A Phase III Study to Evaluate the Efficacy and Safety of Benralizumab in Patients With Hypereosinophilic Syndrome (HES): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Phase III Study to Evaluate the Efficacy and Safety of Benralizumab in Patients With Hypereosinophilic Syndrome (HES) (NCT04191304), a randomized phase 3 study. The primary outcome is Time to First HES Worsening/Flare During the DB Treatment Period.

2. Clinical Question

The central statistical question is whether the time-to-event experience differs between the randomized benralizumab and placebo groups over the double-blind period. A time-to-first-event endpoint retains information about when a first worsening or flare occurs, rather than only whether a participant had one by the end of follow-up. That distinction is useful when participants have different follow-up times or when some have no recorded event before observation ends.

The registry record identifies the trial as Phase III, multicentre, randomized, parallel-group, and placebo-controlled. It lists 134 participants as the enrollment and gives the condition as HES. The record does not provide a primary comparison, confidence interval, p-value, or account of the magnitude or precision of any observed treatment difference. Therefore, the clinical question can be described from the design and endpoint, but not answered from the posted primary results.

3. Trial Design

This is a Phase III, multicentre, randomized, parallel-group study comparing benralizumab with placebo in participants with HES. The registry classifies masking as quadruple and describes the main treatment period as double-blind. The record does not explain which specific groups of people were masked, so the masking classification should not be interpreted more specifically than the registry states.

During the 24-week double-blind treatment period, participants were assigned to benralizumab or matching placebo, in addition to their prior stable HES background therapy. Both study injections were described as subcutaneous and administered every four weeks. The primary endpoint timeframe is baseline to Week 24. The primary database lock was described as occurring after approximately 38 participants had experienced a first HES worsening or flare and all randomized participants had the opportunity to complete the double-blind period. This is a planned database-lock condition in the study description, not a report that the event count was reached.

The study also includes an open-label extension. Participants had to complete the 24-week double-blind period on investigational product to be eligible to enter it, and all participants in the extension were to receive benralizumab. The registry describes a final database lock after the last participant completes the extension. These later observations belong to a different treatment context from the randomized, placebo-controlled period: extension treatment was open-label, and the original placebo group could switch to benralizumab.

The registry lists a total enrollment of 134 and status as active, not recruiting. It records a study start date of 2020-07-20 and a primary completion date of 2025-05-07. Those dates and status do not, on their own, establish that all study periods are complete or that results have been posted. The registry record does not report the allocation ratio, details of the randomization procedure, a sample-size justification for the trial, or the planned statistical analysis in enough detail to describe those aspects.

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: The study consisted of 2 phases: a double-blind (DB) treatment period followed by an open-label extension (OLE) period. A total of 127 participants completed the DB period, of whom 126 subsequently entered the OLE period. One participant did not enroll in the OLE period due to withdrawal.

Double-blind (DB) Treatment Period

Reasons for not completing this period:

Open-label Extension (OLE) Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set: All participants who were randomized and received at least 1 dose of IP, irrespective of their protocol adherence and continued participation in the 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.

Population: Full Analysis Set: All participants who were randomized and received at least 1 dose of IP, irrespective of their protocol adherence and continued participation in the study.

6. Primary Endpoint

The registry lists the primary outcome as Time to First HES Worsening/Flare During the DB Treatment Period, measured over DB period (Baseline to Week 24).

The primary endpoint is time to first HES worsening or flare during the double-blind treatment period, from baseline to Week 24. The registry defines event time using the start date of the first worsening or flare relative to the randomization date, with one day added. Participants without a recorded event are censored at the earliest of the first benralizumab open-label dose, study day 183, last contact, or the data cut-off date.

Censoring means that an event was not observed during a participant’s available period of follow-up; it does not mean that the participant is known never to have an event. In a time-to-event analysis, this distinction allows information from participants who have not experienced the event by their last observation to contribute without treating them as event-free indefinitely. The registry says that the number of participants with events and censored observations is presented. It does not identify an analysis model or report a comparative estimate.

Time to first event is used when the timing of an initial worsening or flare is relevant, and it can account for differing observation times. It does not describe the total number of recurrent flares after the first one. The registry lists recurrent-event frequency as a separate secondary outcome, reinforcing that the primary endpoint and the total burden of repeated events answer different questions. No primary endpoint result, uncertainty interval, or statistical test is reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation begins with identifying the estimand-like question in plain terms: the registry’s primary endpoint concerns the time to a first HES worsening or flare during the double-blind period. The population is the Full Analysis Set, defined as randomized participants who received at least one dose of investigational product, regardless of protocol adherence or continued participation. The treatment comparison is benralizumab versus placebo, with stable background therapy described in the study summary. The registry record does not give a fuller estimand specification, such as how every possible post-randomization event or treatment discontinuation would be handled.

What does censoring mean?

General explanation: in time-to-event analysis, censoring records that a participant was observed for a period without a recorded event, but that the event time is not known beyond the end of observation. Such a participant is not automatically treated as event-free for all future time. The registry defines censoring at the earliest of the first benralizumab open-label dose, study day 183, last contact, and data cut-off. This definition matters because the analysis period is limited to the double-blind treatment period, whereas some participants may go on to receive open-label treatment.

General explanation: methods such as Kaplan–Meier estimation can describe the proportion remaining free of an event over time, and a log-rank test or a regression model may be used in some trials to compare groups. These are examples of general time-to-event methods, not claims about the analysis used in this study. The registry record does not report the primary analysis method, a hazard ratio, a test statistic, a confidence interval, or a p-value. No particular model or test should therefore be attributed to this trial based on the record described.

How should an estimate and confidence interval be read?

General explanation: a treatment-effect estimate expresses the contrast between groups on a chosen scale, while a confidence interval conveys the range of values compatible with the observed data under the assumptions of the method. A narrow interval indicates greater statistical precision than a wide interval, but precision alone does not establish clinical importance. For a time-to-event outcome, the interpretation depends on the scale and direction of the reported contrast, the event definition, the follow-up period, and the assumptions used to handle censoring. No estimate or confidence interval for the primary comparison is reported in the registry record, so those interpretations cannot be made for this study.

General explanation: p-values address compatibility between the observed data and a specified null hypothesis under the analysis assumptions; they do not measure the probability that a treatment is effective or the size of an effect. Because no primary p-value is reported, there is no basis to characterize the primary comparison as statistically significant or not statistically significant. The registry record also does not report a prespecified threshold for interpreting the primary endpoint or a minimal clinically important difference.

What does the planning information mean?

The registry includes a sample-size-assumptions description for planning illustrations, rather than the trial’s own design justification. It describes a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation, with the target effect expressed as a fraction of the observed effect. For time-to-event outcomes, the description says that planning illustrations use a total number of events; other outcomes are expressed as participants per arm. These are planning assumptions, not observed trial results and not a report of the trial’s original sample-size calculation. The record does not report a numeric planning illustration in the information available for this analysis.

General explanation: planning calculations estimate how much information a proposed study might need under chosen assumptions. They do not show that a study had a particular probability of detecting an effect after the data are observed. Post hoc calculations based on an observed effect can also be unstable, especially if the observed effect is imprecise. Any planning illustration should therefore be read as conditional on its assumptions, not as an observed outcome or a substitute for the estimate and its uncertainty.

Why do repeated events and over-dispersion matter?

General explanation: a first-event endpoint differs from a recurrent-event endpoint. Time to first worsening or flare records the initial event only; it does not by itself describe how often further episodes occur. Recurrent-event analyses must account for repeated observations within the same participant. When event counts vary more than a simple model expects, over-dispersion can make standard errors too small if it is ignored, leading to intervals or tests that appear more certain than warranted. These are general considerations, not descriptions of the analysis conducted in this trial. The registry lists an annualized rate of HES worsenings or flares as a secondary outcome but does not report its analysis method or results.

General explanation: an annualized rate expresses events relative to observation time, so it can be useful when participants contribute different amounts of follow-up. Its interpretation depends on how follow-up time is defined and how repeated events are modeled. The registry record does not report those details or the results for that secondary measure. Similarly, it lists several other secondary outcomes with different data types, but no statistical model should be inferred from the outcome names alone.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 13 outcome measures and 20 analyses, as well as multiple secondary outcomes. When several outcomes, time points, or analyses are examined, the chance of at least one apparently unusual result can increase if each is interpreted without accounting for the collection of tests. General approaches to multiplicity include prespecifying a hierarchy, adjusting significance thresholds, or treating secondary analyses as exploratory. The registry record does not report whether any such strategy was planned or used, nor does it describe a testing hierarchy. The presence of multiple outcomes alone does not establish that a particular correction was required or applied.

The registry record does not report how missing primary endpoint data were handled beyond the stated time-to-event censoring definition. Censoring is part of the endpoint analysis, but it does not by itself establish that missingness is harmless or that the assumptions behind an analysis are satisfied. The record does not provide the number of missing observations, reasons for missingness, sensitivity analyses, or a separate missing-data strategy for secondary outcomes.

The primary population is defined as randomized participants who received at least one dose of investigational product, irrespective of protocol adherence and continued participation. This definition identifies who is intended to contribute to the Full Analysis Set. The record does not state whether additional populations were used, how deviations from assigned treatment were handled, or how many participants were included in the primary analysis. Those details are needed to assess the consequences of exclusions and incomplete follow-up. Neither the registry’s endpoint description nor the population definition can substitute for a full statistical analysis plan, which is not reported in the registry record.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cholelithiasis (1.6%), acquired haemophilia (1.6%), hypereosinophilic syndrome (1.6%), bradycardia (1.6%), intussusception (1.6%).

The double-blind safety entries report 5 participants with serious adverse events among 67 at risk in the benralizumab group and 5 among 66 at risk in the placebo group. The record also lists 23 participants with other adverse events among 67 at risk for benralizumab and 18 among 66 at risk for placebo. Deaths are listed as 1 and 0, respectively. These are posted counts, not adjusted comparisons, and the registry record does not provide a statistical analysis of these differences.

For the open-label extension, the entry for participants originally in the benralizumab group lists 11 with serious adverse events among 65 at risk and 42 with other adverse events among 65 at risk; deaths are listed as 0. The entry for participants who switched from placebo to benralizumab lists 10 with serious adverse events among 61 at risk and 45 with other adverse events among 61 at risk; deaths are listed as 0. Because both extension groups received benralizumab and treatment was open-label, these counts do not form a concurrent randomized comparison of benralizumab with placebo.

The registry lists six serious adverse-event terms at 1.6% each: cholelithiasis, acquired haemophilia, hypereosinophilic syndrome, bradycardia, intussusception, and cellulitis. The record does not specify a treatment group for these terms in the listed entry. Counts and listed terms do not establish that an event was caused by study treatment, and the record does not provide exposure-adjusted rates or additional context for interpreting them.

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

The registry record describes a randomized Phase III comparison designed to evaluate benralizumab against placebo for HES during a 24-week double-blind period. Its primary endpoint is time to first HES worsening or flare, with participants who do not have a recorded event censored according to specified follow-up dates. The record also describes a subsequent open-label extension in which participants receive benralizumab.

These details explain what the study was designed to ask and how the primary event time is defined. They do not show whether the groups differed. The registry record does not report event counts by group for the primary endpoint, a treatment-effect estimate, a confidence interval, or a p-value. Therefore, it does not support a conclusion about the direction, magnitude, or statistical precision of a primary treatment effect. It also does not permit a judgment about whether any observed difference would be clinically important.

The safety entries show counts of participants with serious and other adverse events, and deaths, in the double-blind groups and the open-label extension groups. Those descriptive counts should not be interpreted as proof that an event was or was not caused by treatment. Nor should extension counts be treated as if they came from the original randomized comparison: all extension participants received benralizumab, and the extension was open-label.

More broadly, a study design is not the same as a study finding. Randomization and masking describe safeguards intended to support a fair comparison, but do not guarantee that all sources of bias, missing information, or imprecision have been eliminated. Interpreting the primary result would require the group-specific outcome data and the analysis details, including the effect measure, uncertainty interval, handling of censoring, and any prespecified multiplicity strategy. Those details are not reported in the registry record. No treatment recommendation follows from these registry entries.

13. Why This Trial Matters Statistically

The primary endpoint raises a practical statistical issue: the first occurrence of a worsening or flare is not simply a yes-or-no outcome when follow-up time can differ. Recording time to first event can use information about when the event occurred, while censoring permits inclusion of participants whose event status is not observed through the end of follow-up. Correct interpretation depends on the event definition and the rules for ending observation; the registry gives both for this study.

The separation between the randomized double-blind period and the open-label extension is also important. The placebo-controlled period is the part of the design that directly supports a randomized comparison between benralizumab and placebo. In the extension, all participants receive benralizumab, including those who switch from placebo. Extension observations may describe later experience, but they do not preserve the same concurrent randomized contrast.

The record also illustrates why endpoint results need to be read alongside analysis details. A statement that event and censored counts are presented does not reveal the size or precision of a treatment contrast. For that, readers need a specified comparison, an estimate, and an uncertainty interval, as well as enough information to understand the analysis population and censoring. The registry lists several additional outcomes, making it important to know which analyses were primary and whether multiplicity was addressed; the strategy is not reported.

Finally, the safety entries distinguish serious adverse events, other adverse events, and deaths across treatment periods. Keeping these categories and study periods separate avoids treating descriptive counts as equivalent evidence. The trial is statistically relevant because it combines a randomized time-to-event primary endpoint with recurrent-event and other secondary questions, followed by an open-label extension. However, the registry record’s design and safety counts do not replace the missing primary comparative results.

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 principal limitation for interpretation is that the registry record does not report the primary endpoint results. It gives the endpoint definition and population description, but not group-specific event counts, a comparative estimate, a confidence interval, or a p-value. Without these, the magnitude and precision of the randomized comparison cannot be evaluated.

The primary endpoint is limited to time to the first worsening or flare. It does not capture the total number of later flares; the registry lists an annualized flare outcome separately, but its results and analysis are not reported. The stated censoring rule includes the first open-label benralizumab dose among possible censoring dates. The record does not give the number censored, the reasons in practice, or sensitivity analyses assessing the effect of censoring.

The registry does not report the trial’s sample-size justification, statistical analysis plan, multiplicity strategy, or missing-data approach beyond the endpoint’s censoring definition. The planning-assumptions description is explicitly an illustration based on an observed effect, not the trial’s own design calculation; no numeric planning illustration is included in the record information described. These gaps limit evaluation of whether the analysis was prespecified and how uncertainty or multiple testing was addressed.

Safety counts are descriptive and are reported for both randomized double-blind groups and open-label extension groups. The extension was not a randomized placebo comparison, and the record does not provide exposure-adjusted rates, attribution methods, or statistical comparisons. The study status is active, not recruiting, and the registry record does not establish that all follow-up or reporting is complete. These considerations restrict what can be concluded from the posted information.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Phase III Study to Evaluate the Efficacy and Safety of Benralizumab in Patients With Hypereosinophilic Syndrome (HES) — NCT04191304.
• Registry record last updated 2026-07-10; status last verified 2026-07.
• Results first posted 2026-07-10.
• 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 identifies a Phase III, multicentre, randomized, parallel-group, placebo-controlled study of benralizumab in participants with HES. Enrollment is listed as 134. The double-blind treatment period lasted 24 weeks, with participants receiving benralizumab or matching placebo alongside prior stable HES background therapy. The primary endpoint is time to first HES worsening or flare from baseline to Week 24, with observations censored according to the stated follow-up rule.

The study includes an open-label extension in which all participants receive benralizumab; eligibility requires completing the double-blind period on investigational product. The record lists several secondary outcomes and gives descriptive adverse-event counts across double-blind and extension groups. Its status is active, not recruiting. Primary endpoint findings, effect estimates, confidence intervals, p-values, the trial’s statistical analysis plan, and a multiplicity strategy are not reported in the registry record.