An Open Label Study to Determine the Safety and Efficacy of Replacement Factor VIII Protein (Known as rFVIIIFc) in Previously Untreated Males With Severe Hemophilia A: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for An Open Label Study to Determine the Safety and Efficacy of Replacement Factor VIII Protein (Known as rFVIIIFc) in Previously Untreated Males With Severe Hemophilia A (NCT02234323), 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 completed Phase 3, open-label, multicenter, single-group study sponsored by Bioverativ, a Sanofi company. It evaluated rFVIIIFc in previously untreated patients with severe hemophilia A. The registry lists enrollment as 108 and identifies safety as the primary objective. Secondary objectives included evaluating prevention and treatment of bleeding episodes, rFVIIIFc consumption for those purposes, and experience with immune tolerance induction in participants with inhibitors.

Because the study was open-label, participants and study personnel were not masked to treatment assignment. The registry lists no allocation because there was no randomized allocation between study arms. All participants were assigned to the rFVIIIFc intervention; the record does not describe a concurrent control arm. Therefore, changes or event patterns observed during follow-up cannot be separated from the effects of time, clinical care, or other factors by a randomized comparison.

The primary endpoint concerned confirmed inhibitor development, with follow-up stated as up to 3 years. Exposure days were defined as 24-hour periods in which a participant received at least one rFVIIIFc dose. The primary analysis population was not simply described as everyone enrolled: it was defined using exposure and inhibitor-testing criteria, with participants who developed an inhibitor after initial administration also included. The exact endpoint denominator and the observed percentage are not reported in the registry record.

Secondary outcomes included annualized bleeding measures, treatment responses, exposure days, rFVIIIFc consumption, doses used to resolve bleeding episodes, and change in incremental recovery. The registry record does not provide the corresponding results in the registry record for this analysis. Enrollment, endpoint definitions, and outcome lists describe the study’s scope, but they do not by themselves establish the size or precision of any treatment effect.

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: 110 participants screened, 108 enrolled, 103 received drug.

All Enrolled

Reasons for not completing this period:

All Treated

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety analysis set participants who 1) reached \>=10 EDs and had \>=1 inhibitor test performed at \>=10 EDs or who had inhibitor or 2) did not develop inhibitor but reached \>=10 EDs or 3) developed an inhibitor following the initial rFVIIIFc administration.

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 safety analysis set was defined as all participants who received at least 1 dose of rFVIIIFc.

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 was the percentage of participants with confirmed inhibitor development, measured using the Nijmegen-modified Bethesda assay. Inhibitors are antibodies that can interfere with factor VIII activity, so monitoring for their development is an important safety focus in a study of replacement factor VIII among previously untreated participants. The endpoint converts assay findings into a participant-level event: a positive result required a value of >=0.6 BU/mL at central laboratory testing and confirmation on a separate sample collected >=2 weeks after the initial sample.

The registry states that the endpoint covered up to 3 years. Its population definition uses exposure to treatment and availability of inhibitor testing. Participants who reached >=10 exposure days and had an inhibitor test at or beyond that milestone were eligible for the specified analysis population; participants who reached the milestone without an inhibitor were included in the denominator. Participants who developed an inhibitor following initial administration were included in both numerator and denominator. These rules are relevant because the reported percentage depends on who qualifies for the numerator and denominator, not just the registry’s overall enrollment.

A percentage is useful for expressing how common the defined event was in the endpoint population. A confidence interval conveys uncertainty around that estimate. Neither the percentage nor its 95% confidence interval is reported in the registry record, so the endpoint’s observed frequency and precision cannot be described from the available information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the primary percentage represent?

The endpoint is a binary participant-level outcome: a participant either met the registry’s definition of confirmed inhibitor development or did not. The reported percentage would describe the proportion meeting that definition within the specified endpoint population. It is not a measure of the number of positive assay tests, because the definition requires confirmation and the analysis rules determine which participants enter the numerator and denominator.

The threshold was >=0.6 BU/mL by central laboratory testing using the Nijmegen-modified Bethesda assay. Confirmation required another sample collected >=2 weeks after the initial sample. These criteria help distinguish a confirmed endpoint from a single unconfirmed laboratory result. The registry record states that participants who reached >=10 exposure days and had an inhibitor test at or beyond that milestone, as well as those reaching the milestone without an inhibitor, were included in the defined population. Participants developing an inhibitor following initial administration were also included in the numerator and denominator. The resulting denominator is not reported in the registry record.

How should a confidence interval be understood?

In general, a confidence interval expresses the statistical uncertainty around an estimated quantity. For a percentage, the interval gives a range of values that are compatible with the data under the interval’s statistical assumptions. A narrower interval generally indicates greater precision, while a wider interval indicates less precision. The registry identifies a 95% confidence interval as the endpoint’s dispersion measure, but it does not report the interval’s limits or the estimated percentage. It is therefore not possible to judge the endpoint’s precision from the available registry information.

A confidence interval does not correct for weaknesses in the study design, incomplete outcome reporting, or differences between the study population and other populations. In this study, the absence of a concurrent comparator means the interval, if reported, would describe uncertainty around the single-group estimate, not uncertainty around a randomized treatment contrast.

What does the study design allow?

In general, a randomized comparison helps balance measured and unmeasured characteristics between treatment groups, supporting a causal comparison under the design’s assumptions. This study was recorded as open-label and single-group, with no randomized comparator. Its results can describe outcomes observed among participants receiving rFVIIIFc, but they cannot isolate a treatment effect by comparing outcomes with a concurrently randomized control group. The record does not report a different comparison method that would address this limitation.

Open-label conduct also means treatment masking was absent. In general, knowledge of treatment can influence reporting, clinical decisions, or assessment of subjective outcomes. Laboratory-defined inhibitor outcomes have specified testing criteria, but the registry record does not describe procedures for blinded laboratory assessment or other safeguards beyond central laboratory testing and confirmatory sampling. Such details are not reported in the registry record.

What do the planning assumptions mean?

In general, a sample-size calculation estimates the amount of information needed to detect a specified effect under stated assumptions. The planning assumptions described for illustrations use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The target effect is expressed as a stated fraction of the observed effect. These are planning assumptions, not evidence that the trial used a two-arm randomized design. The actual study is recorded as single-group.

For time-to-event planning, the stated convention is to report the total number of events; for other outcomes, it is to report participants per arm. Such planning values are illustrations and should not be described as observed power. The registry record does not report a protocol sample-size justification or establish that these illustration assumptions governed the trial’s design. No planning estimate is reported in the registry record for this analysis.

Why do outcome definitions and denominators matter?

Statistical estimates depend on the population and event definition used. Here, the primary endpoint’s population is tied to exposure-day milestones, testing, and inhibitor status. If different participants were included or excluded, the percentage could change even if the underlying clinical experience did not. That is why the defined analysis population and its denominator are necessary for interpreting a percentage.

The record also lists several secondary outcome types, including annualized bleeding measures and treatment-response assessments. These outcomes require their own definitions, observation periods, and analysis populations. The registry lists outcome names but does not report their results or detailed analysis procedures in the registry record. In general, annualized rates relate event counts to time under observation, while treatment-response scales classify the recorded response to an injection. The record’s outcome list alone does not provide enough information to reconstruct an estimate or assess its precision.

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 VIII Fc Fusion Prot")
n      <- c(90)
events <- c(28)
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 VIII Fc Fusion Prot  90  28  31.1  21.8  41.7  22.5  41.3  22.5  41.3

11. Multiplicity, Missing Data and Analysis Populations

The registry identifies a primary safety endpoint and lists several secondary outcomes, including bleeding rates, spontaneous joint bleeding, treatment response, exposure days, consumption, treatment of bleeding episodes, and incremental recovery. It does not report how statistical testing across these outcomes was organized or whether any adjustment for multiple testing was used. Multiplicity procedures are not reported in the registry record. Without a stated testing hierarchy or adjustment, a reader should not assume that every secondary finding has the same confirmatory status as the primary objective.

The registry record does not report missing-data handling, rules for incomplete follow-up, or sensitivity analyses for missing outcomes. It also does not provide enough detail to determine how participants with incomplete testing or follow-up were handled beyond the stated primary-population criteria. Those criteria specify that participants who reached >=10 exposure days and had an inhibitor test at or beyond that milestone, participants reaching the milestone without inhibitor development, and participants who developed an inhibitor following initial administration were included in the stated population. The resulting denominator is not reported.

The record lists an enrollment of 108, but that figure should not be assumed to be the denominator for the primary endpoint or each secondary outcome. Different outcome definitions may involve different analysis populations. The registry does not report the analysis population and denominator for each secondary outcome, nor does it provide detailed methods for addressing participants without evaluable outcome data.

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: factor viii inhibition (27.2%), central venous catheterisation (25.2%), fall (10.7%), head injury (7.8%), pyrexia (3.9%).

The registry lists serious adverse event information for the rFVIIIFc group, with 103 recorded as at risk and 60 as affected. It separately lists 103 at risk and 85 affected for other adverse events, and reports 1 death. These figures describe the safety information recorded for the group; they are not comparisons against a control group. The registry record does not establish that an event was caused by rFVIIIFc merely because it occurred during the study.

The listed serious adverse event terms and percentages are factor viii inhibition, 27.2%; central venous catheterisation, 25.2%; fall, 10.7%; head injury, 7.8%; pyrexia, 3.9%; and haematoma, 2.9%. These percentages describe the listed terms as recorded in the registry. The record does not report the exact event-count basis or additional detail needed to interpret every percentage as a participant-level risk. The terms may refer to clinical events, and the registry’s listing should not be read as establishing treatment causality.

In general, safety summaries depend on event definitions, observation time, attribution rules, and the population at risk. Those details are not fully reported in the information. Because the study had no randomized control group, the figures cannot show whether the recorded events were more or less frequent than they would have been under another treatment.

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

The registry record establishes that this was an open-label, single-group Phase 3 study of rFVIIIFc in previously untreated males with severe hemophilia A. It identifies confirmed inhibitor development as the primary endpoint, describes the assay threshold and confirmation rule, and states that follow-up extended up to 3 years. It also lists safety information and secondary outcomes intended to describe bleeding, treatment response, exposure, consumption, and incremental recovery.

Those details do not reveal the observed primary endpoint percentage or its 95% confidence interval. The registry record does not report the denominator for that endpoint, and it does not report the secondary outcome estimates in the information available for this analysis. Therefore, the frequency of confirmed inhibitor development, its statistical precision, and the numerical results for the listed secondary outcomes cannot be evaluated from these registry entries alone.

The safety figures describe events recorded during the study, not necessarily events caused by the intervention. In the absence of a concurrent randomized comparator, they cannot establish how event frequency compares with another treatment or with no study intervention. Likewise, the study’s design cannot separate observed outcomes from other influences as a randomized comparison could.

These limitations do not make the registry information meaningless: the study objectives, endpoint definition, population rules, and recorded safety figures provide context for understanding the investigation. But an outcome definition is not an outcome estimate, and a descriptive safety record is not a controlled estimate of comparative risk. The posted information supports a description of what the study set out to assess and some recorded adverse-event data, while leaving key efficacy and primary-endpoint results not reported in the registry record.

14. Why This Trial Matters Statistically

This study raises a statistical issue common in safety-focused clinical research: a meaningful endpoint depends on a clear event definition and a clearly specified analysis population. Confirmed inhibitor development was defined using a laboratory threshold, central testing, and a separate confirmatory sample. The population rules also accounted for exposure and inhibitor-testing milestones. These details are essential to interpreting any eventual percentage because the numerator and denominator are shaped by those rules.

The design also matters to the kind of conclusion the data can support. An open-label, single-group study can document outcomes observed during treatment and follow-up, including safety events. It does not provide a randomized comparison with another treatment. This distinction is especially important when readers encounter percentages or event counts: a descriptive number is not automatically a comparative treatment effect.

The registry lists a range of secondary outcomes, from bleeding measures to treatment consumption and incremental recovery. Each outcome raises its own questions about definition, analysis population, observation time, and precision. The registry record does not report the numerical results or the details needed to assess those analyses. Nor does it report the multiple-testing approach across outcomes.

For biostatisticians and clinical researchers, the record illustrates why interpretation must keep endpoint definition, analysis population, study design, and result reporting in view together. Here, the endpoint is specified, but its estimate and confidence interval are not reported in the registry record. The safety information is descriptive, and the absence of a comparator limits causal interpretation. Stating those boundaries is part of an accurate statistical reading.

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 of the available registry information is that it does not report the primary endpoint percentage or its 95% confidence interval. It also does not report the endpoint denominator. Although the analysis population is defined using exposure days, inhibitor tests, and inhibitor status, the number of participants meeting those rules is not reported in the registry record.

The single-group, open-label design provides no randomized comparator. As a result, the study cannot estimate a randomized contrast between rFVIIIFc and another intervention. Knowledge of treatment assignment may also affect some aspects of event reporting or assessment; details of masking for laboratory work beyond central testing are not reported in the registry record.

Although secondary outcomes are listed, their numerical results are not reported in the registry record for this analysis. The registry record also does not report the statistical analysis plan, handling of missing data, sensitivity analyses, multiplicity procedures, or a protocol-based sample-size justification. The planning assumptions described for illustrations should not be mistaken for the study’s own design rationale or for observed power.

The safety summary provides affected and at-risk figures, serious adverse event terms, and a death count, but does not provide all contextual details needed to interpret attribution, event timing, or the precise denominator underlying each listed term percentage. These limitations restrict conclusions to the design and descriptive information that the registry record reports.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: An Open Label Study to Determine the Safety and Efficacy of Replacement Factor VIII Protein (Known as rFVIIIFc) in Previously Untreated Males With Severe Hemophilia A — NCT02234323.
• Registry record last updated 2022-04-11; status last verified 2022-03.
• Results first posted 2020-08-13.
• 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

NCT02234323 is a completed, open-label, multicenter, single-group Phase 3 study sponsored by Bioverativ, a Sanofi company. It evaluated rFVIIIFc in previously untreated males with severe hemophilia A and lists enrollment as 108. Safety was the primary objective; secondary objectives included bleeding prevention and treatment, factor consumption, and experience with immune tolerance induction.

The primary endpoint was the percentage with confirmed inhibitor development, measured using the Nijmegen-modified Bethesda assay, with follow-up up to 3 years. The record defines the confirmation threshold and analysis population, but does not report the endpoint percentage, confidence interval, or denominator. Safety figures include 60 affected among 103 at risk for serious adverse events, 85 affected among 103 at risk for other adverse events, and 1 death. The single-group design does not support a randomized treatment comparison.