BAY79-4980 Compared to rFVIII-FS in Previously Treated Patients With Severe Hemophilia A: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for BAY79-4980 Compared to rFVIII-FS in Previously Treated Patients With Severe Hemophilia A (NCT00623727), a randomized phase 2 study. The primary outcome is Percentage of Participants With Less Than 9 Total Bleeds Per Year.

2. Clinical Question

3. Trial Design

The registry describes a randomized, active-controlled, parallel-group phase 2 study in previously treated patients with severe hemophilia A. Its official title describes a double-blind study, while the registry masking field records quadruple masking. The posted record does not explain the relationship between those descriptions. The study compared once-weekly BAY79-4980 with rFVIII-FS prophylaxis three times per week.

The intervention arm received BAY79-4980 at 35 IU/kg body weight once per week, with two dummy injections per week. The comparator arm received rFVIII-FS at 25 IU/kg body weight three times per week. The intervention descriptions specify different formulation and blinding details for the injections; the full procedural protocol is not reported in the registry record.

The primary outcome was assessed in the per-protocol population over up to one year. Enrollment was 143. The primary outcome results list 63 participants in the BAY79-4980 arm and 68 in the rFVIII-FS/WFI arm. These are the outcome denominators, not a statement about the disposition of every enrolled participant; a reconciliation of enrollment and analysis populations is not reported in the registry record.

The record lists the study status as terminated, with a start date of 2008-06 and primary completion in 2010-04. The reason for termination, the original design assumptions, and any amendments to the design 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: Of 168 enrolled participants, 25 failed screening.

Double Blind (DB)

Reasons for not completing this period:

Open Label Follow-up

Reasons for not completing this period:

Open Label Extension Period

Analysis population for the primary outcome, as defined in the registry: Per protocol (PP) population

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.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Less Than 9 Total Bleeds Per Year, measured over up to one year.

The primary endpoint is the percentage of participants with fewer than 9 total bleeds per year, assessed over up to one year. It is a binary outcome: each participant either meets the stated threshold or does not. The registry reports this endpoint for the per-protocol population.

The event-counting rules matter to the meaning of the threshold. Bleeds occurring on the same day count as one bleeding event. Bleeds occurring within 72 hours into the same location also count as one event. Thus, the reported total is based on these rules rather than simply counting every reported bleed as a separate event.

As a general statistical point, a threshold endpoint can make an outcome easier to summarize as a proportion, but it compresses information. Participants just on either side of the cutoff are placed in different categories, while participants with different numbers of bleeds may be grouped together if they fall on the same side. The registry also posts joint-bleed outcomes as secondary measures, but the primary question is specifically about total bleeds.

This endpoint describes the share of the analyzed group that met the defined threshold; it does not, by itself, describe the full distribution of bleed counts or the timing of individual events. Those details are not reported in the registry record.

7. Results Posted in the Registry

• rFVIII-FS/WFI (BAY14-2222): 72.1% (49/68) versus 38.1% (24/63) on control; risk difference 34.0 percentage points (95% CI 17.9 to 50.0), risk ratio 1.89 (1.34–2.68); unadjusted two-proportion z-test p = <0.001.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Percentage of Participants With Less Than 5 Joint Bleeds Per Year

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • rFVIII-FS/WFI (BAY14-2222): 63.2% (43/68) versus 38.1% (24/63) on control; risk difference 25.1 percentage points (95% CI 8.6 to 41.7), risk ratio 1.66 (1.15–2.39); unadjusted two-proportion z-test p = 0.004.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for rFVIII-FS/WFI (BAY14-2222) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The posted secondary outcome results follow the same broad direction as the primary endpoint: a higher proportion in the rFVIII-FS/WFI arm met the stated joint-bleed threshold than in the BAY79-4980 arm. The secondary outcomes concern joint bleeds, whereas the primary outcome concerns total bleeds. Their shared direction offers context for the primary pattern, but does not make the endpoints interchangeable.

The registry lists two secondary outcomes: the percentage with fewer than 5 joint bleeds per year and the number of joint bleeds per participant per year in responders. Results are posted for the percentage endpoint; reported analyses are not listed. The registry does not provide a corresponding result for the responder count outcome in the posted secondary results. Details about the responder definition and any related analysis are not reported in the registry record.

As a general statistical point, secondary outcomes can help describe whether a primary pattern appears in related measures, but they are often less definitive when the analysis plan and multiplicity approach are unavailable. Testing multiple outcomes creates more opportunities for apparently notable results to occur by chance. The registry does not report whether these outcomes were prespecified, how they were prioritized, or whether any adjustment for multiple comparisons was planned.

For that reason, the secondary results should be treated as supporting descriptive context rather than as independent confirmation of the primary comparison. They concern related but distinct endpoint definitions and do not resolve the limitations associated with the per-protocol population, missing-data reporting, or the absent analysis plan.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Percentage of Participants With Less Than 5 Joint Bleeds Per Year
• Number of Joint Bleeds Per Participant Per Year in Responders

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary at the participant level: the registry records whether a participant had fewer than 9 total bleeds per year under the stated event-counting rules. The arm results are percentages, so they describe the proportion meeting that threshold rather than an average bleed count. The outcome timeframe is up to one year, and the population is per protocol.

What does a risk difference express?

A risk difference subtracts one arm’s event proportion from the other arm’s event proportion. In this comparison, the reported contrast is rFVIII-FS/WFI against BAY79-4980. A positive value corresponds to a higher proportion meeting the endpoint in the rFVIII-FS/WFI arm. This orientation is important: reversing the order of the arms would reverse the sign without changing the underlying data. The registry reports the risk difference and its interval, while the arm percentages make the direction easier to understand in the endpoint’s original terms.

What does the p-value add?

The unadjusted p-value is reported as p < 0.001 for the primary comparison. As a general statistical explanation, a p-value gauges how unusual data at least as incompatible with a specified null comparison would be under the assumptions of the test. It is not the probability that the null is true, and it does not measure the probability that the result will recur. The exact test and model assumptions are not reported in the registry record. The p-value should therefore be read alongside the observed proportions and the uncertainty interval, not as a stand-alone measure of effect size.

Why is the endpoint definition part of the analysis?

The event-counting rules determine which observations contribute to each participant’s total. Same-day bleeds count as one event, as do bleeds within 72 hours into the same location. A participant is then classified against the threshold of fewer than 9 total bleeds per year. As a general statistical point, changing how events are grouped or where a threshold is set can change who is classified as meeting a binary endpoint. The registry reports the stated rules, but further details about event adjudication are not reported in the registry record.

What does the analysis population imply?

The primary outcome is reported for the per-protocol population. This identifies the group used in the endpoint analysis, but the record does not describe its inclusion criteria or report an intention-to-treat analysis. As a general point, an analysis limited to participants who followed protocol can differ from an analysis that retains everyone according to randomized assignment. Exclusions after randomization can affect comparability if the reasons for exclusion relate to outcomes or differ across arms. The registry does not provide enough detail to evaluate that possibility.

The posted comparison is unadjusted, and no reported analysis details are listed for the secondary outcomes. The record does not report covariate adjustment, a model specification, a prespecified testing hierarchy, or a multiplicity procedure. This matters because the primary outcome is one among several outcomes recorded in the trial. Without the analysis plan, readers cannot determine which analyses were prespecified or how the study intended to handle multiple statistical tests.

Confidence intervals express uncertainty about a comparison under the assumptions used to construct them. As a general concept, a narrower interval indicates greater precision, while a wider interval indicates less precision. The registry supplies intervals for the posted comparisons, but does not state the method used to calculate them. The reported arm sizes and outcome counts describe the analysis data; they do not, on their own, establish that missing outcomes were absent or handled in a particular way.

11. Confidence Intervals and Precision

The registry reports a confidence interval for the primary risk difference. Its limits are both above zero, so the interval is consistent with a higher proportion meeting the threshold in the rFVIII-FS/WFI arm than in the BAY79-4980 arm. The interval provides a range of values compatible with the data under the method’s assumptions; it does not guarantee that the true contrast lies within those limits.

As a general statistical explanation, precision concerns how narrowly an estimate is determined by the data. A confidence interval conveys precision as well as direction: a range that spans more values permits more uncertainty about the size of the contrast. The registry does not report the method used to calculate the interval, so that aspect of the uncertainty assessment cannot be independently evaluated from the record.

The primary outcome percentages are based on 63 participants in the BAY79-4980 arm and 68 in the rFVIII-FS/WFI arm. Those denominators apply to the per-protocol endpoint results. The registry does not report a missing-data analysis or explain how participants without an evaluable outcome were handled. As a result, the interval should not be taken as accounting for uncertainty from unreported missingness or analysis-population decisions.

A confidence interval is not a range of individual participant outcomes and is not a substitute for the endpoint definition. It applies to the estimated between-arm contrast, while the percentages describe the share meeting the threshold. The record also does not report a clinical threshold for judging whether a particular contrast would be important. Statistical precision and clinical importance are different questions.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total events. The endpoint is a binary percentage, and the registry’s stated planning assumptions are a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. The assumed effect to detect is a stated fraction of the observed effect. The original sample-size assumptions used to design the trial are not reported in the registry record.

The 80% power column describes the number of participants per arm estimated to give an 80% chance of detecting the chosen effect under those planning assumptions, if that effect were the true one and the assumptions held. The 90% column has the same interpretation but uses a higher target chance of detection, so its planning figures are larger for each effect scenario. These are prospective planning illustrations, not a report of the trial’s achieved statistical power.

The rows consider planning for 100%, 75%, and 50% of the observed effect. For example, the posted figures for planning around 75% of the observed effect are 60 participants per arm for 80% power and 79 participants per arm for 90% power. The figures for planning around 50% of the observed effect are 135 participants per arm for 80% power and 180 participants per arm for 90% power. These illustrations show the general pattern: smaller effects need more participants to detect under the same assumptions.

The values are not a reconstruction of the trial’s intended enrollment target, and they do not account for any design features beyond those stated. They use the observed effect as their reference, which is itself uncertain. A different target effect or different planning assumptions would produce different figures.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.381; treatment proportion p₁ = 0.721; average p̄ = 0.551.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.7035 = 1.3787.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6612 = 0.5565.
4. n = (1.3787 + 0.5565)² / (0.3396)² = 32.5, rounded up to 33 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.380952380952381                          # control proportion
p1 <- 0.720588235294118                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(623727)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 33 (80% power), 43 (90% power)
 75% of observed effect: n per arm = 60 (80% power), 79 (90% power)
 50% of observed effect: n per arm = 135 (80% power), 180 (90% power)
power.prop.test: 32.5 
Simulated power at n = 33 per arm: 0.839 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists 7 outcome measures and posts 2 secondary outcomes. It records no reported analyses for the secondary outcomes. The primary comparison is available, but the registry record does not report a full statistical analysis plan, a testing hierarchy, or a procedure for controlling multiplicity. It is therefore not possible to determine from the record whether the primary endpoint was the sole confirmatory test or how the study intended to interpret multiple outcome comparisons.

As a general statistical point, multiplicity arises when several hypotheses or outcomes are examined. If each is tested without accounting for the others, the chance of at least one apparently unusual result can increase. That does not mean every secondary finding is false; it means that the strength of evidence depends partly on how the comparisons were planned and interpreted. Those details are not reported in the registry record, so the unadjusted secondary results warrant less weight than a prespecified, fully documented analysis would.

The primary endpoint uses the per-protocol population. The record does not report the criteria for inclusion in that population, the number excluded after randomization, or reasons for exclusion. It also does not report an intention-to-treat analysis, missing outcome counts, imputation methods, or sensitivity analyses. Consequently, readers cannot assess how incomplete follow-up or protocol deviations may have influenced the observed proportions.

The reported enrollment is 143, while the primary outcome denominators are 63 and 68 in the two per-protocol arms. The registry does not explain how enrollment relates to these endpoint denominators, and no reconciliation is reported. The study’s own sample-size justification, interim analyses, and rules for stopping or modifying the trial are not reported in the registry record. The termination reason is also not reported in the registry record. These gaps limit assessment of both the analysis process and the completeness of the posted results.

15. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: varicella (5.0%), glaucoma (1.5%), melaena (1.5%), rectal haemorrhage (1.5%), oedema (1.5%).

The registry reports serious adverse event figures for separate study groups: the double-blind groups, a follow-up group, and an extension group. In the BAY79-4980 double-blind group, serious adverse events were reported for 7 participants among 67 at risk. In the rFVIII-FS/WFI double-blind group, they were reported for 1 participant among 72 at risk. The follow-up group lists 0 among 26 at risk, and the extension group lists 1 among 20 at risk. These groups should be read separately; the registry does not report a combined safety analysis.

The record lists Varicella at 5.0% among the top serious terms, and Glaucoma, Melaena, Rectal haemorrhage, Oedema, and Hypersensitivity at 1.5% each. It does not specify in this record the denominator used for those term percentages. Deaths are not reported in the registry record.

These figures are descriptive counts, not a complete comparison of safety risk. The registry record does not provide exposure-adjusted rates, details of event duration or severity beyond the serious-event classification, or a statistical comparison. Follow-up and extension groups are distinct from the double-blind groups and cannot be combined or directly contrasted without further information.

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

The posted primary result shows that the percentage meeting the fewer-than-9-total-bleeds-per-year threshold was higher in the rFVIII-FS/WFI arm than in the BAY79-4980 arm. The unadjusted comparison and its confidence interval are consistent with that observed direction. This is what the endpoint data show for the per-protocol population over up to one year.

The result does not establish how each participant’s full bleed history was distributed, because the primary outcome reduces total bleeds to a threshold category. Nor does it show the timing or severity of bleeds. The event-counting rules are part of the definition, and outcomes formed under different counting rules might not have the same interpretation.

The result also does not, on its own, establish the reason for the observed difference or how broadly it applies beyond the analyzed population. Randomization is an important design feature, but the primary analysis is per protocol, and the registry does not report the population criteria, missing-data handling, or a complete analysis plan. The status is listed as terminated, with no reason reported in the registry record.

Statistical evidence and clinical importance are not identical. A small p-value does not by itself show that a difference is important to patients, while an interval describes uncertainty about the comparison rather than its practical meaning. The registry does not report a threshold for clinical importance or enough detail to assess all aspects of safety and benefit. The findings should therefore be read as a comparison of posted endpoint results, not as medical advice or a recommendation about treatment.

17. Why This Trial Matters Statistically

This trial raises a useful statistical issue: the intervention schedules differ, but the primary outcome is a thresholded percentage rather than a full description of bleed counts. The distinction between a binary endpoint and the underlying count matters when interpreting what an observed difference represents. A percentage meeting a cutoff can be clear to communicate while concealing variation within each category.

The record also illustrates why the analysis population matters. The primary result is reported for a per-protocol population, and the record does not explain its selection rules or how it relates to enrollment. Randomization supports comparability at assignment, but a restricted analysis population can require additional information to understand whether that comparability remains relevant to the result.

Uncertainty should be considered alongside the point estimate and p-value. The posted confidence interval gives information about the range of contrasts compatible with the data under its calculation assumptions, but the method is not described. The planning illustrations also show how sample-size requirements depend on the effect size selected: planning for a smaller effect requires more participants under the stated assumptions. Those calculations are not the trial’s original design justification.

Finally, this record shows the limits of registry summaries for evaluating multiplicity, missing data, and safety. Outcome results are posted, but the statistical analysis plan and several interpretive details are not. For clinical researchers, the lesson is to distinguish the observed comparison from what can be established about the analysis process and its wider implications.

18. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

Several trial-specific limitations affect interpretation of the posted result. The primary endpoint is reported in the per-protocol population, but its membership rules and the reasons participants may have been excluded are not reported in the registry record. The relationship between the enrollment figure and the endpoint denominators is also not explained. Missing outcome data, imputation, sensitivity analyses, and an intention-to-treat result are not reported.

The endpoint is a threshold measure based on the registry’s rules for combining bleeding events. It records whether participants had fewer than 9 total bleeds per year, rather than reporting the full distribution of bleed counts. The registry does not give further information about event adjudication or the distribution of counts within the endpoint categories.

The study is listed as terminated, but the reason for termination is not reported in the registry record. The original sample-size justification, interim analyses, and the statistical analysis plan are also not reported. Without those details, it is difficult to assess how the endpoint and analysis were chosen or how the study planned to address multiple outcomes.

The record posts safety counts across double-blind, follow-up, and extension groups, but does not report an integrated safety analysis or exposure-adjusted comparisons. The percentage denominators for the listed serious-event terms are not specified in the record. These limitations mean the available safety summaries should be interpreted descriptively and kept separate by study group.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: BAY79-4980 Compared to rFVIII-FS in Previously Treated Patients With Severe Hemophilia A — NCT00623727.
• Registry record last updated 2013-07-15; status last verified 2013-07.
• Results first posted 2011-08-17.
• 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.

22. Record Summary

The registry describes a randomized, parallel-group phase 2 study of BAY79-4980 versus rFVIII-FS/WFI in previously treated patients with severe hemophilia A. The study compared once-weekly BAY79-4980 with rFVIII-FS given three times per week. Enrollment was 143, and the study status is listed as terminated.

The primary endpoint was the percentage of participants with fewer than 9 total bleeds per year over up to one year, analyzed in the per-protocol population. The posted proportions were 38.1% for BAY79-4980 and 72.1% for rFVIII-FS/WFI, with an unadjusted p-value of p < 0.001. The record also includes joint-bleed outcomes and separate serious adverse event summaries.

The reason for termination, original sample-size justification, missing-data methods, analysis plan, and multiplicity approach are not reported in the registry record. These omissions should be considered when interpreting the posted comparisons.