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 Hemophilia Adult Prophylaxis Study: Factor VIII in Severe Hemophilia A (NCT01405742), a randomized phase 3 study. The primary outcome is Number of Bleeds.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01405742 |
| Phase | Phase 3 |
| Condition | Severe Hemophilia A |
| Allocation | Randomized |
| Design model | Crossover |
| Masking | None (open label) |
| Enrollment | 4 |
| Arms in the primary outcome | 2 |
| Lead sponsor | University of Pittsburgh |
| Results posted | Yes |
2. Clinical Question
Population
Adults with severe hemophilia A were eligible for the study. The registry record reports enrollment of 4 and says that 3 participants completed the study and were analyzed for the primary outcome. Further eligibility details are not reported in the registry record.
Intervention
One treatment period used recombinant factor VIII at 40 IU/kg by once-weekly intravenous injection. The arm description specifies a 26-week period. The study’s brief summary describes the purpose as assessing the feasibility of a larger study of prophylaxis schedules.
Comparator
The alternative schedule used recombinant factor VIII at 40 IU/kg by thrice-weekly intravenous injection. The trial was randomized and crossover: the arm descriptions indicate that participants switched schedules after 26 weeks and a 72 hour washout period.
Primary question
The primary outcome was the number of bleeds over the two treatment periods, reported as total events by arm rather than as a per-participant measure. The registry record lists 3 bleeds for once-weekly prophylaxis and 16 for thrice-weekly prophylaxis. These totals describe the posted results; they do not, by themselves, establish a comparative treatment effect.
The key statistical question is whether the observed bleeding totals can be interpreted as evidence about the relative schedules, given the very small number of participants, the crossover design, and the way the outcome was reported. The registry record does not post participant-level results, an inferential comparison, or an estimate of uncertainty for the difference between schedules. As a result, the totals are descriptive. They do not show how the events were distributed across participants or periods, and cannot characterize the precision of a treatment comparison.
3. Trial Design
This was a randomized, unmasked, crossover trial registered as phase 3. Its official title describes it as an R34 pilot feasibility randomized noninferiority trial comparing once-weekly with thrice-weekly recombinant factor VIII prophylaxis in adults with severe hemophilia A. The registry record lists University of Pittsburgh as sponsor and enrollment of 4. The study status is terminated.
The planned comparison involved two schedules of recombinant factor VIII at 40 IU/kg by intravenous injection. In one period, treatment was once weekly; in the other, it was thrice weekly. Each arm description specifies 26 weeks on the initial schedule, followed by crossover after a 72 hour washout period. The descriptions indicate that participants switched to the other frequency. The registry record does not report the sequence-generation method, allocation concealment, or further operational details of the crossover.
The trial’s stated purpose was to determine the feasibility of a large single dose Phase III study. The brief summary lists bleeding frequency, factor usage, joint range of motion, cost, quality-of-life, F.VIII level, and inter-dose hypocoagulability by thrombin generation as efficacy measures. Safety was to be assessed through inhibitor formation and bleeding events unresponsive to up to two rescue doses. The primary outcome posted in the registry is Number of Bleeds, with a timeframe of Weeks 26 (first intervention) and 52 (second intervention).
Three participants completing the study were analyzed for the primary outcome. The registry record reports the total number of events for each arm, not per-participant results. Although the design is crossover, the posted outcome does not provide paired participant-period observations or a sequence-specific analysis. The reason for termination and the reasons that one enrolled participant did not appear among the three completers are not reported in 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.
Before assignment: Following enrollment, subjects initiated study drug according to the randomization to Arm A (once-weekly FVIII) or Arm B (thrice-weekly FVIII) for a 26 week period followed by a 72 hour washout period prior to crossover to the other arm for the second 26 week period.
Overall Study
| Stage | Once-Weekly Then Thrice-Weekly FVIII | Thrice-Weekly Then Once-Weekly FVIII |
|---|---|---|
| STARTED | 2 | 2 |
| COMPLETED | 1 | 2 |
| NOT COMPLETED | 1 | 0 |
Reasons for not completing this period:
| Reason | Once-Weekly Then Thrice-Weekly FVIII | Thrice-Weekly Then Once-Weekly FVIII |
|---|---|---|
| Lost to Follow-up | 1 | 0 |
Analysis population for the primary outcome, as defined in the registry: 3 completing study were analyzed
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 | Severe Hemophilia A |
|---|---|---|
| Participants analysed | 3 | |
| Age, Categorical: <=18 years | Participants | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 3 |
| Age, Categorical: >=65 years | Participants | 0 |
| Age, Continuous | year | 25.5 (19 to 33) |
| Sex: Female, Male: Female | Participants | 0 |
| Sex: Female, Male: Male | Participants | 3 |
| Region of Enrollment: United States | participants | 3 |
6. Primary Endpoint
The registry lists the primary outcome as Number of Bleeds, measured over Weeks 26 (first intervention) and 52 (second intervention).
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | bleeds per 26 weeks |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is Number of Bleeds, described in the registry record as bleed frequency. Its unit is bleeds per 26 weeks, and its stated timeframe is Weeks 26 (first intervention) and 52 (second intervention). The posted description clarifies that the values are total events for each arm, not per-participant counts. The results list 3 for once-weekly factor VIII and 16 for thrice-weekly factor VIII.
Bleeding frequency is used in this trial because the study’s stated purpose was to compare prophylaxis schedules in relation to bleeding. A count outcome can describe how many events were recorded during a defined treatment period. That makes the measure relevant to the question of whether bleeding patterns differ between schedules, while also making the reporting unit important: a total count does not reveal how events were distributed among participants.
General statistical context: event counts may vary substantially between people, and multiple events from one person are not independent observations. In a crossover trial, results may also depend on each participant’s experience during both treatment periods. Participant-level counts and period-specific results would help readers assess that structure. They are not reported in the registry record, so the arm totals cannot support a participant-level rate estimate or a paired comparison on their own.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record reports 3 total bleeds for once-weekly recombinant factor VIII and 16 for thrice-weekly recombinant factor VIII. The primary outcome description says that these are totals by arm, not per-participant results. Three participants completing the study were analyzed. The numbers therefore describe the events recorded in this small completed group, rather than a broad estimate of what would occur in a larger population.
No confidence interval, hypothesis test, or other inferential analysis for the primary outcome is posted in the registry record. The registry record lists no posted analyses. Without an estimate of uncertainty, the totals do not indicate how compatible the observed results might be with a range of underlying differences between schedules. They should not be treated as a precise estimate of comparative effect or as evidence establishing noninferiority.
The crossover design is relevant to interpretation. In general, crossover studies can use within-participant comparisons, which may account for differences between participants. That requires results and an analysis that preserve the paired structure, including information about treatment sequence and period. The registry record reports only aggregate event totals by arm, so it is not possible to evaluate within-participant contrasts, period effects, or sequence effects from the posted primary outcome.
The small number of completers also limits how much can be learned from the observed totals. A total count can be influenced by how events are distributed across individuals; the registry record does not report that distribution. Nor does it report the number of participants contributing data to each specific period beyond the statement that 3 completing study were analyzed. Reasons for noncompletion and the handling of missing outcome data are not reported in the registry record.
The trial was described as a pilot feasibility study intended to inform a larger study. This context matters: a pilot’s stated purpose can be feasibility rather than a definitive test of efficacy. However, specific feasibility criteria or results are not reported in the registry record. The designation of noninferiority in the official title does not supply a noninferiority margin, a statistical analysis plan, or an inferential result. Those details are not reported in the registry record.
Overall, the posted primary results are descriptive event totals from 3 completers. They permit a statement about the recorded counts in this study, but not a reliable conclusion about the magnitude or precision of a treatment difference. The results do not establish that either schedule is superior, equivalent, or noninferior.
9. Statistical Methods Explained
The reported primary outcome is a count of bleeding events, with the results presented as total events by treatment arm. The registry record gives no dispersion measure, confidence interval, or inferential test for those counts. Consequently, the available primary result is descriptive. It does not quantify uncertainty around a comparative estimate.
What does a confidence interval contribute?
General statistical context: a confidence interval expresses the uncertainty around an estimated quantity under a specified statistical method. It can show which effect sizes remain compatible with the observed data and the method’s assumptions. For a count outcome in a crossover study, the estimate and interval would need to reflect the event-count distribution and the fact that participants received both schedules. No confidence interval is reported in the registry record, so the precision of a schedule comparison cannot be assessed from the posted primary outcome.
Why does the crossover structure matter?
General statistical context: each participant in a crossover trial contributes experience under more than one treatment condition. Analyses can compare outcomes within the same participant, which may account for stable differences between people. But that approach requires information that maintains the pairing of observations. The registry record supplies aggregate totals by arm, not the individual participants’ counts in each period, treatment sequence, or paired differences. It therefore does not permit readers to reconstruct a paired analysis or evaluate whether period and sequence should be considered.
The arm descriptions specify an initial 26-week treatment period and crossover following a 72 hour washout period. The primary timeframe is Weeks 26 (first intervention) and 52 (second intervention). These details describe the intended schedule, but they do not establish how the analysis handled treatment period, sequence, or any carryover. The statistical plan for those issues is not reported in the registry record.
How should the event totals be read?
General statistical context: count outcomes often show over-dispersion when their variability exceeds what a simple Poisson model would expect. Over-dispersion matters because a model that understates variability can produce intervals that are too narrow and tests that are too optimistic. Evaluating it requires suitable data, such as participant-level event counts or a reported model. Neither an over-dispersion assessment nor a count model is reported in the registry record. No model should be inferred from the aggregate totals alone.
The counts are also not rates calculated for each participant. Although the endpoint unit is bleeds per 26 weeks, the registry description explicitly says that results are total events for each arm and not per-participant. Exposure time by participant, the distribution of counts, and any adjustment for differing observation time are not reported in the registry record. The posted values should therefore be read as arm totals, not as individually observed rates.
What can the planning illustrations tell readers?
General statistical context: sample-size planning uses assumptions about the outcome, the effect worth detecting, the significance level, allocation, and analysis method. The planning illustrations accompanying the posted results are not the trial’s observed power and do not describe the number of participants actually studied. They are calculated from the observed effect under stated assumptions, including a two-sided significance level of 0.05, equal allocation, and a normal approximation. For non-time-to-event outcomes, they are expressed as participants per arm. Such illustrations are highly sensitive to the observed effect in a very small study and should not be interpreted as a validated design recommendation.
The registry record does not report the original sample-size justification or the assumptions used to plan this pilot. It also does not report a prespecified noninferiority margin. Accordingly, the planning illustrations cannot substitute for a protocol-based sample-size rationale or establish whether the study was designed with adequate precision for a particular clinical question.
What analyses are available?
The registry record lists the primary endpoint and secondary outcomes of Inter-dose Hypocoagulability by Thrombin Generation and F.VIII Activity. It reports 3 outcome measures but no posted analyses. No inferential method, adjustment strategy, or analysis population definition beyond the statement that 3 completing study were analyzed for the primary outcome is reported in the registry record. The published counts are therefore best interpreted as descriptive registry results, not as outputs of a reported comparative statistical model.
10. Multiplicity, Missing Data and Analysis Populations
The registry record names two secondary outcomes: Inter-dose Hypocoagulability by Thrombin Generation and F.VIII Activity. It lists 3 outcome measures and reports the primary outcome as Number of Bleeds. No secondary outcome results or analyses are posted. The prespecified hierarchy among outcomes, if any, is not reported in the registry record.
Multiplicity arises when several outcomes or comparisons are tested: the chance of at least one apparently unusual result can increase as the number of tests grows. General statistical context: a plan may address this through a hierarchy or an adjustment strategy. The statistical plan and any multiplicity adjustment are not reported in the registry record, so it is not possible to determine how multiple outcomes were intended to be interpreted. With no inferential analyses posted, there are no reported p-values to assess in this regard.
The primary outcome analysis population is described as 3 completing study were analyzed. Enrollment was 4. The reason for the difference, participant flow, and the treatment of any incomplete observations are not reported in the registry record. The record does not state whether the primary analysis followed an intention-to-treat, per-protocol, or other defined population. Nor does it report a missing-data method or sensitivity analysis.
These omissions matter for a crossover design because completeness across treatment periods affects whether within-participant comparisons can be made. The posted totals do not show whether every analyzed participant contributed outcomes to both periods or how any absent period data were handled. No assumptions about missing outcomes or analysis populations should be inferred from the aggregate totals.
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 |
|---|---|---|---|
| Arm A Once-weekly F.VIII at 40 IU/kg | 0 | 4 | 0.0% |
| Arm B Thrice-weekly F.VIII at 40 IU/kg | 0 | 4 | 0.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Arm A Once-weekly F.VIII at 40 IU/kg | 1 of 4 |
| Arm B Thrice-weekly F.VIII at 40 IU/kg | 0 of 4 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Arm A Once-weekly F.VIII at 40 IU/kg | Arm B Thrice-weekly F.VIII at 40 IU/kg |
|---|---|---|---|
| sinus infection | Infections and infestations | 1 of 4 | 0 of 4 |
The registry record lists 4 participants at risk in each arm for serious adverse events. It reports 0 participants affected by serious adverse events in the once-weekly arm and 0 in the thrice-weekly arm. No serious adverse event terms are listed. Death counts are not reported in the registry record.
For other adverse events, 1 participant was affected in the once-weekly arm and 0 in the thrice-weekly arm; 4 participants were at risk in each arm. These figures are participant counts in the registry’s adverse-event summary, not a measure of event severity beyond the serious-versus-other classification. The record does not provide further detail about the other adverse event.
General statistical context: an observed count of zero serious adverse events in a small group does not establish that the risk is absent. The registry figures describe the safety events recorded among participants at risk in this study; they do not provide a precise estimate of risk in a larger population. The record also does not report an inferential comparison of safety between schedules.
12. What the Result Does, and Does Not, Mean
The primary results establish a limited descriptive fact: the registry record reports 3 total bleeds for once-weekly factor VIII and 16 for thrice-weekly factor VIII among 3 participants who completed the study. The values are event totals by arm, not per-participant results. The study was a randomized crossover pilot, and its stated purpose was to assess feasibility for a larger study.
Those totals do not establish the size or precision of a comparative treatment effect. The registry record does not report a confidence interval, statistical test, participant-level outcome distribution, or paired crossover analysis. It also does not report a noninferiority margin. Thus, the official title’s noninferiority framing should not be mistaken for a posted demonstration of noninferiority.
The results also do not establish that one schedule is clinically preferable, or that either schedule is effective or ineffective. Such claims would go beyond the posted data and the precision available from the registry record. General statistical context: a small pilot can help identify practical questions for a larger study, but estimates from a very small sample may be unstable and should not be treated as definitive.
The trial’s feasibility purpose is relevant, but specific feasibility criteria and results are not reported in the registry record. The termination status is recorded, while the reason for termination is not reported. The study therefore offers a small set of descriptive bleeding counts and adverse-event figures, alongside important gaps in the information needed to evaluate comparative efficacy, noninferiority, and feasibility.
13. Why This Trial Matters Statistically
This trial illustrates why an outcome’s reporting unit is central to interpretation. The primary endpoint is described as bleeds per 26 weeks, but the registry clarifies that the posted values are total events for each arm, not per-participant counts. Aggregate totals do not reveal whether events were spread evenly among participants or concentrated in one participant. That distinction affects both statistical analysis and the meaning of a treatment comparison.
The crossover design also highlights the need to preserve the structure of the data. Each participant was intended to receive both schedules, with a crossover after the first treatment period. A paired analysis could be relevant in general, but the posted arm totals do not show participant-level changes between schedules. Without those paired data or a reported model, readers cannot assess period effects, sequence effects, or within-participant variability.
The study’s pilot feasibility purpose and small number of completers make restraint especially important. A pilot can inform decisions about whether and how to conduct a larger study, but the registry record does not report specific feasibility criteria or a sample-size justification. The posted event counts do not supply those missing design details.
Finally, the record demonstrates the difference between a trial’s title and its reported statistical evidence. Although the official title identifies a noninferiority trial, no margin or inferential analysis is posted. A noninferiority conclusion depends on a prespecified margin and an analysis that estimates uncertainty relative to that margin. Those elements are not reported in the registry record, so the descriptive counts cannot answer the noninferiority question.
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.
Interpretation is constrained by the very small completed analysis group: 3 participants were analyzed for the primary outcome, while enrollment was 4. The reason for noncompletion is not reported in the registry record. Participant characteristics beyond the condition are also not reported in the registry record, limiting assessment of how well the study group represents the intended population.
The primary outcome is available only as total bleeding events by arm. Participant-level counts, period-specific counts, exposure time, and paired comparisons are not reported in the registry record. This prevents assessment of variation between participants and of how the crossover structure was handled statistically. No confidence interval, hypothesis test, or model result is posted.
The study status is terminated, but the reason for termination is not reported in the registry record. Specific feasibility outcomes, the original sample-size rationale, the noninferiority margin, and the statistical analysis plan are also not reported. The registry record does not describe missing-data handling or define the analysis population beyond stating that 3 completing study were analyzed.
Safety reporting is limited to adverse-event counts. Death counts are not reported in the registry record, and no serious adverse event terms are listed. The detail about the single participant affected by another adverse event is not reported. These limitations mean the safety figures are descriptive and do not provide a precise comparative assessment.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Hemophilia Adult Prophylaxis Study: Factor VIII in Severe Hemophilia A — NCT01405742.
- Registry record last updated 2016-10-07; status last verified 2016-09.
- Results first posted 2016-09-19.
- 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 record describes a randomized, unmasked, crossover pilot comparing once-weekly and thrice-weekly recombinant factor VIII at 40 IU/kg in adults with severe hemophilia A. The study was registered as phase 3, enrolled 4 participants, and is listed as terminated. Each treatment period was described as 26 weeks, with crossover after a 72 hour washout period.
The primary endpoint was Number of Bleeds. Among 3 participants completing the study, the registry reports total counts of 3 for once-weekly treatment and 16 for thrice-weekly treatment; these are not per-participant results. No inferential analyses are posted. Serious adverse events affected 0 participants in either arm, while other adverse events affected 1 participant in the once-weekly arm and 0 in the thrice-weekly arm.
The study’s stated purpose was feasibility assessment for a larger trial. The reason for termination, statistical plan, noninferiority margin, missing-data handling, and participant-level results are not reported in the registry record.