Safety and Efficacy of Benefix in Patients With Hemophilia B in Usual Care Settings in China: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Benefix in Patients With Hemophilia B in Usual Care Settings in China (NCT02336178), a registered phase 4 study. The primary outcome is Percentage of Participants Who Developed Factor IX Inhibitor.

2. Clinical Question

This is a descriptive question about inhibitor development among people receiving BeneFIX in routine-care circumstances. The record also identifies safety and several bleeding-related outcomes, including adverse events, annualized bleeding rates in prophylaxis and on-demand settings, responses to on-demand treatment of bleeds, infusions per new bleed, and factor IX use. These outcomes add context about treatment experience, but no results for them are reported in the registry record.

Because the trial has one treatment arm, it can describe events observed during BeneFIX use but cannot establish how those outcomes compare with an untreated group or another treatment. The registry record does not report a comparator group, random assignment, or masking; masking is listed as none. It also does not provide a primary endpoint result or confidence interval, so the size and precision of the inhibitor-development estimate cannot be assessed from the reported information.

3. Trial Design

This was a phase 4, open-label, single-arm, post-authorization pragmatic clinical trial of BeneFIX in people with hemophilia B in usual-care settings in China. The study is listed as completed. Its recorded start was 2015-01, and its primary completion was 2016-07. Enrollment was 70.

Participants in the sole BeneFIX arm were treated by the investigator according to usual care in China and in accord with the China BeneFIX Package Insert. The registry record describes the purpose as evaluating safety and efficacy in that setting. It does not report a fixed dosing schedule, so no particular dose or dosing frequency can be inferred from the treatment description.

The open-label, pragmatic, single-arm structure is relevant to interpretation. Treatment was not masked, and the record does not identify a concurrent control group. Outcomes describe what was recorded among participants receiving BeneFIX under the study's usual-care approach; they do not constitute a randomized comparison with another intervention. The allocation field is not stated in the record.

The primary outcome was the percentage of participants who developed a factor IX inhibitor, assessed up to 6 months. The record defines the primary population as participants who received at least 1 dose of BeneFIX. Safety outcomes include the number of participants with treatment-emergent adverse events and serious adverse events. Other listed outcomes concern bleeding during prophylaxis or on-demand treatment, treatment response, infusion counts, infusion dose, and factor IX consumption. The registry record does not report results for these secondary outcomes.

The record does not state the study's sample-size justification, detailed statistical analysis plan, or approach to interim analyses. Any planning illustration based on an observed effect is not the trial's design or an observed-power result.

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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants who received at least 1 dose of BeneFIX during the study. Participants in each arm were not mutually exclusive.

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 baseline analysis population included all enrolled participants who received the study drug.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants Who Developed Factor IX Inhibitor, measured over Up to 6 months.

The primary endpoint is the percentage of participants who developed a factor IX inhibitor during follow-up of up to 6 months. An inhibitor is identified using a Bethesda assay: development is defined as a titer greater than the laboratory's normal range or a titer of at least 0.6 Bethesda Unit per milliliter. The registry record describes the analysis population as all participants who received at least 1 dose of BeneFIX during the study.

This endpoint is used to describe whether inhibitor development was observed during treatment, an outcome relevant to the study's stated safety and efficacy evaluation. A percentage expresses the frequency relative to the participants included in the endpoint population. Its interpretation depends on both the number of participants meeting the endpoint definition and the denominator used for the analysis.

The registry record does not report the primary endpoint percentage, the number meeting the definition, the denominator analyzed, or the 95% confidence interval. Consequently, the observed frequency and its precision cannot be described from the registry information available. The definition alone does not show whether any participant developed an inhibitor. Nor does it establish a comparison with another treatment or with an untreated group.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical information in the registry record is enough to identify the main outcome type and the design, but not enough to reconstruct the full analysis. The primary outcome is a percentage of participants with an event: factor IX inhibitor development. In general, an event percentage is formed from the number meeting a defined event criterion relative to the eligible analysis population. The record defines the population as people who received at least 1 dose of BeneFIX and describes the event criterion using Bethesda inhibitor titers. It does not report the analyzed denominator or the number meeting that criterion.

The primary outcome is also associated with a 95% confidence interval. In general, a confidence interval conveys uncertainty around an estimated quantity under a statistical method and its assumptions. A narrower interval indicates greater precision than a wider interval, but its interpretation depends on how it was calculated and on the data. The registry record does not report the primary estimate or either confidence-interval limit, nor does it specify the calculation method. No claim about precision can therefore be made for this endpoint.

The threshold rule combines two ways of defining inhibitor development: a Bethesda inhibitor titer greater than the laboratory's normal range, or a titer of at least 0.6 Bethesda Unit per milliliter. The laboratory-specific normal range matters because it is part of the endpoint definition. The record does not provide laboratory details, participant-level measurements, or information about repeated testing. It is not possible to infer how borderline results were handled beyond the stated definition.

The outcome type is binary at the participant level: a participant either meets the endpoint definition or does not, according to the rule. This differs from a continuous measurement, such as a laboratory value analyzed across its full numeric range. Describing a binary outcome as a percentage is useful for communicating the proportion of participants meeting a criterion, but the estimate depends on who is counted and how missing endpoint assessments are treated. The missing-data approach is not reported in the registry record.

The safety results are also participant counts. The record lists 70 participants at risk for serious adverse events and 2 participants with serious adverse events. For other adverse events, it lists 70 at risk and 55 affected. These are descriptive counts, not a treatment-versus-control effect estimate. The serious event terms listed are Factor IX inhibition and Oral mucosa haematoma, each at 1.4%. The record does not provide a causal attribution for these terms or describe how adverse events were adjudicated. Deaths are not reported.

General statistical interpretation of adverse-event counts should distinguish the number of participants affected from the number of event episodes. The record's safety summary is phrased as numbers of participants with events; it does not provide episode counts, event duration, severity grading beyond the serious-event classification, or person-time. Therefore, these counts should not be treated as rates over a specified amount of follow-up.

The design is single-arm and open-label. In general, a single-arm study can describe outcomes among treated participants, but without a concurrent comparator it cannot directly estimate a between-group treatment effect. Open-label status means treatment masking was absent; the record does not report whether outcome assessors were masked. The pragmatic usual-care setting may describe treatment under the stated clinical context, but the registry description alone does not establish how broadly the findings apply to other settings.

The sample-size assumptions describe a planning illustration, not the trial's own design: two-sided significance level 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a stated fraction of the observed effect. For time-to-event tables, the planning quantity is described as total events; for other outcomes, it is participants per arm. These are planning conventions, not evidence of observed power. The record does not report a trial-specific sample-size justification, and the numerical planning estimates are not reported in the registry record. Since the study itself is single-arm, the hypothetical equal-allocation two-arm assumptions do not describe its actual design.

The record does not report the statistical method used for the primary confidence interval, a hypothesis test, covariate adjustment, or interim analyses. It lists no analysis records. In general, those choices can affect how an estimate is calculated and interpreted; without the specified methods and endpoint results, they cannot be reconstructed or evaluated. The registry information supports reading the design and stated endpoint definition, while leaving important details of estimation and inference unresolved.

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("Pediatric Participants <6 Years of Age", "Pediatric Participants ≥6 to ≤12 Years of Age", "Previously Untreated Participants (PUPs)", "Participants Receiving Prophylaxis Treatment", "Severe Participants (Factor IX Activity <1%)")
n      <- c(30, 31, 11, 57, 36)
events <- c(1, 0, 0, 1, 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  Pediatric Participants <6 Years of Age  30  1  3.3  0.1  17.2  0.6  16.7  0.8  16.7
ARM  Pediatric Participants ≥6 to ≤12 Years of Age  31  0  0.0  0.0  11.2  0.0  11.0  0.1  10.9
ARM  Previously Untreated Participants (PUPs)  11  0  0.0  0.0  28.5  -0.0  25.9  0.2  26.5
ARM  Participants Receiving Prophylaxis Treatment  57  1  1.8  0.0  9.4  0.3  9.3  0.4  9.2
ARM  Severe Participants (Factor IX Activity <1%)  36  0  0.0  0.0  9.7  -0.0  9.6  0.1  9.5

11. Multiplicity, Missing Data and Analysis Populations

The registry record identifies one primary endpoint: the percentage of participants who developed a factor IX inhibitor. It also lists multiple secondary outcomes concerning adverse events, bleeding rates in prophylaxis and on-demand settings, breakthrough bleeds, response to on-demand treatment, infusions per new bleed, infusion dose, and factor IX consumption. The results for these secondary outcomes are not reported in the registry information available.

When a study evaluates multiple outcomes, multiplicity can matter because examining many results can increase the chance of finding an apparently notable result by chance. Statistical plans may address this through a prespecified hierarchy, adjustment, or another approach. The registry record does not report a multiplicity strategy, testing hierarchy, or adjustment method. It also does not report a primary hypothesis test or p-value. No claim about control of multiplicity can be made.

The primary population is defined as participants who received at least 1 dose of BeneFIX. The record does not report the number analyzed for the primary endpoint, how missing inhibitor assessments were handled, or whether participants without an assessment were excluded or classified in another way. Reasons for missing data and sensitivity analyses are not reported. These omissions matter because an event percentage depends on the analysis denominator and the handling of unavailable outcome measurements.

The record lists zero analysis records. This does not supply the missing endpoint estimates or explain the statistical analysis in detail. The registry record also does not report an interim-analysis plan. In the absence of these details, the endpoint definition and population description can be stated, but the completeness and inferential procedures for the outcome cannot be assessed.

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: factor ix inhibition (1.4%), oral mucosa haematoma (1.4%).

The BeneFIX safety summary lists 70 participants at risk for serious adverse events, with 2 participants affected. For other adverse events, 70 participants were at risk and 55 were affected. These are participant counts in the registry record, not comparative estimates against another treatment group.

Factor IX inhibition and oral mucosa haematoma are each listed as serious adverse event terms at 1.4%. The registry record does not state whether either event was judged related to BeneFIX. A listed serious adverse event is not, by itself, evidence that treatment caused it. The record also does not report the number of deaths.

These figures should be read descriptively and in light of the single-arm, open-label design. There is no concurrent control group with which to compare event frequencies. The safety information also does not provide event timing, exposure-adjusted rates, or details about duration. It therefore describes the reported participant counts and terms without establishing comparative risk or causation.

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

The registry record establishes that a phase 4, open-label, single-arm study evaluated BeneFIX in usual-care settings in China. It identifies a primary endpoint based on factor IX inhibitor development and gives the operational definition used for that endpoint. It also reports some adverse-event participant counts and two serious adverse event terms, each listed at 1.4%.

The primary outcome result itself is not reported in the registry record. The percentage of participants meeting the inhibitor definition, the number analyzed, and the 95% confidence interval are absent. Thus, the stated endpoint and definition do not reveal how often inhibitor development occurred or how precisely it was estimated. Results for the listed bleeding-related secondary outcomes are also not reported.

The safety counts describe events reported among participants in the BeneFIX arm. They do not demonstrate that BeneFIX caused those events, and they cannot show whether event frequencies were higher or lower than they would have been with another treatment. The absence of a control group is central to that limitation.

The study's usual-care setting provides context for the treatment approach: investigators treated participants according to usual care in China and in accord with the China BeneFIX Package Insert. The registry record does not provide enough detail to infer a fixed dosing regimen or to generalize beyond the described setting. The available information is therefore best understood as a description of the study design, endpoint definition, and reported safety counts, rather than a comparative estimate of treatment effect or a complete account of the clinical outcomes.

14. Why This Trial Matters Statistically

This trial is statistically notable for the questions it can describe and the comparisons it cannot make. Its single-arm, open-label, pragmatic design records outcomes during BeneFIX use in usual-care settings in China. That design is consistent with descriptive monitoring after authorization, but it does not provide a concurrent control group for estimating a comparative treatment effect.

The primary endpoint is explicitly defined, including the Bethesda titer criteria and the follow-up period of up to 6 months. Clear endpoint criteria are important because they establish what counts as an event. Yet the registry record does not report the endpoint estimate or its 95% confidence interval. Without those results, the primary outcome cannot be interpreted quantitatively, even though the outcome definition is available.

The record also illustrates why safety counts need context. It reports participants with serious and other adverse events, along with serious-event terms, but not a control comparison or causal assessment. The counts can describe what was recorded in the treatment arm, but cannot establish a treatment-attributable risk difference.

Finally, the record lists several secondary outcomes but does not report their results, and it does not provide details of missing-data handling, multiplicity procedures, or a full statistical analysis plan. Those gaps limit assessment of completeness and inferential strength. For biostatistical interpretation, the distinction between a defined outcome and a reported outcome is essential: the record specifies what was intended to be measured, while leaving the principal result and important analysis details unavailable.

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 main trial-specific limitation is the absence of the primary endpoint result. Although inhibitor development is defined and a 95% confidence interval is specified as the dispersion measure, neither the percentage nor the interval limits are reported in the registry record. The analyzed denominator and the number meeting the endpoint definition are also not reported.

The single-arm design provides no concurrent control comparison. The registry record is open-label, with masking listed as none, and the allocation field is not stated. Consequently, safety counts and any potential outcome descriptions cannot be interpreted as randomized comparative effects. The record does not report whether outcome assessors were masked.

Results for the listed secondary outcomes are not reported. These include bleeding rates, breakthrough bleeds, response to on-demand treatment, infusion counts, infusion dose, and factor IX consumption. The registry record also does not report a multiplicity plan, detailed statistical methods, missing-data procedures, interim analyses, or a trial-specific sample-size justification. Deaths are not reported.

The treatment description refers to investigator-directed usual care in China and the China BeneFIX Package Insert, but does not specify a dosing schedule. The available description therefore does not support assumptions about uniform dosing or exposure. These limitations constrain interpretation to the design and reported safety information; they prevent a full evaluation of the primary outcome, secondary outcomes, or comparative effects.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Efficacy of Benefix in Patients With Hemophilia B in Usual Care Settings in China — NCT02336178.
• Registry record last updated 2017-05-04; status last verified 2017-03.
• Results first posted 2017-05-04.
• 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

NCT02336178 is a completed phase 4, open-label, single-arm, post-authorization pragmatic clinical trial of BeneFIX in hemophilia B in usual-care settings in China. Enrollment was 70. The recorded start was 2015-01, and primary completion was 2016-07.

The primary endpoint was the percentage of participants developing a factor IX inhibitor up to 6 months, among participants who received at least 1 dose. The result and 95% confidence interval are not reported in the registry record. Safety figures list 2 participants with serious adverse events and 55 with other adverse events; deaths are not reported. Results for the listed secondary outcomes and detailed analysis procedures are also not reported.