This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Recombinant Coagulation Factor VIII Fc Fusion Protein (rFVIIIFc) in Previously Treated Pediatric Subjects With Hemophilia A (NCT01458106), a na phase 3 study. The primary outcome is Occurrence of FVIII Inhibitor Development.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01458106 |
| Phase | Phase 3 |
| Condition | Hemophilia A |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 71 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Bioverativ Therapeutics Inc. |
| Results posted | Yes |
2. Clinical Question
Population
Previously treated pediatric participants with hemophilia A. The registry describes the safety analysis set as participants who received at least one dose of prestudy FVIII or rFVIIIFc. Safety results are organized into age groups younger than 6 years and 6 to younger than 12 years.
Intervention
The study evaluated recombinant coagulation factor VIII Fc fusion protein, identified as rFVIIIFc and BIIB031, for prevention and treatment of bleeding episodes. Prestudy FVIII is also listed for pharmacokinetic assessment in a subgroup.
Comparator
There was no randomized comparison group. The registry classifies the study as single-group, with allocation and masking listed as not applicable and none, respectively. The listed intervention groups therefore do not constitute a like-for-like control comparison.
Primary question
The primary endpoint was the occurrence of confirmed FVIII inhibitor development, expressed as a percentage of participants. The registry describes assessment through Week 26 ± 7 days, or through 50 exposure days if reached earlier. The numerical endpoint result is not reported in the registry record.
The study’s primary objective was to evaluate safety in previously treated pediatric participants with hemophilia A. Secondary objectives addressed prevention and treatment of bleeding episodes, pharmacokinetics, and rFVIIIFc consumption for bleeding prevention and treatment. The registry lists secondary outcomes including annualized bleeding rate, annualized spontaneous joint bleeding rate, response assessments, consumption, and measures of treatment required to resolve bleeding episodes. These objectives frame the questions the study was designed to address; without numerical outcome results, they do not establish the size or precision of any observed effects.
3. Trial Design
This was a Phase 3, open-label, multicenter evaluation of rFVIIIFc in pediatric participants with hemophilia A. The registry identifies the model as single-group, allocation as not applicable, and masking as none. The study is listed as completed, with a start date of 2012-11 and a primary completion date of 2013-12. Enrollment is listed as 71.
The design is important for interpreting the evidence. A single-group study can describe outcomes observed among participants receiving the study intervention, but it does not provide a randomized control group for estimating a treatment contrast. Any before-and-after or other comparative interpretation would require details and analyses not reported in the registry record. The registry explicitly notes that its arms are not a like-for-like control comparison.
The intervention listing includes BIIB031 (rFVIIIFc) and FVIII for the pharmacokinetic subgroup only. The arm description states that subgroup participants received a prestudy FVIII injection for pharmacokinetic assessment at the baseline visit, after a washout period of at least 72 hours. It specifies a dose of 50 IU/kg, rounded up to the nearest 250 IU increment, administered intravenously over 5 ± 2 minutes. The remaining arm-description text is incomplete in the registry record, so the full sequence of study procedures is not reported there.
The primary endpoint timeframe extended to Week 26 ± 7 days, or to 50 exposure days if that threshold was reached before Week 26. The registry also lists 35 outcome measures, including several bleeding, response, and consumption measures. The posted record does not give numerical primary endpoint results or numerical results for the listed secondary outcomes. Consequently, the design and objectives can be described, but the magnitude and precision of the study’s outcome findings cannot be evaluated from the registry record.
4. Participant Flow and Accounting
The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.
Overall Study
| Stage | Participants < 6 Years Old | Participants 6 to < 12 Years Old |
|---|---|---|
| STARTED | 36 | 35 |
| PK Subgroup | 25 | 35 |
| Non-PK Subgroup | 11 | 0 |
| COMPLETED | 33 | 34 |
| NOT COMPLETED | 3 | 1 |
Reasons for not completing this period:
| Reason | Participants < 6 Years Old | Participants 6 to < 12 Years Old |
|---|---|---|
| Withdrawal by Subject | 2 | 0 |
| Pre-rFVIIIFc Adverse Event | 1 | 0 |
| Withdrawn Per Protocol | 0 | 1 |
Analysis population for the primary outcome, as defined in the registry: Safety Analysis Set: participants who received at least 1 dose of prestudy FVIII, or at least 1 dose of rFVIIIFc; n=number of participants with given number of exposure days who had a valid inhibitor test.
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.
| Characteristic | Unit | Participants < 6 Years Old | Participants 6 to < 12 Years Old | Total |
|---|---|---|---|---|
| Participants analysed | 36 | 35 | 71 | |
| Age, Continuous | years | 4.0 (1 to 5) | 8.0 (6 to 11) | 5.0 (1 to 11) |
| Sex: Female, Male: Female | Participants | 0 | 0 | 0 |
| Sex: Female, Male: Male | Participants | 36 | 35 | 71 |
6. Primary Endpoint
The registry lists the primary outcome as Occurrence of FVIII Inhibitor Development, measured over Up to Week 26 +/- 7 days, or up to 50 exposure days (EDs) if reached prior to Week 26.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | 95% Confidence Interval |
| Unit | percentage of participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint was the occurrence of FVIII inhibitor development, measured as a percentage of participants. An inhibitor result was considered positive when the test was at least 0.6 Bethesda units per milliliter and the finding was confirmed on two separate samples drawn 2 to 4 weeks apart. Both tests were to be performed by the central laboratory using the Nijmegen-modified Bethesda assay.
This endpoint is used to identify participants with a confirmed inhibitor result under the registry’s stated definition. Requiring confirmation on separate samples makes the endpoint depend on more than a single test result. The registry planned to summarize incidence among participants with at least 50 exposure days to rFVIIIFc and also among all participants regardless of exposure days. The primary endpoint timeframe was through Week 26 ± 7 days, or through 50 exposure days if reached before Week 26.
The registry describes exact 95% confidence intervals for the proportion, calculated with the Clopper-Pearson method. However, the numerical event count, denominator, percentage, and confidence interval for this endpoint are not reported in the registry record. The endpoint definition therefore explains what would count as an event, but does not reveal how often it occurred in this study.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry establishes the study’s design, target population, outcome definitions, and some safety counts, but it does not report a numerical result for the primary endpoint. The occurrence of confirmed FVIII inhibitor development is therefore not quantifiable from the registry record. No percentage or confidence interval can be interpreted, and the precision of the primary endpoint estimate cannot be assessed. The same limitation applies to the listed secondary bleeding, response, pharmacokinetic, and consumption outcomes: their names are present, but their numerical results are not reported in the registry record.
The primary endpoint was defined with a specific laboratory threshold and confirmation process. That definition helps establish which observations would qualify as inhibitor development, but a definition alone is not an outcome finding. The record describes results intended for participants with at least 50 exposure days and for all participants irrespective of exposure days. Because numerical results and endpoint denominators are absent, the two intended summaries cannot be compared or assessed.
The study was single-group and open-label, with no randomized comparator. It can be understood as an evaluation of outcomes among participants receiving the study intervention, not as a randomized estimate of differences between treatment groups. Any causal comparison with another treatment or with no treatment would require a comparator and analysis not reported in the registry record. The study’s design also means that the record cannot support a treatment contrast by simply comparing the listed age groups: those are safety categories, not randomized study arms.
The registry lists enrollment as 71, while the primary endpoint description defines its denominator according to participants with a valid inhibitor test and their exposure-day status. Enrollment should not be treated as the denominator for the primary endpoint without the relevant result counts. The safety record supplies age-specific risk and affected counts for serious and other adverse events, but these counts do not substitute for the missing primary endpoint result.
For general statistical interpretation, an estimate describes the observed frequency in the analyzed participants, while a confidence interval conveys uncertainty about the underlying proportion under the method’s assumptions. A narrow or wide interval cannot be inferred without the interval itself. Nor should an absent result be read as zero events, evidence of no effect, or evidence of safety. The registry record supports a description of what was planned and some safety observations; it does not support conclusions about the magnitude or precision of the primary endpoint or secondary outcomes.
9. Statistical Methods Explained
The registry’s primary endpoint is a binary participant-level outcome: a participant either met the stated confirmed-inhibitor definition or did not. The endpoint is reported as a percentage of participants. The registry specifies an exact 95% confidence interval using the Clopper-Pearson method for a binomial proportion. The record does not report the resulting percentage, interval limits, event count, or denominator, so the method can be described but its numerical output cannot be interpreted.
What does the endpoint definition require?
The registry defines a positive inhibitor result using a threshold of at least 0.6 Bethesda units per milliliter, with confirmation on two separate samples drawn 2 to 4 weeks apart. It states that the central laboratory was to perform both tests with the Nijmegen-modified Bethesda assay. This definition is more specific than a single positive test: a participant must meet the threshold and the confirmation requirement to qualify as an endpoint event. The registry record does not report how many participants had positive tests, how many met the confirmation requirement, or whether any participants lacked a valid test.
Why use an exact confidence interval?
General explanation: a binomial proportion is based on a count of participants with an event out of an analyzed group. An exact confidence interval is a method for expressing uncertainty around that proportion, particularly when the event count or denominator may be limited. The interval is not a guarantee that the true value lies within its limits; it describes uncertainty using the method’s statistical framework. Without the event count, denominator, and interval limits, there is no basis for judging the precision of this study’s primary estimate. The registry’s choice of method does not itself indicate whether the endpoint was common or rare.
How should exposure days be understood?
The endpoint description distinguishes participants with at least 50 exposure days to rFVIIIFc from all participants regardless of exposure days. These are intended summaries for different exposure definitions, not separate randomized groups. The record says the endpoint timeframe was through Week 26 ± 7 days, or through 50 exposure days if reached before Week 26. Exposure-day thresholds help define which observations enter a particular summary; they do not provide the missing numerator or denominator. The primary endpoint population is also described as participants with a valid inhibitor test for the relevant number of exposure days.
What can a single-group design estimate?
General explanation: a single-group study can describe outcomes among the participants observed under the study conditions. Without a randomized comparator, it cannot by itself estimate a randomized difference between the intervention and another treatment or control. In this record, allocation is listed as not applicable, masking as none, and the model as single-group. The registry also cautions that the arms are not a like-for-like control comparison. Therefore, age-stratified safety counts should not be interpreted as comparative treatment effects.
What do the planning illustrations mean?
The stated sample-size assumptions describe planning illustrations, not observed power. They specify a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. The registry says that time-to-event illustrations give total events and other illustrations give participants per arm. These are hypothetical planning quantities, not outcomes observed in this single-group trial, and they do not establish that the study had a particular probability of detecting an effect. The numerical planning scenarios are not reported in the registry record.
The registry lists 35 outcome measures and eight named secondary outcomes, but it does not report a statistical analysis plan or numerical results for those outcomes. The number of outcomes alone does not reveal which analyses were performed, which were primary to any particular question, or how results were selected for reporting. The registry’s primary endpoint description supplies the test definition and confidence-interval method; details such as covariate adjustment, interim analyses, and handling of missing endpoint observations are not reported in the registry record.
General explanation: over-dispersion matters when data vary more than a model’s assumptions allow, which can make standard errors and uncertainty estimates unreliable if not addressed. The registry record does not report an over-dispersion model for the primary binary endpoint, and the exact binomial method is the stated approach for its interval. This general consideration should not be mistaken for evidence that over-dispersion was present in this study. For the secondary bleeding outcomes, the analytical distributions and models are not reported in the registry record, so their statistical methods cannot be evaluated.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 35 outcome measures, including the primary inhibitor endpoint and several secondary bleeding, response, pharmacokinetic, and consumption outcomes. When a study assesses multiple outcomes, the chance of at least one apparently notable result can depend on how many tests are performed and how those tests are interpreted. General explanation: multiplicity procedures can help control that risk, but their selection and application must be specified to evaluate their role. A multiplicity adjustment or other strategy for interpreting multiple outcomes is not reported in the registry record.
The outcome list does not establish that every measure was analyzed, nor does it identify a complete hierarchy among the secondary measures. The registry record does not report the statistical analysis plan, interim analyses, or an approach to selecting or prioritizing secondary results. Numerical results for the listed secondary outcomes are not reported in the registry record, limiting assessment of both the findings and the impact of multiple testing.
The primary endpoint description defines the relevant analysis population as participants with a valid inhibitor test for the applicable exposure-day group. The broader Safety Analysis Set is described as participants who received at least one dose of prestudy FVIII or at least one dose of rFVIIIFc. These definitions are not interchangeable: the primary endpoint denominator depends on valid test availability and exposure days, while the safety-set definition depends on treatment receipt. Counts for the primary endpoint populations are not reported in the registry record.
How missing or invalid inhibitor tests were handled is not reported in the registry record. The record also does not report imputation, sensitivity analyses, or rules for excluding participants from individual secondary outcomes. Without those details and the outcome denominators, the effect of missing data on the reported findings cannot be assessed. Enrollment should not be substituted for an endpoint-specific analysis denominator.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Participants < 6 Years Old | 4 | 35 | 11.4% |
| Participants 6 to < 12 Years Old | 1 | 34 | 2.9% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Participants < 6 Years Old | 31 of 35 |
| Participants 6 to < 12 Years Old | 28 of 34 |
Most frequent serious adverse event terms
| Event term | Organ system | Participants < 6 Years Old | Participants 6 to < 12 Years Old |
|---|---|---|---|
| Head Injury | Injury, poisoning and procedural complications | 2 of 35 | 0 of 34 |
| Bacillus Infection | Infections and infestations | 0 of 35 | 1 of 34 |
| Croup Infectious | Infections and infestations | 1 of 35 | 0 of 34 |
| Escherichia Infection | Infections and infestations | 0 of 35 | 1 of 34 |
| Metapneumovirus Infection | Infections and infestations | 1 of 35 | 0 of 34 |
| Fall | Injury, poisoning and procedural complications | 1 of 35 | 0 of 34 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Participants < 6 Years Old | Participants 6 to < 12 Years Old |
|---|---|---|---|
| Cough | Respiratory, thoracic and mediastinal disorders | 7 of 35 | 6 of 34 |
| Upper Respiratory Tract Infection | Infections and infestations | 7 of 35 | 2 of 34 |
| Nasopharyngitis | Infections and infestations | 2 of 35 | 4 of 34 |
| Abdominal Pain Upper | Gastrointestinal disorders | 1 of 35 | 4 of 34 |
| Vomiting | Gastrointestinal disorders | 3 of 35 | 2 of 34 |
| Fall | Injury, poisoning and procedural complications | 3 of 35 | 2 of 34 |
| Headache | Nervous system disorders | 1 of 35 | 4 of 34 |
| Diarrhoea | Gastrointestinal disorders | 3 of 35 | 1 of 34 |
| Fatigue | General disorders | 1 of 35 | 3 of 34 |
| Seasonal Allergy | Immune system disorders | 2 of 35 | 2 of 34 |
Serious events with the highest arm-level rate: head injury (5.7%), bacillus infection (2.9%), escherichia infection (2.9%), croup infectious (2.9%), metapneumovirus infection (2.9%).
The safety record separates participants younger than 6 years from participants 6 to younger than 12 years. For serious adverse events, it lists 4 affected participants among 35 at risk in the younger group and 1 among 34 at risk in the older group. For other adverse events, the corresponding listed counts are 31 among 35 and 28 among 34. These are descriptive counts within the registry’s age categories, not randomized comparisons.
The registry’s listed serious-event terms include Head Injury at 5.7%, and Bacillus Infection, Escherichia Infection, Croup Infectious, Metapneumovirus Infection, and Fall at 2.9% each. The denominator and counting details for these term percentages are not reported in the registry record. The percentages should therefore be read as listed descriptive figures, not as comparative risks or as evidence about cause.
Deaths are not reported in the registry record. The safety figures do not establish whether an event was related to treatment, and the registry record does not report attribution details in the registry record. Counts of participants with events are distinct from counts of event episodes, which are not reported. These safety observations are best interpreted as descriptive summaries for the recorded age groups; they do not replace the missing numerical primary endpoint result or establish a comparison with another treatment.
12. What the Result Does, and Does Not, Mean
The registry record documents a completed Phase 3, open-label, single-group study in previously treated pediatric participants with hemophilia A. It describes the study’s objectives, the primary inhibitor endpoint definition, the assessment timeframe, and some age-stratified adverse-event counts. These details explain what the study set out to assess and how the primary endpoint was defined.
The record does not report the numerical primary endpoint result. It therefore does not show the percentage of participants with confirmed inhibitor development or the associated 95% confidence interval. Numerical findings for the listed secondary bleeding, response, pharmacokinetic, and consumption outcomes are also not reported in the registry record. Absence of those results cannot be interpreted as zero events, no inhibitor development, or no observed change.
The study design also sets limits on what can be concluded. With a single group and no randomized comparator, the registry record does not provide a randomized estimate of how outcomes differ from those under another treatment or control. The age categories used for safety summaries are not treatment arms. The record’s sample-size assumptions describe planning illustrations, not observed power and not evidence that a particular treatment difference was detected.
General explanation: statistical precision depends on the observed data and the method used to quantify uncertainty. Here, the registry describes an exact confidence-interval method but gives no endpoint estimate or interval limits. As a result, the precision of the primary result cannot be judged. The adverse-event counts are available as descriptive information, but the record does not report attribution details or a comparator that would support a comparative safety interpretation.
The appropriate reading is therefore bounded: the registry defines a study and its intended outcomes, and it records selected safety summaries, but it does not report the principal numerical outcome findings needed to assess the primary endpoint’s frequency or precision. Neither treatment benefit nor lack of benefit can be inferred from an absent endpoint result.
13. Why This Trial Matters Statistically
This trial is statistically informative in part because its endpoint definition is explicit. The registry specifies a laboratory threshold, confirmation on two samples, a central assay, and an exact confidence-interval method for the primary proportion. Such details clarify what qualifies as an endpoint event and what method was intended to express uncertainty. They also make clear what numerical information would be needed for interpretation: the relevant event count, denominator, proportion, and interval.
The design illustrates why the study model matters. A single-group, open-label study can provide descriptive evidence about participants observed in the study, but it does not furnish a randomized comparison. The registry’s age-specific safety summaries therefore should not be read as treatment contrasts. Nor can planning illustrations based on hypothetical two-arm assumptions be treated as observed trial power or as a substitute for a control group.
The registry also distinguishes the broader safety population from the primary endpoint’s valid-test and exposure-day populations. This is statistically important because the denominator can vary with endpoint definition and participant availability. Enrollment alone is not enough to reconstruct those denominators.
Finally, the record highlights the importance of outcome reporting. It lists a range of secondary outcomes and defines the primary endpoint, but numerical results for the primary and secondary outcomes are not reported in the registry record. Without estimates and uncertainty intervals, readers cannot assess the size or precision of the endpoint findings. The documented safety counts remain descriptive evidence, not a substitute for those missing 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.
A central limitation of the available registry record is the absence of numerical results for the primary endpoint. The record describes the confirmed-inhibitor definition and planned confidence-interval method, but does not report the number of events, endpoint denominator, percentage, or interval. Numerical results for the listed secondary outcomes are also not reported in the registry record. This prevents assessment of the magnitude and precision of the main and secondary findings.
The single-group, open-label design has no randomized control group. Consequently, the study record does not support a randomized comparison with another treatment or control. The age-stratified safety groups are descriptive categories, not comparable randomized arms. The record does not report masking, which is listed as none, and it does not report a statistical analysis plan or an approach to interim analyses.
The primary endpoint’s denominator is defined by exposure days and valid inhibitor testing, but the corresponding counts are not reported in the registry record. Handling of missing or invalid tests, missing secondary outcome data, and participant exclusions from specific analyses is also not reported in the registry record. The enrollment figure cannot resolve those endpoint-specific denominator questions.
The registry lists 35 outcome measures and does not report a multiplicity strategy. Numerical results and their uncertainty are unavailable for the listed secondary outcomes, so their interpretation and relationship to the primary endpoint cannot be evaluated. The serious adverse-event term percentages are listed without denominator details in the registry record, and deaths are not reported in the registry record. These limitations constrain interpretation of both efficacy-related outcomes and safety summaries.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Recombinant Coagulation Factor VIII Fc Fusion Protein (rFVIIIFc) in Previously Treated Pediatric Subjects With Hemophilia A — NCT01458106.
- Registry record last updated 2020-12-19; status last verified 2018-08.
- Results first posted 2014-12-12.
- 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.
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18. Record Summary
The registry describes a completed, Phase 3, open-label, multicenter, single-group study of rFVIIIFc in previously treated pediatric participants with hemophilia A. Enrollment is listed as 71. The primary objective was safety; secondary objectives included efficacy for prevention and treatment of bleeding episodes, pharmacokinetics, and treatment consumption.
The primary endpoint was confirmed FVIII inhibitor development, assessed through Week 26 ± 7 days or through 50 exposure days if reached earlier. The record defines the confirmation criteria and specifies an exact 95% confidence interval, but the numerical primary result is not reported in the registry record. Numerical secondary outcome results are also not reported there.
The registry lists age-specific serious and other adverse-event counts. Because the study had no randomized comparator, these are descriptive safety summaries rather than comparative treatment estimates. The record does not report the statistical analysis plan, missing-data handling, or multiplicity strategy.