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 A Safety and Efficacy Study of a Recombinant Fusion Protein Linking Coagulation Factor IX With Albumin (rIX-FP) in Patients With Hemophilia B (NCT01496274), a non-randomized phase 2, phase 3 study. The primary outcome is Change in Frequency of Spontaneous Bleeding Events Between On-demand and Prophylaxis Treatments (Annualized).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01496274 |
| Phase | Phase 2, Phase 3 |
| Condition | Hemophilia B |
| Allocation | Non-Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 63 |
| Arms in the primary outcome | n/a |
| Lead sponsor | CSL Behring |
| Results posted | Yes |
2. Clinical Question
Population
People with hemophilia B who had previously received factor replacement therapy. The primary analysis included participants assigned to the on-demand arm who received at least 1 dose of rIX-FP during both the on-demand and prophylaxis regimens.
Intervention
Weekly prophylaxis with rIX-FP, following an on-demand treatment period for the participants included in the primary comparison. The separate prophylaxis arm also received routine weekly prophylaxis; individualized dosing intervals could be tested in a subgroup during the second part of the trial.
Comparator
On-demand rIX-FP treatment for bleeding episodes, compared within the same participants with their subsequent weekly prophylaxis period. This is a before-and-after comparison, not a randomized comparison between independent treatment groups.
Primary question
How did each participant’s annualized frequency of spontaneous bleeding events during the on-demand regimen compare with that during the prophylaxis regimen? The registry record specifies a median and inter-quartile range as the summary measures, but does not report the primary outcome values.
3. Trial Design
This completed Phase II/III study evaluated rIX-FP in people with hemophilia B who had previously received factor replacement therapy. The registry describes a non-randomized, open-label, multicenter study with a parallel-group structure and enrollment of 63. Its stated aims included safety, pharmacokinetics and efficacy for control and prevention of bleeding episodes.
The arms followed different treatment schedules. Participants in the Prophylaxis arm received routine weekly prophylaxis and episodic treatment for bleeding episodes. The registry says that an individualized dosing interval could be tested in a subgroup during the second part of the trial. Participants in the On-demand arm received episodic treatment for bleeding episodes during the first 6 months, then switched to routine weekly prophylaxis for a further 6 months. Participants in either arm could take part in a surgical sub-study involving rIX-FP before, during and after surgery.
The primary outcome comparison is narrower than the overall arm comparison: it uses participants assigned to the On-demand arm who received at least 1 dose in each regimen. For those participants, spontaneous bleeding frequency during on-demand treatment is compared with frequency during subsequent prophylaxis. The registry describes the on-demand observation period as up to 26 weeks and the prophylaxis period as between 1 and 17 months. This sequence means regimen and period are linked; the comparison does not separate their effects through random assignment.
The registry lists a study start of 2012-02, primary completion of 2014-07 and status as completed. Allocation was non-randomized and masking was none. The record does not report a comparator receiving no rIX-FP or a randomized control treatment.
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 69 subjects provided informed consent and were screened for study participation. Of these, 63 subjects were enrolled and treated with rIX-FP.
Overall Study
| Stage | Prophylaxis | On-demand |
|---|---|---|
| STARTED | 40 | 23 |
| COMPLETED | 37 | 18 |
| NOT COMPLETED | 3 | 5 |
Reasons for not completing this period:
| Reason | Prophylaxis | On-demand |
|---|---|---|
| Protocol Violation | 0 | 1 |
| Adverse Event | 1 | 1 |
| Withdrawal by Subject | 2 | 0 |
| Lost to Follow-up | 0 | 3 |
Analysis population for the primary outcome, as defined in the registry: This analysis includes only the participants assigned to the on-demand arm who received at least 1 dose of rIX-FP in the on-demand regimen and at least 1 dose of rIX-FP in the prophylaxis regimen.
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: Safety Population
| Characteristic | Unit | Prophylaxis | On-demand | Total |
|---|---|---|---|---|
| Participants analysed | 40 | 23 | 63 | |
| Age, Customized: 0 to 11 years | participants | 0 | 0 | 0 |
| Age, Customized: 12 to 17 years | participants | 7 | 0 | 7 |
| Age, Customized: 18 to 64 years | participants | 33 | 23 | 56 |
| Age, Customized: 65 years and over | participants | 0 | 0 | 0 |
| Sex: Female, Male: Female | Participants | 0 | 0 | 0 |
| Sex: Female, Male: Male | Participants | 40 | 23 | 63 |
6. Primary Endpoint
The registry lists the primary outcome as Change in Frequency of Spontaneous Bleeding Events Between On-demand and Prophylaxis Treatments (Annualized), measured over Up to 26 weeks for on-demand regimen, and between 1 and 17 months for prophylaxis regimen..
| Element | Registry entry |
|---|---|
| Result type | Median |
| Measure of spread | Inter-Quartile Range |
| Unit | bleeds/year/subject |
| Endpoint classification | Time-to-Event Analysis |
The primary endpoint is the change in annualized spontaneous bleeding-event frequency between on-demand and prophylaxis treatment. It is expressed in bleeds/year/subject. The registry describes annualizing each participant’s spontaneous bleeding rate during each regimen, then comparing the same participant’s rates across the two periods. The reported summary measure is the median, with an inter-quartile range for dispersion.
Annualizing a rate allows periods with different durations to be described on a common time scale. This is relevant because on-demand treatment could continue for up to 26 weeks, while the stated prophylaxis observation period ranged between 1 and 17 months. As a general statistical concept, rates can help distinguish event frequency from the length of time under observation. Annualization does not, by itself, remove differences in observation time, event recording, or treatment sequence.
The endpoint is restricted to spontaneous bleeding events, rather than all bleeding episodes or all safety events. It focuses on a clinically relevant outcome that can be counted over treatment periods. However, the record does not report the median rates, their inter-quartile ranges, or a numerical estimate of the change. It therefore does not permit the magnitude or direction of the primary endpoint result to be described.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The central statistical feature is a within-participant comparison. The same participants contribute a rate for the on-demand regimen and a rate for the subsequent prophylaxis regimen. This can account for stable differences between participants, such as a participant’s usual tendency to experience bleeding, because each participant serves as their own reference. It does not make the treatment sequence randomized, and it cannot by itself separate regimen effects from changes over time.
The registry record specifies that the primary outcome is summarized using the median and inter-quartile range. A median describes the middle of the observed distribution, while the inter-quartile range describes the spread of its central portion. As a general statistical point, this approach is less driven by unusually high values than a mean may be. It does not show the full distribution, and it does not give the precision of an estimated treatment contrast unless an uncertainty measure for that contrast is also reported.
The registry does not report the actual median spontaneous bleeding rates, inter-quartile ranges, a change estimate, or a confidence interval for the primary comparison. Consequently, the posted results cannot establish from the record whether the observed rate was higher or lower in either regimen, or how precisely any difference was estimated. No statistical significance result for this endpoint is reported in the registry record. A numerical conclusion should not be inferred from the study title or stated objective.
The trial’s non-randomized allocation and open-label status matter when interpreting comparisons. Participants and study staff were not masked, and treatment was not assigned randomly. Awareness of regimen can affect decisions about treatment, reporting, and assessment. The primary comparison also follows a fixed sequence in which the on-demand period precedes prophylaxis. Time-related changes, differences in exposure, or other changes during participation could therefore accompany the regimen change. The record does not report methods that quantify or adjust for these possibilities.
The record reports enrollment of 63, but the primary analysis population is defined by treatment exposure: participants in the On-demand arm must have received at least 1 dose during both regimens. Enrollment alone therefore does not indicate how many participants contributed to that endpoint. The number included in the primary analysis is not reported in the registry record.
These limits do not make the comparison meaningless; they define what it can describe. It is a within-participant observation across two treatment periods in a non-randomized study. The registry record does not provide enough primary outcome information to characterize the observed effect or its uncertainty.
9. Statistical Methods Explained
The endpoint and design determine how the result should be read. The registry describes a median annualized rate and an inter-quartile range, with the same participant assessed during the on-demand regimen and the subsequent prophylaxis regimen. The numerical endpoint results and the statistical test or model used to compare the periods are not reported in the registry record.
What does a median summarize?
As a general statistical concept, the median is the middle value after observations are ordered. It describes a typical location without requiring the distribution to be symmetric. Bleeding-event rates can vary across participants, so a median may be informative when some observations are much higher than others. The median alone does not show how variable individual rates are; the registry’s stated inter-quartile range provides information about the spread of the middle part of the data.
A median in each regimen is not necessarily the same as a median of participant-level changes. In general, summaries calculated separately for each period do not reveal how each person’s paired change is distributed. The registry describes comparing the same participants’ rates, but does not report the numerical paired-change summary or specify whether a formal paired analysis was used. The analysis method, including any test statistic or model, is not reported in the registry record.
Why annualize a bleeding rate?
As a general explanation, annualization expresses events relative to a common time unit when follow-up periods differ. Here, the stated on-demand period was up to 26 weeks, and the prophylaxis period ranged between 1 and 17 months. A common time scale can make rates easier to describe than raw event counts from periods of unequal duration. It does not make periods identical: estimates based on shorter observation can be less stable, and annualizing a rate does not correct for changes in participants’ circumstances or event ascertainment.
The registry does not give the exact calculation procedure, how partial exposure was handled, or how missing rate data were treated. It also does not report a confidence interval or other uncertainty measure for the primary comparison. Without those details, readers cannot assess the precision of the estimated contrast from the registry record.
What does a within-participant comparison contribute?
As a general concept, paired observations can reduce the influence of characteristics that remain relatively stable within a participant, because the comparison is made against that participant’s own experience in another period. This feature is relevant to spontaneous bleeding, which may differ substantially between people. Pairing does not eliminate time trends or effects tied to the order of treatment. In this study, the on-demand period came before prophylaxis for the primary analysis population. The record does not report randomization of regimen order or an analysis that separates period effects from regimen effects.
The study as a whole is described as parallel-group, but the primary endpoint comparison is not simply a comparison of the Prophylaxis and On-demand arm summaries. It is specifically a comparison across regimens among eligible participants assigned to the On-demand arm. The registry says those participants had to receive at least 1 dose in both periods. This exposure requirement defines the analysis population, but the number meeting it is not reported.
How should the treatment comparison be understood?
Because allocation was non-randomized and masking was none, general causal interpretations require caution. Non-random allocation can leave treatment groups different in ways that affect outcomes. In the primary within-participant comparison, stable participant differences are partly addressed by design, but time, sequence, and exposure duration remain relevant. Open-label treatment may also influence reporting or assessment. The record does not report adjustments for these potential sources of bias.
The registry lists 13 outcome measures and 1 analysis. That information does not establish whether the primary endpoint was tested alongside other outcomes under a prespecified multiplicity procedure. The multiplicity strategy, missing-data approach, and detailed statistical analysis plan are not reported in the registry record. No model choice or significance threshold for the primary comparison should be inferred from the endpoint description.
For a separate general concept, over-dispersion occurs when event-count variability exceeds what a simple count model would expect. It can affect standard errors and interval estimates if a model assumes less variability than the data contain. The registry record does not say that an event-count model was used, nor does it report an assessment of over-dispersion. This concept should not be mistaken for a description of the analysis actually conducted.
Finally, the record’s method information should be distinguished from numerical findings. It identifies the endpoint, summary measure, period definitions and analysis population, but does not report the primary outcome values or their uncertainty. The statistical method used to produce a comparison estimate is not reported in the registry record.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 13 outcome measures and 1 analysis. These counts alone do not show whether multiple outcomes were tested, whether analyses were prespecified, or whether any adjustment was made to account for multiplicity. The multiplicity strategy is not reported in the registry record. It would therefore be inappropriate to assume that a particular correction, hierarchy, or primary testing procedure was used.
The primary analysis population is described as participants assigned to the On-demand arm who received at least 1 dose during both the on-demand and prophylaxis regimens. This defines who was eligible for the comparison, but the number included in that analysis is not reported. The record does not state how participants who stopped treatment, had incomplete follow-up, or lacked a rate for either period were handled.
The missing-data method, any imputation approach, and any sensitivity analysis are not reported in the registry record. The record also does not give the number of participants with missing endpoint data or the reasons for missingness. Without this information, the effect of incomplete follow-up on the endpoint cannot be assessed.
The registry identifies the primary summary measure as a median with an inter-quartile range, but does not report the detailed statistical analysis plan, a comparison test or model, or an uncertainty interval for the contrast. The endpoint values themselves are also not reported. These omissions limit assessment of both the analysis process and the reliability of a numerical treatment comparison.
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 |
|---|---|---|---|
| Prophylaxis | 1 | 40 | 2.5% |
| On-demand | 2 | 23 | 8.7% |
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 |
|---|---|
| Prophylaxis | 36 of 40 |
| On-demand | 18 of 23 |
Most frequent serious adverse event terms
| Event term | Organ system | Prophylaxis | On-demand |
|---|---|---|---|
| ACQUIRED EPILEPTIC APHASIA | Nervous system disorders | 0 of 40 | 1 of 23 |
| SYNOVITIS | Musculoskeletal and connective tissue disorders | 0 of 40 | 1 of 23 |
| PAIN IN EXTREMITY | Musculoskeletal and connective tissue disorders | 1 of 40 | 0 of 23 |
| MUSCLE HAEMORRHAGE | Musculoskeletal and connective tissue disorders | 1 of 40 | 0 of 23 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Prophylaxis | On-demand |
|---|---|---|---|
| NASOPHARYNGITIS | Infections and infestations | 10 of 40 | 6 of 23 |
| HEADACHE | Nervous system disorders | 11 of 40 | 4 of 23 |
| ARTHRALGIA | Musculoskeletal and connective tissue disorders | 9 of 40 | 0 of 23 |
| INFLUENZA | Infections and infestations | 4 of 40 | 3 of 23 |
| LIMB INJURY | Injury, poisoning and procedural complications | 5 of 40 | 1 of 23 |
| BACK PAIN | Musculoskeletal and connective tissue disorders | 4 of 40 | 2 of 23 |
| DIARRHOEA | Gastrointestinal disorders | 2 of 40 | 3 of 23 |
| TOOTHACHE | Gastrointestinal disorders | 4 of 40 | 1 of 23 |
| UPPER RESPIRATORY TRACT INFECTION | Infections and infestations | 5 of 40 | 0 of 23 |
| BRONCHITIS | Infections and infestations | 4 of 40 | 1 of 23 |
Serious events with the highest arm-level rate: acquired epileptic aphasia (4.3%), synovitis (4.3%), pain in extremity (2.5%), muscle haemorrhage (2.5%).
The registry reports serious adverse events and other adverse events by arm. In the Prophylaxis group, 1 participant among 40 at risk was reported with a serious adverse event, and 36 among 40 at risk were reported with other adverse events. In the On-demand group, 2 participants among 23 at risk were reported with a serious adverse event, and 18 among 23 at risk were reported with other adverse events. These are separate categories in the registry; they should not be added together to infer a total number of affected participants.
The serious adverse-event terms listed with percentages are ACQUIRED EPILEPTIC APHASIA, 4.3%; SYNOVITIS, 4.3%; PAIN IN EXTREMITY, 2.5%; and MUSCLE HAEMORRHAGE, 2.5%. The registry record does not provide further event-level context in the registry record for these terms. Death counts are not reported in the registry record.
These safety figures are descriptive. The study was non-randomized and open-label, so the groups are not a like-for-like randomized control comparison. The counts do not establish that rIX-FP caused an event, and they do not by themselves quantify comparative risk. They should be read alongside the study population, treatment schedules, and the limits of the registry reporting.
12. What the Result Does, and Does Not, Mean
The record describes a study of rIX-FP in people with hemophilia B and specifies a primary comparison of spontaneous bleeding frequency during on-demand treatment and subsequent prophylaxis. The primary analysis uses participants in the On-demand arm with exposure to both regimens. Its within-participant structure is useful for describing how rates differed across periods for the same people, while the non-randomized, open-label design limits causal interpretation.
The registry record does not report the primary endpoint values, the numerical change, or an uncertainty interval. As a result, it is not possible from this record to state the direction or magnitude of the observed primary comparison, or how precisely it was estimated. The study title and stated objective are not substitutes for numerical results.
The result also cannot be treated as a randomized comparison between the two arms. The primary contrast is not an independent comparison of the Prophylaxis and On-demand groups: it compares two regimens over time among eligible participants in the On-demand arm. The on-demand period came first, followed by prophylaxis, so regimen and period are linked in this analysis.
The safety counts describe participants reported with serious and other adverse events, but do not establish causation or provide a randomized estimate of comparative safety. Other questions, including pharmacokinetic outcomes and the listed secondary outcomes, are part of the study record, but their numerical results are not reported in the registry record. No broader claim about efficacy, safety, or treatment choice follows from the available registry entries alone.
In practical statistical terms, the record communicates the endpoint definition and analysis population more clearly than the primary result itself. Readers can identify what was intended to be compared and some design constraints, but cannot judge the size, precision, or statistical significance of the primary outcome from the reported information.
13. Why This Trial Matters Statistically
This trial is statistically instructive because its primary comparison is within participants, while the study itself is non-randomized and open-label. Those features answer different questions. Pairing can account for stable differences between individuals when describing their outcomes across periods, but it does not provide the protection against time-related confounding that random assignment can offer.
The endpoint also illustrates why outcome definition matters. The registry focuses on spontaneous bleeding events, annualized to a common time scale, and summarizes rates with a median and inter-quartile range. That choice distinguishes the endpoint from a simple count of all events and from an average that may be more affected by unusually high observations. The observation periods nevertheless differ, and annualization alone does not erase that difference.
The analysis population is defined by treatment exposure in both periods. This makes the intended comparison explicit, but the number analyzed and the handling of missing endpoint data are not reported. These details matter because eligibility for a within-participant comparison depends on having usable observations across both regimens.
The registry also demonstrates the distinction between a stated objective and a reported result. It identifies a primary question and a summary method, but does not report the numerical primary outcome or its uncertainty. Statistical interpretation depends on those results as well as on design and methods. The record therefore supports discussion of the comparison’s structure and limitations, but not a conclusion about the size or direction of the primary endpoint result.
14. Limitations
- The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
- Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
The primary endpoint values are not reported in the registry record. The record gives no median spontaneous bleeding rates, inter-quartile ranges, numerical change, confidence interval, or reported significance result. Thus the primary comparison cannot be quantified from the registry entries.
Non-randomized allocation and no masking limit causal interpretation. The primary comparison is within participants, but treatment sequence is fixed: on-demand treatment precedes prophylaxis. Period effects, changes in exposure, and differences in event reporting or assessment could be associated with the switch. The registry does not report methods used to account for these possibilities.
The eligible analysis population requires at least 1 dose during each regimen, but its size is not reported. The record also does not report how incomplete observations, withdrawals, or missing endpoint data were handled. The precise annualization procedure and the statistical test or model for the comparison are not reported in the registry record.
The study included a surgical sub-study, and the Prophylaxis arm could include individualized dosing intervals for a subgroup. These features describe possible variation in study participation or regimen, but the record does not report how they relate to the primary analysis. Safety counts are descriptive and are not from a randomized comparison. Finally, the multiplicity strategy is not reported, so the relationship between the primary outcome and the other listed outcomes cannot be assessed.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Safety and Efficacy Study of a Recombinant Fusion Protein Linking Coagulation Factor IX With Albumin (rIX-FP) in Patients With Hemophilia B — NCT01496274.
- Registry record last updated 2016-05-09; status last verified 2016-04.
- Results first posted 2016-05-09.
- 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
NCT01496274 is a completed Phase II/III, open-label, non-randomized, multicenter study of rIX-FP in people with hemophilia B who had previously received factor replacement therapy. Enrollment was 63. The registry lists a study start of 2012-02 and primary completion of 2014-07.
The primary endpoint compares annualized spontaneous bleeding frequency during on-demand treatment and subsequent prophylaxis among eligible participants in the On-demand arm. It is summarized using the median and inter-quartile range. The numerical primary outcome result is not reported in the registry record.
The record also reports adverse-event counts by arm and lists secondary outcomes, including related adverse events, antibodies, hemostatic efficacy, consumption and pharmacokinetic measures. These details do not replace the missing primary endpoint estimates. The fixed treatment sequence, non-randomized allocation, open-label design, and unreported missing-data and multiplicity methods are important when interpreting the record.