated sample-size section is a planning illustration, not a report of what the study was designed to detect. Its stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; it uses a stated fraction of the observed effect. These assumptions do not convert the illustration into the study’s original design rationale. The sample-size justification is not reported in the registry record. Such calculations are planning tools and should not be described as observed power or as evidence that the study could or could not detect a particular result.

What can be inferred from the posted safety summaries?

The serious-event figures and other adverse-event figures are descriptive summaries for the listed group. A participant may appear in more than one event category, and event categories can overlap; therefore, separate counts should not be added together as if they necessarily represented distinct participants. As a general point, percentages and counts from a small group can change substantially with only a few participants, so they should not be treated as stable estimates of risk. The posted figures do not substitute for the missing numerical result for the primary TEAE endpoint.

The registry lists 20 outcome measures and 0 analyses. The statistical analysis plan, choice of inferential methods, handling of missing data, and any multiplicity procedure are not reported in the registry record. Without those details and the endpoint results, readers cannot assess whether analyses were adjusted, how incomplete observations were treated, or whether reported estimates correspond to prespecified methods.

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("CINRYZE 1000 U")
n      <- c(8)
events <- c(7)
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  CINRYZE 1000 U  8  7  87.5  47.3  99.7  52.9  97.8  51.8  97.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 20 outcome measures and 0 analyses. It does not report a statistical analysis plan describing which outcomes were confirmatory, how outcomes were prioritized, or whether any adjustment was planned for examining multiple outcomes. A multiplicity procedure is not reported in the registry record.

As a general statistical explanation, considering many outcomes can increase the chance of finding an apparently notable result by chance if each is tested separately. How much that matters depends on the planned analyses and their interpretation. The registry’s outcome count alone is not enough to determine which results were tested, whether tests were conducted, or how any findings should be adjusted. No such details are reported in the registry record.

The handling of missing outcome data, withdrawals, and incomplete follow-up is not reported in the registry record. The primary population is described as the ITT-S set, including participants who received any amount of investigational product. The record does not provide further details about population definitions for other analyses or how participants with missing endpoint information were handled.

Because the primary endpoint’s numerical result is not reported, it is not possible to assess the endpoint denominator, completeness of follow-up, or the relationship between missing observations and the reported safety figures. A documented analysis plan would be needed to evaluate these choices; it is not reported in the registry record.

12. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hereditary angioedema (12.5%), acute myocardial infarction (12.5%).

For the CINRYZE 1000 U group, the registry records 8 participants at risk for serious adverse events and 2 affected. It records 8 at risk in the other adverse-event category and 7 affected, with deaths recorded as 0. The record lists Hereditary angioedema and Acute myocardial infarction as top serious adverse-event terms, each reported as 12.5%.

These are descriptive safety entries. The serious-event terms do not, on their own, show that treatment caused the events: the registry defines adverse events as not necessarily causally related to treatment. The posted information does not describe the event timing, participant circumstances, severity details beyond the serious-event classification, or the basis for attribution. The primary endpoint result for TEAEs is not reported in the registry record, so these figures should not be treated as a substitute for that endpoint.

As a general statistical point, participants can experience more than one type of event, so separate categories need not represent different people. The small group also limits precision. The recorded figures describe this study group and should not be read as stable estimates of event frequency beyond it.

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

This record describes a small, open-label, non-randomized Phase 3 study of intravenous CINRYZE in Japanese participants with HAE. It documents age-based dose regimens and a safety-focused primary endpoint: the number of participants with TEAEs during the stated study period. The posted safety figures provide limited descriptive information for the CINRYZE 1000 U group, including serious-event and other adverse-event counts, the listed serious-event terms, and a death count of 0.

The record does not report the numerical result for the primary endpoint. It therefore does not allow readers to state how many participants experienced a TEAE according to that endpoint definition, or to quantify the uncertainty around such a result. The registry also does not report comparative estimates or confidence intervals. Any tables or plots on the page should be read alongside this limitation: visual presentation cannot replace a missing result or create a randomized comparison.

The design does not establish a like-for-like comparison between the dose groups. Since allocation was non-randomized and the regimens are described by age, differences between groups cannot be attributed to dose alone. Nor do descriptive adverse-event entries prove causation. The registry does not report a sample-size justification, a detailed analysis plan, or how missing data and multiplicity were handled.

These findings should therefore be understood as a limited registry account of study design and selected safety information, not as a definitive comparative assessment. The available record does not establish a treatment effect on attacks or provide enough information to make a broad claim about safety. It also does not establish that an event would or would not occur outside the observed study group. The distinction is between what was recorded and what the design and posted results can support.

14. Why This Trial Matters Statistically

This study illustrates why design features matter as much as outcome labels. A participant-count safety endpoint can be straightforward to describe, but its interpretation depends on a clear event definition, a stated observation period, complete results, and a design appropriate to the question. The registry defines TEAEs and their timeframe, yet does not report the numerical primary endpoint result. That gap limits even a basic description of the main outcome.

The non-randomized, open-label structure also shapes what can be learned. The dose regimens are described for different age groups, and the registry cautions that the arms are not like-for-like controls. A comparison across these groups would mix dose differences with potential differences between participants. This is an important distinction for clinical researchers: a two-arm layout does not automatically make a study a controlled comparison.

The enrollment of 8 places the safety summaries in a small-study context. Counts are useful for documenting what occurred in the study, but they offer limited precision and little information about uncommon events. Clear reporting of denominators, endpoint results, analysis populations, and uncertainty is especially important in such a study.

Finally, the record lists 20 outcome measures but 0 analyses. Without a reported analysis plan or outcome estimates, readers cannot evaluate multiplicity, missing-data handling, or the intended inferential framework. The sample-size illustrations are planning calculations under stated assumptions, not evidence about the study’s original planning or observed statistical power. Together, these features show why registry results must be interpreted according to both the design and the information actually posted.

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 most direct limitation is that the numerical result for the primary TEAE endpoint is not reported in the registry record. This prevents a complete account of the outcome the study identifies as primary. The record also does not report an estimate of uncertainty for that endpoint.

Only 8 participants were enrolled, limiting the amount of safety information available and the precision of event summaries. The registry’s listed adverse-event figures cover the CINRYZE 1000 U group; a comparable numerical safety summary for the 500 U group is not reported in the registry record. The record does not give the number enrolled in each dose or age group, so group-level denominators beyond the posted entries cannot be characterized.

Allocation was non-randomized, masking was absent, and the dose descriptions are age-based. These features limit the interpretation of between-group differences and allow possible influences from participant characteristics and unmasked assessment. The registry itself notes that the arms are not a like-for-like control comparison. There is no randomized control contrast described in the record.

Further limitations include the absence of a reported statistical analysis plan, sample-size justification, interim-analysis information, multiplicity procedure, and missing-data approach. The record lists 20 outcome measures and 0 analyses, leaving the analysis framework unclear. The posted safety terms do not include enough context to assess timing or causal attribution. These limitations concern the available registry record; details beyond it are not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of C1 Inhibitor (Human) for the Prevention of Angioedema Attacks and Treatment of Breakthrough Attacks in Japanese Subjects With Hereditary Angioedema (HAE) — NCT02865720.
• Registry record last updated 2021-06-02; status last verified 2021-05.
• Results first posted 2018-12-31.
• 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

The registry describes a completed Phase 3, open-label, single-period, parallel study with non-randomized allocation. It enrolled 8 Japanese participants with hereditary angioedema and evaluated intravenous CINRYZE, with regimens described by age: 500 U twice weekly for 12 weeks for participants 2 to 5 years of age, and 1000 U twice weekly for 12 weeks for participants 6 years of age and older.

The primary endpoint was the number of participants with TEAEs from the start of study drug administration up to Week 12. Its numerical result is not reported in the registry record. The record includes selected safety figures for the 1000 U group and lists 20 outcome measures and 0 analyses. It cautions that the arms are not a like-for-like control comparison. A sample-size justification, detailed statistical plan, missing-data approach, and multiplicity procedure are not reported in the registry record.