Study to Determine the Safety and Efficacy of rFIXFc in Previously Untreated Males With Severe Hemophilia B: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Determine the Safety and Efficacy of rFIXFc in Previously Untreated Males With Severe Hemophilia B (NCT02234310), a na phase 3 study. The primary outcome is Percentage of Participants With Confirmed Inhibitor Development as Measured by the Nijmegen-Modified Bethesda Assay.

2. Clinical Question

3. Trial Design

This was a phase 3, open-label, multicenter, single-group study of rFIXFc in previously untreated males with severe hemophilia B. The registry lists enrollment of 33 participants and a completed status. The record gives a start date of 2014-11-13 and a primary completion date of 2019-08-20. These dates describe the registry timeline; they do not establish the duration of follow-up for each participant.

Because there was no randomized allocation or concurrent control arm, the study is a descriptive evaluation of participants treated with rFIXFc rather than a comparative trial. The open-label design means masking was absent. The registry does not report a separate control treatment, a blinded outcome assessment process, or further detail on how the multicenter conduct was coordinated.

The primary objective was safety, specifically confirmed inhibitor development. Secondary objectives concerned prevention and treatment of bleeding episodes and rFIXFc consumption. The listed secondary outcomes include annualized bleeding episodes, spontaneous joint bleeding, treatment-response categories, exposure days, annualized consumption, injections and dose needed to resolve bleeding episodes, and change in incremental recovery. The registry record names these outcomes but does not report their results in the available record.

The treatment description identifies intravenous rFIXFc and gives the start of a prophylactic regimen: 50 IU/kg weekly until at least 50 exposure days. The remainder of the description is incomplete in the registry record, so additional dosing and treatment details are not reported there. The record also does not report a protocol rationale for enrollment, a sample-size justification, or details of any interim monitoring.

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 38 participants were screened. A total of 33 participants were enrolled, 22 participants began study participation on episodic treatment regimen and 11 participants began study participation on prophylactic treatment regimen.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Analysis performed on Safety Analysis set which included all participants who had received at least 1 dose of study treatment.

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: Analysis was performed on Safety Analysis Set which included all participants who received at least 1 dose of study rFIXFc.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Confirmed Inhibitor Development as Measured by the Nijmegen-Modified Bethesda Assay, measured over Up to 3 years.

The primary endpoint is the percentage of participants with confirmed inhibitor development, assessed with the Nijmegen-modified Bethesda assay. An inhibitor was defined by a result of at least 0.60 BU/mL and confirmation by a second result of at least 0.60 BU/mL from a separate sample. The confirming sample was drawn 2 to 4 weeks after the original sample, and both tests were performed by the central laboratory. The stated timeframe was up to 3 years.

This endpoint describes the proportion of the safety analysis population meeting a prespecified laboratory-based definition. Such a definition makes the event operational: it specifies the test, threshold, confirmation requirement, and sample timing used to classify inhibitor development. Requiring confirmation distinguishes the endpoint from a single test result, though the registry record does not provide additional detail on adjudication or handling of unconfirmed results.

The endpoint is reported as a percentage with a 95% confidence interval. In general, a confidence interval conveys the statistical uncertainty around an estimated proportion; it does not by itself establish whether a result is clinically important. The registry record gives the endpoint definition and analysis population but does not report the observed percentage or the confidence interval. Therefore, the frequency and precision of the primary endpoint estimate cannot be evaluated from this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a binary proportion as the primary outcome: participants either met the confirmed inhibitor definition during the stated observation period or did not meet it. The outcome is expressed as a percentage of participants. The registry specifies a 95% confidence interval but does not provide the calculated estimate or interval limits. It also does not report the statistical method used to calculate that interval.

What does a confidence interval describe?

In general, a confidence interval expresses uncertainty around an estimate calculated from a sample. For a proportion, the interval reflects that the observed group is not necessarily identical to the wider population about which researchers may wish to learn. An interval’s width depends on the amount of information and the statistical method. It should be read alongside the point estimate and the analysis population; an interval is not a range containing every participant’s outcome. In this study, the confidence interval is named as the dispersion measure, but its limits and the corresponding estimate are not reported in the registry record.

Why does the endpoint require confirmation?

The endpoint definition requires a Nijmegen-modified Bethesda assay result of at least 0.60 BU/mL and a confirming result at the same threshold from a separate sample drawn 2 to 4 weeks later. In general, confirmation rules make the classification depend on repeated evidence rather than a single test. They also define which test patterns count as an event. The record states that both tests were performed by the central laboratory. It does not report how participants with a missing confirmation sample, an uninterpretable test, or a result that did not meet the confirmation rule were handled.

What does the analysis population mean?

The primary analysis was described as being performed on the Safety Analysis set, which included all participants who had received at least 1 dose of study treatment. This definition identifies the group eligible for the safety analysis. It is not necessarily the same as the number enrolled or the number with complete endpoint data. The registry record does not give the number analyzed for the primary endpoint, the number with missing test results, or the number who completed follow-up.

In general, analysis populations matter because changing who is included can change the estimate and its interpretation. A safety population based on treatment received is commonly useful for describing events observed after exposure, while missing observations can leave uncertainty about event status. The record does not describe a missing-data strategy, a rule for incomplete follow-up, or sensitivity analyses for the primary endpoint.

How does the single-group design affect inference?

The study had one treatment group and no randomized comparator. A proportion estimated in a single group is descriptive of that group and its observation conditions. Without a concurrent control, there is no direct randomized contrast to estimate how the outcome would differ under another treatment or under no study treatment. General statistical adjustment cannot create a randomized control group when none is present. The registry record does not report an adjusted analysis for the primary endpoint.

The open-label design means treatment was not masked. The primary endpoint uses a laboratory assay and a confirmation rule, and the record identifies a central laboratory. Those features describe how the endpoint was assessed; they do not establish that every element of outcome assessment was blinded. Blinding of laboratory personnel or other safeguards beyond central testing is not reported in the registry record.

What can be concluded from the listed adverse-event counts?

Adverse-event counts are descriptive summaries of participants with events. The record identifies participants at risk and affected for serious and other adverse events, and lists selected serious-event terms with percentages. In general, event terms can overlap: a participant may experience more than one event, and a participant may appear under more than one term. The registry record does not explain the counting rules for the selected terms or state whether terms are mutually exclusive. These summaries should therefore be read as safety descriptions, not as a comparative treatment effect.

The registry record does not report the statistical analysis plan, the method for handling multiplicity across secondary outcomes, interim analyses, or a sample-size justification. General principles such as confidence intervals, prespecified definitions, and transparent analysis populations help explain how trial results are assessed, but they cannot fill in those missing methodological details. No unreported statistical procedure should be assumed for this study.

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("Recombinant Coagulation Factor IX Fc Fusion Protei")
n      <- c(33)
events <- c(1)
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  Recombinant Coagulation Factor IX Fc Fusion Protei  33  1  3.0  0.1  15.8  0.5  15.3  0.7  15.3

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary safety endpoint and multiple secondary outcomes, including bleeding rates, spontaneous joint bleeding, treatment response, exposure days, consumption, injections needed to resolve bleeding, dose per injection, and incremental recovery. The record does not report a multiplicity procedure or explain whether formal hypothesis tests were planned across these outcomes. Without that information, the handling of the chance of false-positive findings across multiple tests is not reported in the registry record.

The registry record also does not describe the statistical analysis plan, interim analyses, or a sample-size justification. The primary endpoint is specified with a 95% confidence interval, but neither its observed estimate nor the interval is reported. No primary endpoint analysis count is available in the record.

The stated primary analysis population included all participants who received at least 1 dose of treatment. The number in that population is not reported separately from enrollment, and the record does not give the number with complete inhibitor testing or endpoint follow-up. Missing-data procedures, censoring rules, and sensitivity analyses are not reported in the registry record. These omissions prevent assessment of whether missing outcome information could affect the estimate.

In general, multiplicity and missing data are distinct concerns. Multiplicity concerns interpretation when several outcomes or tests are evaluated; missing data concern incomplete observation and how it is handled. The registry does not provide enough methodological detail to determine the approaches used for either concern.

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: central venous catheterisation (27.3%), fall (15.2%), head injury (9.1%), poor venous access (9.1%), anaemia (3.0%).

The adverse-event summary reports 33 participants at risk for serious adverse events and 23 participants affected. For other adverse events, it reports 33 participants at risk and 27 affected. The registry also reports 0 deaths. These are descriptive participant counts; the record does not provide a concurrent comparison group.

The selected serious-event terms and their reported percentages are Central venous catheterisation, 27.3%; Fall, 15.2%; Head injury, 9.1%; Poor venous access, 9.1%; Anaemia, 3.0%; and Factor ix inhibition, 3.0%. These entries identify terms appearing in the serious-event summary. The record does not explain whether participants could contribute to more than one term, so the percentages should not be added together or treated as mutually exclusive categories.

In general, an adverse event occurring during a trial is not by itself proof that the study treatment caused it. The summary gives descriptive safety information, while the single-group design provides no randomized comparison for causal attribution. The registry record does not report further event-level timing, severity details beyond the serious-event classification, or a causal assessment for each listed term.

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

The record establishes that a study was conducted to assess rFIXFc in previously untreated males with severe hemophilia B, with safety as the primary objective. It defines confirmed inhibitor development using a specified assay, threshold, confirmation sample, and timeframe. It also describes a safety analysis population and lists adverse-event summaries. These details clarify what the study set out to measure and how the primary event was classified.

The registry record does not report the primary endpoint’s observed percentage or 95% confidence interval. It therefore does not show how many participants met the confirmed inhibitor definition, how uncertain the estimated percentage was, or how the primary safety outcome was distributed over follow-up. The listed secondary outcomes also lack numerical results in the record, so their findings cannot be interpreted from the information available.

The adverse-event summary reports affected participants, selected serious-event terms, and deaths, but these figures are descriptive. A single-group study cannot supply a randomized comparison against a control group. The record also does not establish that a listed event was caused by rFIXFc. Counts should not be interpreted as comparative risks or as proof of causation.

In general, a trial’s endpoint definition and observed estimate answer different questions: the definition states what qualifies as an event, while the result states how often that event was observed in the analyzed group. Here, the definition is reported, but the primary estimate is not. The registry record consequently supports an understanding of the design and outcome definitions, not a conclusion about the numerical primary result or a comparative treatment effect.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of a safety-focused, single-group study with a laboratory-defined primary endpoint. The registry makes the inhibitor definition explicit: it specifies the assay, threshold, confirmation requirement, central laboratory testing, and observation timeframe. Such operational detail matters because the interpretation of a proportion depends on which observations qualify as events.

The study also illustrates why a clearly defined endpoint is only part of the statistical account. A reader needs the observed estimate, its uncertainty, the analyzed population, and information about incomplete follow-up to assess a result. The registry record names the 95% confidence interval and defines the safety population, but it does not report the estimate, interval limits, or the number included in the endpoint analysis.

The single-group, open-label design is another important statistical feature. It can describe outcomes among participants treated in the study, but does not provide a randomized concurrent comparison. This distinction helps separate descriptive safety information from comparative evidence. The adverse-event summary can be read as a record of reported events in the group; it cannot, by itself, identify how those events compare with another treatment or establish their cause.

Finally, the listed secondary outcomes span bleeding, treatment response, exposure, consumption, and recovery. The registry record does not provide their results or describe how multiplicity was handled. That absence highlights the importance of reporting the analysis plan and results alongside outcome definitions. A transparent record should make it possible to see not only what was measured, but also how the planned analyses were conducted and what estimates resulted.

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 primary limitation for interpretation is the absence of the primary endpoint result in the registry record. Although the endpoint definition, analysis population, timeframe, and confidence-interval measure are described, the observed percentage and interval limits are not reported. The event count and number contributing data to the endpoint are also not reported.

The registry does not report participant-level follow-up duration, completion of inhibitor testing, handling of missing samples, or rules for incomplete follow-up. Enrollment is reported as 33, but enrollment does not indicate how many participants had complete endpoint data. The treatment description is incomplete, so dosing details beyond the stated start of the prophylactic regimen are not reported in the registry record.

The single-group, open-label design has no randomized comparator. This limits comparative interpretation and means that descriptive event counts cannot establish a treatment-caused effect. The record does not report an adjusted primary analysis or an outcome-assessment blinding procedure beyond noting central laboratory testing for the inhibitor assay.

Methodological details are also limited. The statistical analysis plan, sample-size justification, interim analyses, multiplicity approach, and missing-data methods are not reported in the registry record. The listed secondary outcomes have no numerical results in the record. The adverse-event summary provides selected serious-event terms, but does not explain their counting rules or whether terms can overlap. These gaps constrain assessment of precision, completeness, and the broader safety and efficacy findings.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study to Determine the Safety and Efficacy of rFIXFc in Previously Untreated Males With Severe Hemophilia B — NCT02234310.
• Registry record last updated 2022-03-25; status last verified 2022-03.
• Results first posted 2020-07-31.
• 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, multicenter, single-group study of intravenous rFIXFc in previously untreated males with severe hemophilia B. Enrollment was 33. The primary objective concerned safety, with confirmed inhibitor development measured by the Nijmegen-modified Bethesda assay over up to 3 years. The primary analysis population was defined as participants who received at least 1 dose.

The record lists secondary outcomes related to bleeding, response, exposure, consumption, and recovery. It also reports serious and other adverse-event counts, selected serious-event terms, and 0 deaths. However, the primary endpoint estimate and its 95% confidence interval are not reported in the registry record, and numerical results for the listed secondary outcomes are not reported there. The design provides descriptive information without a randomized comparator.