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 Study of Recombinant Von Willebrand Factor (rVWF) in Pediatric and Adult Participants With Severe Von Willebrand Disease (VWD) (NCT03879135), a non-randomized phase 3 study. The primary outcome is Spontaneous Annualized Bleeding Rate (sABR).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT03879135 |
| Phase | Phase 3 |
| Condition | Von Willebrand Disease (VWD) |
| Allocation | Non-Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 38 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Baxalta now part of Shire |
| Results posted | Yes |
2. Clinical Question
Population
Pediatric and adult participants with severe von Willebrand disease (VWD) who met the entry criteria and received any amount of study drug. The registry record describes a full analysis set (FAS) using those criteria. The enrolled total was 38 participants.
Intervention
Recombinant von Willebrand factor (rVWF, vonicog alfa), given as prophylaxis or on demand according to the study regimen. Participants could receive treatment for a maximum of 3 years. The on-demand description allows rVWF with or without ADVATE; the prophylaxis description lists rVWF.
Comparator
There was no randomized control group. The record describes on-demand and prophylaxis treatment groups, but the study was non-randomized, open-label, and uncontrolled. Those treatment groups should not be read as like-for-like randomized comparison groups.
Primary question
During the first 12 months of prophylactic rVWF treatment, what was the mean spontaneous annualized bleeding rate (sABR), measured as spontaneous bleeds per year? The registry record gives the endpoint definition but does not report the numerical primary result.
The study concerns the frequency of spontaneous bleeding during prophylaxis, rather than bleeding associated with trauma. The endpoint description says that bleeds with unknown cause were classified as spontaneous, while investigators assessed the cause of other bleeds. That classification rule is relevant to interpreting the endpoint: the reported measure would depend both on recorded bleeding episodes and on their cause assignments.
The registry record identifies a safety and efficacy study in participants with severe VWD, with adult and pediatric cohorts. It lists secondary safety outcomes including treatment-emergent adverse events, serious treatment-emergent adverse events, thromboembolic events, hypersensitivity reactions, and antibodies to VWF and FVIII. The primary question is narrower: the mean sABR during prophylactic treatment. Neither the primary endpoint value nor its variability is reported in the registry record, so the amount of bleeding observed during the stated period cannot be characterized from that record.
3. Trial Design
The registry describes a Phase 3b, prospective, open-label, uncontrolled, multicenter study. Allocation was non-randomized, masking was absent, and the study model was parallel. The record lists an enrollment of 38 and a status of completed. Its stated dates are 2019-04-01 for study start and 2025-01-30 for primary completion.
Participants with severe VWD received rVWF as prophylaxis or on demand, with treatment permitted for a maximum of 3 years. The on-demand arm description says participants received rVWF with or without ADVATE. The prophylaxis description specifies rVWF. The registry lists rFVIII as an intervention as well, but further details about its use are not reported in the registry record.
Because allocation was not randomized and the study was uncontrolled, treatment groups do not constitute a randomized comparison. Any differences between groups could reflect differences in participant characteristics, treatment selection, or other factors, as well as treatment. The record does not report a protocol-based control group, a blinding procedure, or a planned comparative effect estimate. It also does not report details of how participants entered each cohort or how treatment assignment was determined.
The primary endpoint covers sABR during the first 12 months of prophylactic treatment, while the study treatment period could extend to a maximum of 3 years. These are distinct time windows: the primary question focuses on the specified first-year period, not the entire possible treatment duration. The registry lists 30 outcome measures, but reports no analyses count. The numerical primary endpoint result, its uncertainty, and the number of participants contributing to it 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: A total of 38 participants with diagnosis of Von Willebrand disease were enrolled. Only participants who received treatment in study(N=35) were included in analysis. These participants received recombinant von Willebrand factor (rVWF) \[vonicog alfa\], 50±10 international units per kilogram (IU/kg),intravenous(IV) infusion in either prophylaxis or on demand cohorts. Some participants received supportive treatment with ADVATE for treating bleeding episodes (BEs) if deemed necessary by investigator.
Overall Study
| Stage | Cohort 1: Prophylaxis | Cohort 2: Prophylaxis | Cohort 3: Prophylaxis | Cohort 4: Prophylaxis | Cohort 5: On Demand | Cohort 6: On Demand |
|---|---|---|---|---|---|---|
| STARTED | 10 | 1 | 1 | 5 | 16 | 2 |
| COMPLETED | 10 | 1 | 1 | 3 | 15 | 1 |
| NOT COMPLETED | 0 | 0 | 0 | 2 | 1 | 1 |
Reasons for not completing this period:
| Reason | Cohort 1: Prophylaxis | Cohort 2: Prophylaxis | Cohort 3: Prophylaxis | Cohort 4: Prophylaxis | Cohort 5: On Demand | Cohort 6: On Demand |
|---|---|---|---|---|---|---|
| Physician Decision | 0 | 0 | 0 | 1 | 0 | 0 |
| Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 |
| Site Closed by Sponsor | 0 | 0 | 0 | 1 | 1 | 0 |
Analysis population for the primary outcome, as defined in the registry: The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug.
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 Full Analysis Set (FAS) consisted of all participants who satisfied all entry criteria and received any amount of study drug.
Only the first 6 of 7 groups are shown.
| Characteristic | Unit | Cohort 1: Prophylaxis | Cohort 2: Prophylaxis | Cohort 3: Prophylaxis | Cohort 4: Prophylaxis | Cohort 5: On Demand | Cohort 6: On Demand |
|---|---|---|---|---|---|---|---|
| Participants analysed | 10 | 1 | 1 | 5 | 16 | 2 | |
| Age, Customized: <6 years | Participants | 0 | 0 | 0 | 0 | 3 | 0 |
| Age, Customized: >=6 to <12 years | Participants | 0 | 0 | 0 | 0 | 5 | 0 |
| Age, Customized: >=12 to <18 years | Participants | 0 | 0 | 1 | 2 | 6 | 0 |
| Age, Customized: >=18 years | Participants | 10 | 1 | 0 | 3 | 2 | 2 |
| Sex: Female, Male: Female | Participants | 4 | 1 | 0 | 2 | 9 | 1 |
| Sex: Female, Male: Male | Participants | 6 | 0 | 1 | 3 | 7 | 1 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 1 | 0 | 0 | 0 | 1 | 0 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 8 | 0 | 1 | 5 | 14 | 2 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 1 | 1 | 0 | 0 | 1 | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): White | Participants | 9 | 0 | 1 | 4 | 14 | 2 |
| Race (NIH/OMB): More than one race | Participants | 0 | 0 | 0 | 0 | 1 | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 1 | 1 | 0 | 1 | 1 | 0 |
6. Primary Endpoint
The registry lists the primary outcome as Spontaneous Annualized Bleeding Rate (sABR), measured over Up to 12 months.
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | Standard Deviation |
| Unit | spontaneous bleeds per year |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is spontaneous annualized bleeding rate (sABR), expressed as spontaneous bleeds per year. It is derived by dividing the number of treated bleeds by the duration of observation in years. The registry says that bleeds with unknown causality were considered spontaneous and that investigators assessed the cause of bleeds. The measure is specified for the first 12 months of prophylactic rVWF treatment.
Annualizing a count places observation periods of different lengths on a common time scale. In general, this can make rates easier to describe when participants have different amounts of follow-up, though the interpretation depends on how the event count and observation time are defined and recorded. The registry definition focuses on treated bleeds; it does not state how untreated bleeding episodes were handled.
A mean is used to summarize the average participant-level endpoint in the analysis population. Bleeding counts can vary considerably across participants, so the mean alone would not describe how widely individual rates differed. The registry identifies standard deviation as the dispersion measure, but neither the mean nor the standard deviation is reported in the registry record. The endpoint value, number analyzed, and any confidence interval are also not reported. Consequently, the endpoint definition is available, but the observed level and precision of sABR cannot be assessed from the record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record identifies the primary outcome and its calculation, but does not state the numerical sABR result. It therefore supports describing what the study intended to measure, not the observed average bleeding rate. The mean, standard deviation, number of participants contributing to the primary analysis, and confidence interval are not reported in the registry record. No primary endpoint p-value or formal comparison is reported there either.
That absence matters for interpretation. A defined outcome is not the same as a reported result. Without the endpoint estimate and its uncertainty, readers cannot determine from this record how variable participant rates were or how precisely the average was estimated. The enrollment of 38 does not establish how many participants were included in the primary analysis; the analysis population size is not reported in the registry record.
The study design also limits what any eventual endpoint estimate could establish. It was open-label, uncontrolled, and non-randomized. A mean sABR measured during prophylaxis would describe the observed group under the study conditions. Without a randomized control group, it would not by itself isolate the effect of rVWF from changes over time, participant selection, differences in follow-up, or other influences. The registry explicitly cautions that the arms are not a like-for-like control comparison.
The endpoint is restricted to spontaneous bleeds and uses investigator-assessed cause, with unknown-cause bleeds classified as spontaneous. This operational definition helps specify which events count, but it also means the measure depends on how bleeding events are captured and categorized. Further details about adjudication, completeness of event ascertainment, or sensitivity analyses are not reported in the registry record.
The safety information is reported by cohort as counts of participants at risk and affected. These figures should be read within each listed cohort, rather than combined into a treatment comparison. The registry lists zero deaths in each group. It also lists serious-event terms and percentages, but the record does not supply enough context to infer comparative risk or causality from those entries. Counts in small cohorts are descriptive and do not, by themselves, establish whether an event was caused by treatment.
Overall, the posted record is informative about the intended endpoint, treatment groups, and selected safety counts. It does not report the primary outcome estimate or a comparative efficacy analysis. Conclusions about the magnitude, precision, or comparative effect of treatment are therefore not available from the registry record.
9. Statistical Methods Explained
The registry specifies a mean of a continuous measure as the primary endpoint summary, with standard deviation as the dispersion measure. The endpoint itself is a rate calculated from treated spontaneous bleeds and duration of observation in years. The following points explain these methods in general and distinguish them from results that are not reported in the registry record.
What does an annualized rate represent?
In general, an annualized rate expresses an event count relative to time observed. Participants may contribute different amounts of follow-up, and dividing by duration converts the count into a rate per year. The rate is not the same thing as a simple count of events: it incorporates the observation period. For this study, the registry defines the calculation using treated bleeds and duration in years. It does not report participant-level observation durations or the exact handling of incomplete periods.
The endpoint is specifically spontaneous bleeding. The registry states that unknown-causality bleeds were counted as spontaneous and that investigators assessed cause. As a general methodological matter, event classification rules should be understood alongside the rate: changes in classification can change which events enter the numerator. How cause assessments were reviewed, and whether any adjudication process was used, are not reported in the registry record.
What do the mean and standard deviation describe?
In general, the mean summarizes the average value across participants in an analysis population. The standard deviation describes how spread out participant values are around that average. They answer different questions: a mean describes the central level, while a standard deviation describes between-participant variability. Neither value alone indicates the precision of the mean; a confidence interval or other uncertainty estimate is often needed for that purpose. The primary mean and standard deviation, along with a confidence interval, are not reported in the registry record.
Rates based on event counts may be unevenly distributed across participants, particularly when some participants have more events than others. As a general statistical consideration, a mean can be influenced by relatively high values. The registry identifies the mean and standard deviation but does not report distributional summaries, a model for the rate, or an analysis of influential observations. It is therefore not possible to assess from the record whether alternative summaries or models were considered.
What is the analysis population?
The registry defines the FAS as participants who satisfied all entry criteria and received any amount of study drug. This definition identifies the intended population for the primary endpoint, but it does not state how many participants met that definition or how many contributed endpoint data. Those counts are not reported in the registry record. The enrollment figure is 38; enrollment should not be assumed to equal the number analyzed.
In general, analysis populations can differ depending on eligibility, treatment received, and outcome availability. Clear reporting of the population definition and the number included helps readers understand which participants the estimate represents. The FAS definition is recorded, but the registry does not state how missing endpoint observations affected the analysis or whether additional analysis populations were used.
What can an uncontrolled design estimate?
In general, an uncontrolled study can describe outcomes observed among its participants during treatment. It does not provide a randomized counterfactual showing what would have happened to comparable participants under another treatment or no treatment. Non-random allocation also means that groups may differ before or during treatment for reasons unrelated to treatment. Here, the registry describes the study as non-randomized and uncontrolled, and it cautions that the arms are not a like-for-like control comparison.
Open-label means that masking was absent, as recorded in the study design. In general, knowledge of treatment can affect reporting or assessment, especially for outcomes requiring judgment. The endpoint uses investigator assessment of bleeding cause. The record does not report additional procedures for reducing or evaluating assessment effects.
What do the planning illustrations mean?
The registry's planning assumptions describe an illustration based on the observed effect: a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect set as a stated fraction of the observed effect. In general, such calculations explore the sample size that might be needed under specified assumptions; they are not observed power and do not establish the probability that the study detected an effect. The registry does not report its own sample-size justification. The numerical planning outputs are not reported in the registry record.
No interim-analysis plan, detailed statistical analysis plan, model specification, or prespecified approach to missing endpoint data is reported in the registry record. Those details should not be inferred from the endpoint definition or from the planning assumptions. Without reported estimates and uncertainty, the primary outcome remains defined but cannot be quantitatively interpreted.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 30 outcome measures, including the primary sABR endpoint and several safety outcomes. It reports zero analyses, and does not describe a multiplicity adjustment or a hierarchy for testing outcomes. Whether statistical testing was planned for multiple endpoints, or how any such testing was to be handled, is not reported in the registry record.
In general, when multiple hypotheses are tested, the chance of at least one apparently unusual result can increase unless the analysis plan addresses multiplicity. This general concern does not establish that the study conducted multiple tests: the registry record does not report analyses or p-values. The primary endpoint result itself is not reported in the registry record.
The registry defines the FAS as participants meeting all entry criteria and receiving any amount of study drug. It does not state the number in this population or how many had data available for the primary endpoint. Missing-data methods, reasons for missing observations, and sensitivity analyses are not reported in the registry record. The observed enrollment of 38 should not be taken as the number included in any particular analysis.
In general, missing outcome data can affect a summary if the participants without measurements differ from those with measurements. The extent and direction of any effect depend on the amount and pattern of missingness and the assumptions used in analysis. Since the registry does not report endpoint completeness or a missing-data approach, those issues cannot be evaluated from the record. The same applies to withdrawals and their handling in the primary analysis.
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 |
|---|---|---|---|
| Cohort 1: Prophylaxis: Adult ≥18 Years | 3 | 10 | 30.0% |
| Cohort 2: Prophylaxis: Adult ≥18 Years | 0 | 1 | 0.0% |
| Cohort 3: Prophylaxis: Pediatric 12 to <18 Years | 0 | 1 | 0.0% |
| Cohort 4: Prophylaxis: Pediatric 12 to <18 Years | 0 | 2 | 0.0% |
| Cohort 4: Prophylaxis: Adult ≥18 Years | 1 | 3 | 33.3% |
| Cohort 5: On Demand: Pediatric <6 Years | 2 | 3 | 66.7% |
| Cohort 5: On Demand: Pediatric 6 to <12 Years | 1 | 5 | 20.0% |
| Cohort 5: On Demand: Pediatric 12 to <18 Years | 0 | 6 | 0.0% |
| Cohort 5: On Demand: Adult ≥18 Years | 0 | 2 | 0.0% |
| Cohort 6: On Demand: Adult ≥18 Years | 1 | 2 | 50.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Cohort 1: Prophylaxis: Adult ≥18 Years | 0 of 10 |
| Cohort 2: Prophylaxis: Adult ≥18 Years | 0 of 1 |
| Cohort 3: Prophylaxis: Pediatric 12 to <18 Years | 0 of 1 |
| Cohort 4: Prophylaxis: Pediatric 12 to <18 Years | 0 of 2 |
| Cohort 4: Prophylaxis: Adult ≥18 Years | 0 of 3 |
| Cohort 5: On Demand: Pediatric <6 Years | 0 of 3 |
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 |
|---|---|
| Cohort 1: Prophylaxis: Adult ≥18 Years | 8 of 10 |
| Cohort 2: Prophylaxis: Adult ≥18 Years | 1 of 1 |
| Cohort 3: Prophylaxis: Pediatric 12 to <18 Years | 1 of 1 |
| Cohort 4: Prophylaxis: Pediatric 12 to <18 Years | 2 of 2 |
| Cohort 4: Prophylaxis: Adult ≥18 Years | 2 of 3 |
| Cohort 5: On Demand: Pediatric <6 Years | 3 of 3 |
Most frequent serious adverse event terms
| Event term | Organ system | Cohort 1: Prophylaxis: Adult ≥18 Years | Cohort 2: Prophylaxis: Adult ≥18 Years | Cohort 3: Prophylaxis: Pediatric 12 to <18 Years | Cohort 4: Prophylaxis: Pediatric 12 to <18 Years | Cohort 4: Prophylaxis: Adult ≥18 Years | Cohort 5: On Demand: Pediatric <6 Years |
|---|---|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | 1 of 10 | 0 of 1 | 0 of 1 | 0 of 2 | 0 of 3 | 0 of 3 |
| Bacteraemia | Infections and infestations | 1 of 10 | 0 of 1 | 0 of 1 | 0 of 2 | 0 of 3 | 0 of 3 |
| Coronavirus infection | Infections and infestations | 0 of 10 | 0 of 1 | 0 of 1 | 0 of 2 | 0 of 3 | 1 of 3 |
| Fall | Injury, poisoning and procedural complications | 0 of 10 | 0 of 1 | 0 of 1 | 0 of 2 | 0 of 3 | 1 of 3 |
| Fibula fracture | Injury, poisoning and procedural complications | 0 of 10 | 0 of 1 | 0 of 1 | 0 of 2 | 1 of 3 | 0 of 3 |
| Haemoglobin decreased | Investigations | 1 of 10 | 0 of 1 | 0 of 1 | 0 of 2 | 0 of 3 | 0 of 3 |
| Hypotension | Vascular disorders | 0 of 10 | 0 of 1 | 0 of 1 | 0 of 2 | 0 of 3 | 1 of 3 |
| Medical device site extravasation | General disorders | 0 of 10 | 0 of 1 | 0 of 1 | 0 of 2 | 0 of 3 | 1 of 3 |
| Pneumonia | Infections and infestations | 0 of 10 | 0 of 1 | 0 of 1 | 0 of 2 | 1 of 3 | 0 of 3 |
| Post procedural haemorrhage | Injury, poisoning and procedural complications | 1 of 10 | 0 of 1 | 0 of 1 | 0 of 2 | 0 of 3 | 0 of 3 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Cohort 1: Prophylaxis: Adult ≥18 Years | Cohort 2: Prophylaxis: Adult ≥18 Years | Cohort 3: Prophylaxis: Pediatric 12 to <18 Years | Cohort 4: Prophylaxis: Pediatric 12 to <18 Years | Cohort 4: Prophylaxis: Adult ≥18 Years | Cohort 5: On Demand: Pediatric <6 Years |
|---|---|---|---|---|---|---|---|
| COVID-19 | Infections and infestations | 1 of 10 | 0 of 1 | 1 of 1 | 0 of 2 | 2 of 3 | 3 of 3 |
| Headache | Nervous system disorders | 3 of 10 | 1 of 1 | 0 of 1 | 2 of 2 | 0 of 3 | 0 of 3 |
| Pyrexia | General disorders | 1 of 10 | 0 of 1 | 0 of 1 | 1 of 2 | 1 of 3 | 2 of 3 |
| Vomiting | Gastrointestinal disorders | 0 of 10 | 0 of 1 | 0 of 1 | 1 of 2 | 1 of 3 | 3 of 3 |
| Abdominal pain | Gastrointestinal disorders | 1 of 10 | 1 of 1 | 0 of 1 | 1 of 2 | 0 of 3 | 1 of 3 |
| Cough | Respiratory, thoracic and mediastinal disorders | 0 of 10 | 0 of 1 | 0 of 1 | 1 of 2 | 0 of 3 | 2 of 3 |
| Diarrhoea | Gastrointestinal disorders | 1 of 10 | 0 of 1 | 0 of 1 | 1 of 2 | 0 of 3 | 1 of 3 |
| Muscle spasms | Musculoskeletal and connective tissue disorders | 0 of 10 | 1 of 1 | 0 of 1 | 1 of 2 | 1 of 3 | 0 of 3 |
| Abdominal pain upper | Gastrointestinal disorders | 2 of 10 | 0 of 1 | 0 of 1 | 0 of 2 | 0 of 3 | 0 of 3 |
| Anaemia | Blood and lymphatic system disorders | 1 of 10 | 0 of 1 | 0 of 1 | 0 of 2 | 1 of 3 | 0 of 3 |
Serious events with the highest arm-level rate: ovarian cyst ruptured (50.0%), coronavirus infection (33.3%), fall (33.3%), fibula fracture (33.3%), hypotension (33.3%).
The registry reports safety counts separately for each listed cohort. Within a cohort, “at risk” is the number of participants in the safety group, and “affected” is the number recorded with the corresponding serious or other adverse-event category. These are participant counts, not event rates per unit of follow-up. The record lists zero deaths in every group.
The group sizes vary, and some cohorts contain only a small number of participants. Read each affected count in the context of its own at-risk count; do not combine cohorts or compare them as if treatment had been randomly assigned. The study was non-randomized and uncontrolled, and the registry cautions that its arms are not like-for-like control groups. The figures therefore provide descriptive safety information rather than a controlled estimate of comparative risk.
The record also lists serious-event terms with percentages: ovarian cyst ruptured, 50.0%; coronavirus infection, 33.3%; fall, 33.3%; fibula fracture, 33.3%; hypotension, 33.3%; and medical device site extravasation, 33.3%. These entries alone do not establish causality or comparative frequency. The registry lists outcomes related to treatment-emergent events, severity, causality, thromboembolic events, hypersensitivity, and antibodies, but further numerical results for those outcomes are not reported in the registry record.
12. What the Result Does, and Does Not, Mean
The record establishes that the study was designed to assess spontaneous annualized bleeding rate during the first 12 months of prophylactic rVWF treatment in pediatric and adult participants with severe VWD. It also defines how sABR was calculated and describes the intended analysis population. Those details clarify the outcome the investigators intended to measure.
However, the record does not report the numerical primary endpoint result. It therefore does not establish the observed mean sABR, its variability, the number analyzed, or the precision of the estimate. No confidence interval or primary endpoint test result is reported in the registry record. Without those data, readers cannot quantify the outcome from this record.
Even if an observed rate were available, an uncontrolled, non-randomized study would describe outcomes in the treated participants rather than provide a randomized comparison. In general, an observed change or rate during treatment cannot by itself separate treatment effects from other factors that may influence bleeding or its recording. The stated design does not support treating the on-demand and prophylaxis groups as interchangeable controls.
The safety counts provide descriptive information by cohort, including serious and other adverse-event counts and zero deaths in each listed group. They do not establish that an event was caused by treatment, nor do they provide a controlled comparison of safety between regimens. The registry record also does not report detailed analyses for the listed secondary safety outcomes.
Thus, the record is useful for understanding the study question, design, endpoint definition, and selected safety reporting. It does not contain the primary efficacy result needed to characterize the observed bleeding rate or its precision. No conclusion about treatment benefit or lack of benefit follows from the absence of that result in the registry record.
13. Why This Trial Matters Statistically
This study raises several statistical issues that matter when reading clinical research. Its primary endpoint is an annualized event rate rather than a simple event count. In general, rates account for time observed, but interpretation depends on reliable follow-up duration and consistent event capture. The registry defines the calculation and the treatment of bleeds with unknown cause, which makes the endpoint more explicit, while leaving event-ascertainment details unreported.
The design also matters. This was a prospective, open-label, uncontrolled, non-randomized study. Such a design can describe outcomes in participants receiving study treatment, but it cannot offer the protection against confounding that random allocation is intended to provide. The registry itself warns that the arms are not a like-for-like control comparison. This makes it important to distinguish within-study description from a comparative treatment effect.
Precision is another key issue. A primary mean and standard deviation would help characterize the observed rates and their variation; a confidence interval would help convey uncertainty in the estimated mean. None of those primary results is reported in the registry record. The enrollment figure of 38 does not reveal the endpoint analysis size, and the analysis population count is not reported.
Finally, the registry lists many outcome measures but does not describe multiplicity handling, missing-data methods, or a detailed analysis plan. These are important elements for judging how results were selected and how incomplete data might affect estimates. The record's safety counts remain useful as descriptive entries, but their cohort-specific denominators and the non-randomized design limit direct comparisons. Together, these features show why a clear endpoint definition is necessary but not sufficient: interpretation also requires results, uncertainty, and analysis details.
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 main limitation for interpreting efficacy is that the registry record does not report the primary sABR estimate. It also does not report the standard deviation, confidence interval, primary analysis size, or numerical results for the listed secondary outcomes. The outcome definition is therefore available without the result needed to describe the observed bleeding rate or its precision.
The study was open-label, non-randomized, and uncontrolled. As a result, the listed treatment groups are not randomized comparison groups, and the registry cautions that they are not like-for-like controls. The record does not report how treatment assignment was determined or provide a protocol-based control arm. Comparative effects cannot be isolated from these design details alone.
Although the record defines the FAS, it does not report the number of participants in that population or how many had endpoint data. Missing-data methods, participant withdrawals, and sensitivity analyses are not reported in the registry record. The enrollment of 38 should not be assumed to be the analysis size.
Other details relevant to statistical interpretation are also absent from the record: the protocol's sample-size justification, a detailed statistical analysis plan, interim-analysis information, multiplicity procedures, and the model used for the primary endpoint. The registry gives planning assumptions for illustrations, but those do not establish the study's own design justification. The record also does not report further event-ascertainment or adjudication procedures. These limitations are specific to what is recorded and do not establish what may have been described elsewhere.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Study of Recombinant Von Willebrand Factor (rVWF) in Pediatric and Adult Participants With Severe Von Willebrand Disease (VWD) — NCT03879135.
- Registry record last updated 2025-09-03; status last verified 2025-08.
- Results first posted 2025-09-03.
- 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 3b, prospective, open-label, uncontrolled, multicenter study of rVWF in pediatric and adult participants with severe VWD. Allocation was non-randomized, masking was absent, and enrollment was 38. Participants received prophylactic or on-demand treatment, with a maximum treatment duration of 3 years.
The primary endpoint was mean spontaneous annualized bleeding rate during the first 12 months of prophylactic treatment. The record defines the rate calculation and the FAS, but does not report the endpoint result, its standard deviation, confidence interval, or analysis population size. It lists 30 outcome measures and reports zero analyses.
Safety counts are reported by cohort, with zero deaths listed in each group. The registry does not report a randomized comparison, and cautions that the arms are not like-for-like controls. The primary numerical result and detailed analysis methods are not reported in the registry record.