Postmarketing Immunogenicity Study in HAE Subjects Treated With Berinert: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Postmarketing Immunogenicity Study in HAE Subjects Treated With Berinert (NCT01467947), a na phase 4 study. The primary outcome is Number of Subjects With Inhibitory Anti-C1-esterase-inhibitor Antibodies.

2. Clinical Question

The study asked whether inhibitory anti-C1-esterase-inhibitor antibodies were detected after treatment with Berinert in people with congenital C1-INH deficiency and acute hereditary angioedema attacks. It was a prospective postmarketing investigation, not a comparison of Berinert with another treatment or a control group. The primary outcome was the number of subjects who had no positive baseline result and at least one positive post-baseline result for inhibitory anti-C1-INH antibodies over baseline to approximately 9 months.

The registry record does not report the primary outcome count. As a result, it does not establish how many participants met the antibody endpoint or how precisely that quantity was estimated. The listed secondary outcome concerns subjects with any anti-C1-esterase-inhibitor antibodies, whether inhibitory or non-inhibitory; its result is also not reported in the registry record.

3. Trial Design

NCT01467947 is a completed phase 4 postmarketing study sponsored by CSL Behring. The registry describes it as prospective, international, multicenter, non-randomized, single-arm, and open-label. Enrollment was 46. The recorded start was 2011-11, and primary completion was 2014-10. These registry dates describe the study record; they do not supply participant-level follow-up or outcome timing.

All participants were assigned to the Berinert group; there was no parallel control group. The intervention is described as Berinert lyophilizate for intravenous application, containing 500 IU C1-INH to be reconstituted with 10 mL water for injection. The study description specifies 20 IU Berinert/kg body weight per attack and an individual treatment duration of 9 months, irrespective of the number of treated attacks. These are study-description details, not a report of each participant’s actual dosing or duration.

Open-label means the study did not mask treatment assignment. In a single-group study, the observed outcomes describe participants treated within the study; they do not provide a like-for-like untreated or alternative-treatment comparison. The registry lists the allocation as not applicable and explicitly indicates that the arms are not a comparable control comparison.

The primary outcome was a count of subjects meeting a specified antibody definition, assessed from baseline to approximately 9 months. One secondary outcome is listed, concerning any inhibitory or non-inhibitory anti-C1-esterase-inhibitor antibodies. The registry lists two outcome measures and no analysis records. The protocol’s detailed statistical analysis plan, analysis populations, 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: 60 subjects were screened and enrolled in the study. 14 subjects did not experience an HAE attack before the study ended and so did not receive study treatment. 46 subjects started and completed the active treatment period of the study.

Overall Study

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 Number of Subjects With Inhibitory Anti-C1-esterase-inhibitor Antibodies, measured over Baseline to approximately 9 months.

The primary endpoint is the number of subjects with inhibitory anti-C1-esterase-inhibitor antibodies. The registry defines a qualifying subject as one with no positive baseline result and at least one positive post-baseline result for inhibitory anti-C1-INH antibodies. The stated assessment period runs from baseline to approximately 9 months.

This definition focuses on newly detected positive results after baseline rather than counting a positive baseline result as an endpoint event. That distinction is important for interpreting what the endpoint is intended to capture: the reported count would refer to subjects who meet the study’s specified baseline and follow-up criteria. It would not, by itself, describe the amount of antibody, the timing of a positive result, or the clinical consequences of a result.

A count is a direct way to describe how many participants met a binary criterion. To interpret the count as a frequency in the study population, readers also need an appropriate denominator and information about whether participants had evaluable baseline and follow-up assessments. Those details, along with the primary endpoint result, are not reported in the registry record. The endpoint is therefore defined, but its observed value and precision cannot be evaluated from the registry information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a single-group study with a binary primary outcome recorded as a number of subjects. A binary outcome classifies each assessed subject according to whether the endpoint definition was met. Here, that definition requires no positive baseline result and at least one positive post-baseline result for inhibitory anti-C1-INH antibodies. The registry does not provide the observed endpoint count or an analysis denominator.

What does a count tell the reader?

A count describes the number of subjects meeting an outcome definition. By itself, it does not indicate how common the outcome was among all enrolled participants, because that interpretation depends on the denominator used. The enrollment figure is 46, but the registry record does not report whether all enrolled participants had the required baseline and post-baseline assessments or were included in the primary analysis. It would therefore be inappropriate to assume that enrollment is the endpoint denominator.

For a binary endpoint, an analysis may report a count and a proportion, with an uncertainty interval. General statistical practice treats the interval as a way to communicate precision, subject to the assumptions of the chosen method and the quality of the observed data. The registry record does not report a primary endpoint estimate, proportion, or confidence interval, nor does it state which method would have been used to calculate one.

Why does the single-group design matter?

The study has one treatment group and no like-for-like control group. Its results, if reported, would describe the participants observed under the study conditions. A treatment effect in the comparative sense requires a contrast between groups or conditions. Without a concurrent control, changes over time cannot be separated from other explanations through a randomized comparison. The open-label design also means treatment was not masked, but the registry does not report whether outcome assessment was independently masked.

Randomization is not listed as part of the design; allocation is recorded as not applicable. This is consistent with the registry’s description of a single-arm study. It does not mean that the endpoint itself is randomized or that the observed count is a controlled estimate. No group comparison or analysis is listed in the registry record.

What is the role of the antibody definition?

The baseline condition in the endpoint definition matters because the endpoint is intended to count qualifying post-baseline positive results only among subjects without a positive baseline result. The follow-up condition requires at least one positive post-baseline result. This is a subject-level rule: repeated positive results in one subject would not, under the wording of the endpoint, automatically represent multiple subjects. The registry does not report the number of tests, testing schedule, assay characteristics, or handling of missing antibody assessments. Those details are not reported in the registry record.

How should planning illustrations be read?

Any sample-size illustrations associated with the posted results are planning exercises, not observed power and not evidence about what the trial was designed to detect. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is expressed as a fraction of the observed effect. Those assumptions describe an illustration, whereas this study itself is single-group and has no randomized comparison. A planning calculation cannot substitute for a reported endpoint analysis or establish that the study had a particular probability of detecting an effect.

In general, statistical power is a design concept tied to a specified hypothesis, effect, variability, sample size, and analysis method. Observed power calculated after a study is not a replacement for reporting the estimate and its uncertainty. The registry record does not report a sample-size justification for the trial or a detailed statistical analysis plan. The planning assumptions should therefore be kept separate from the study’s design and from any interpretation of its unreported primary outcome.

Why can over-dispersion matter in general?

Over-dispersion is a general issue for count data when the variability in the observations is greater than a model assumes. If present and ignored, standard errors and uncertainty estimates can be misleading. This study’s primary outcome is registered as a number of subjects meeting a binary definition, not as a repeated-event count. The registry record does not report an over-dispersion assessment or a model for the primary endpoint, so no claim about over-dispersion in this study is supported.

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("C1 Esterase Inhibitor")
n      <- c(46)
events <- c(0)
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  C1 Esterase Inhibitor  46  0  0.0  0.0  7.7  0.0  7.7  0.1  7.5

11. Multiplicity, Missing Data and Analysis Populations

The registry lists two outcome measures: the primary count of subjects with inhibitory anti-C1-esterase-inhibitor antibodies and a secondary count of subjects with any inhibitory or non-inhibitory anti-C1-esterase-inhibitor antibodies. It does not report how multiple outcomes were handled statistically, whether any adjustment for multiple testing was planned, or whether a hierarchy of testing was specified. The multiplicity strategy is not reported in the registry record.

In general, evaluating multiple outcomes can increase the chance of obtaining at least one apparently notable result by chance if each is tested separately. Statistical plans may address this in different ways, but the registry record does not identify a method or provide results that would allow its use to be assessed. No analysis records are listed.

The registry does not describe how missing baseline or post-baseline antibody assessments were handled, whether any participants were excluded from an outcome analysis, or how the analysis population was defined. The enrollment figure of 46 does not establish that all participants contributed data to each outcome. The number of participants with evaluable antibody measurements, reasons for missing data, and any sensitivity analyses are not reported in the registry record. These omissions limit interpretation of the endpoint definition and prevent assessment of whether incomplete follow-up could affect the reported estimate.

Although the study is marked completed, completion status does not resolve missing-data questions or supply a statistical analysis. The record also does not report a protocol-specific approach to interim analyses. No interim-analysis plan should be inferred from the available registry information.

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 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 (2.2%), abortion spontaneous (2.2%).

For the C1 Esterase Inhibitor group, the registry lists 46 participants at risk for serious adverse events and 2 participants with a serious adverse event. It separately lists 46 at risk for other adverse events and 7 participants with other adverse events. These are participant counts, not a comparison between treatment groups; the study has no control arm.

The serious-event terms listed are Hereditary angioedema and Abortion spontaneous, each with a reported value of 2.2%. These term-level entries should be read as registry descriptions, not as evidence that Berinert caused the events. The record does not provide enough detail to determine whether the term entries involve distinct participants or how events were judged related to treatment. Deaths are not reported in the registry record.

Seriousness is a classification of adverse events and should not be confused with treatment causality. The listed counts also do not describe event timing, duration, outcome, or severity beyond the serious-versus-other grouping. The safety entries are descriptive for the participants recorded in this single group; they do not establish comparative risk.

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

The registry record identifies a completed postmarketing study that followed subjects with hereditary angioedema types I and II treated with Berinert. It defines a primary antibody endpoint over baseline to approximately 9 months and lists one secondary antibody outcome. It also records the study’s single-group, open-label design and descriptive adverse-event counts. These details clarify what the study set out to examine and how its design constrains interpretation.

The primary result itself is not reported in the registry record. Consequently, the record does not show how many subjects met the inhibitory-antibody endpoint, how many had any anti-C1-esterase-inhibitor antibodies, or the precision of either outcome. Missing results must not be treated as zero events. Nor can the completed status be used to infer the findings.

The safety counts describe adverse events in the Berinert group, but they do not establish that treatment caused an event. With no control group, the registry does not support a randomized comparison of event frequency or antibody outcomes against another treatment or no treatment. The listed serious-event terms and percentages remain descriptive entries, not causal estimates.

In general, a well-defined endpoint is only one part of an interpretable result. The observed count, denominator, handling of missing assessments, and statistical uncertainty are also needed to understand the result. The registry record does not report those elements for the primary endpoint. Therefore, the available record supports conclusions about the study’s design and registered outcome definitions, but not a conclusion about the frequency of inhibitory antibodies or a comparative treatment effect.

14. Why This Trial Matters Statistically

This study is statistically informative as an example of why design and result availability must be considered together. It addresses a postmarketing antibody question using a prospective, open-label, single-group design. The endpoint is specifically defined around baseline status and post-baseline antibody findings, which makes the intended subject-level criterion clear. At the same time, the absence of a control group means the design is descriptive rather than a randomized comparative test.

The distinction between a registered endpoint and a reported endpoint is central. The registry identifies what investigators intended to count, but it does not report the observed primary outcome or its uncertainty. A precise outcome definition cannot compensate for a missing result. Readers also need the denominator and information about which participants had evaluable assessments to interpret a count as a frequency.

The safety entries illustrate another statistical distinction: counts and percentages can describe events in a study group without establishing causation or comparative risk. The group has no control arm, and the record does not state that the events were attributed to the intervention. Descriptive reporting should therefore remain separate from causal interpretation.

Finally, planning illustrations should not be mistaken for the trial’s own design assumptions or for observed power. The stated assumptions for those illustrations include equal allocation between two arms, while the registered study has one group. Keeping planning calculations separate from the actual design prevents an inappropriate reading of the study’s evidential strength.

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 principal limitation for interpreting this trial record is that the primary and secondary antibody outcome results are not reported in the registry record. Without those results, there is no observed antibody count or estimate of its precision to interpret. The record also does not report the analysis denominator or the number of participants with evaluable baseline and follow-up assessments.

The single-group, open-label design has no randomized comparator. It can describe the recorded experience of participants in the study, but it cannot establish a comparative treatment effect. The study description specifies an intended treatment duration and dose per attack; the registry does not report individual exposure or whether all participants followed that description.

Additional details relevant to interpretation are not reported in the registry record: assay characteristics and testing schedule, analysis populations, missing-data handling, the statistical analysis plan, multiplicity handling, and a trial sample-size justification. The registry lists 46 enrolled participants, but that number alone does not establish how many were included in each outcome analysis. Safety information is also limited to the listed participant counts and serious-event terms; details on timing, outcomes, and treatment attribution are not reported.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Postmarketing Immunogenicity Study in HAE Subjects Treated With Berinert — NCT01467947.
• Registry record last updated 2017-02-06; status last verified 2015-10.
• Results first posted 2015-11-16.
• 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.

19. Record Summary

NCT01467947 is a completed phase 4, prospective, international, multicenter, open-label, non-randomized, single-group postmarketing study sponsored by CSL Behring. The registry records 46 participants enrolled and an individual treatment duration of 9 months. The intervention is intravenous Berinert, described at 20 IU/kg body weight per attack.

The primary outcome is the number of subjects with no positive baseline result and at least one positive post-baseline result for inhibitory anti-C1-INH antibodies, assessed from baseline to approximately 9 months. One secondary antibody outcome is listed. The registry record does not report either outcome result or an analysis record.

For the C1 Esterase Inhibitor group, the registry lists 2 participants with serious adverse events and 7 with other adverse events, with 46 at risk in each category. The record lists two serious-event terms, each at 2.2%. It does not provide a control-group comparison.