Assess the Safety and Efficacy of Individually Tailored Prophylaxis With Human-cl rhFVIII in Patients With Severe Haemophilia A: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Assess the Safety and Efficacy of Individually Tailored Prophylaxis With Human-cl rhFVIII in Patients With Severe Haemophilia A (NCT01863758), a na phase 3 study. The primary outcome is Annualized Number of Bleeding Episodes (BE) in Phase II.

2. Clinical Question

The clinical question is about bleeding during a prophylactic regimen, not a randomized estimate of the difference between two treatments. Participants received individually determined doses and intervals, and the primary endpoint counted bleeding episodes whether treated or untreated. Bleeding episodes related to surgery were excluded. The endpoint covered the beginning to the end of Phase II, described as 6 months, and converted each participant’s observed count to an annualized measure using the treatment-period duration.

The historical benchmark gives the study a reference point, but it does not make the comparison equivalent to a concurrent controlled trial. Differences between participants or study circumstances could contribute to any contrast between the prophylaxis experience and the historical on-demand rate. The registry record does not report the historical rate, the observed primary endpoint estimate, or an inferential comparison for that endpoint. Accordingly, the clinical question can be stated from the design, but the magnitude and precision of the observed result are not reported in the registry record.

3. Trial Design

This was a Phase 3b, prospective, open-label, multicenter study. The registry lists a single-group model, no masking, and allocation as not applicable. The study status is completed. Enrollment was 66. The record gives a start date of 2013-08 and a primary completion date of 2015-01.

The intervention was Human-cl rhFVIII, administered intravenously as prophylaxis at an individually determined dose and dose interval. The intervention description states up to 60-80 IU/kg. Because treatment was open-label and there was no randomized allocation, the registry does not describe a concurrent control arm for the principal comparison. Instead, the brief summary describes comparing breakthrough bleeding under tailored prophylaxis with a historical bleeding rate among patients receiving Human-cl rhFVIII on demand.

The primary endpoint was the annualized number of bleeding episodes in Phase II. The endpoint description defines the relevant population as those who received at least 1 dose during Phase II and had any data collected after treatment. The record describes Phase II as lasting 6 months for the primary endpoint timeframe. Secondary outcomes listed include spontaneous bleeding episodes, bleeding episodes in participants with two or fewer treatments per week, median dosing interval, and dosage per week in Phase II.

A single-group design can describe outcomes observed during treatment, but it cannot by itself separate treatment-associated changes from changes that might have occurred over time or from differences between the study population and a historical cohort. Open-label status also means masking was not used. The registry record does not report further details of allocation procedures, protocol deviations, or the statistical plan for the historical comparison. Those details 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.

Pharmacokinetic Assessment

Prophylactic Treatment-Phase I

Prophylactic Treatment-Phase II

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Prophylactic treatment population: All participants who received at least 1 dose of Human-cl rhFVIII in Phase II and had any data collected after treatment with Human-cl rhFVIII.

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: Intent-to-treat/prophylactic/safety population: All participants who received at least 1 dose of Human-cl rhFVIII in Phase II and had any data collected after treatment with Human-cl rhFVIII.

6. Primary Endpoint

The registry lists the primary outcome as Annualized Number of Bleeding Episodes (BE) in Phase II, measured over Beginning to the end of Phase II (6 months).

The primary endpoint is the annualized number of total bleeding episodes during Phase II. A bleeding episode was defined to include any episode, whether treated or not; episodes related to surgery were excluded. The registry describes calculating a participant-specific annualized count by multiplying the observed number of episodes by 365.25 and dividing by the number of treatment-period days. This expresses follow-up experience on a yearly scale, allowing periods of different duration to be represented in a common unit.

The endpoint is a mean of a continuous measure: each participant contributes an annualized count, and the group-level measure is described as a mean with standard deviation. Bleeding counts are count data, but annualizing participant-level counts produces values that need not be whole numbers. A mean can communicate the average burden across the analyzed group, while the standard deviation describes how much participant-level values vary around that mean. Neither measure alone describes the full shape of the distribution.

The registry states that the study was considered to show efficacy if the annualized number of bleeding episodes was reduced by 50% compared with the number observed in study GENA-01, where patients with severe haemophilia A received on-demand treatment. That is the stated benchmark criterion, not a reported result. The registry record does not report the primary endpoint mean, its standard deviation, the historical rate, or whether the criterion was met. The endpoint’s practical interpretation is therefore limited to what it was designed to measure; the observed size and precision of the result are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does annualization do? General explanation: annualization rescales an observed count to the duration of a year. In this study, the registry says that each participant’s count was multiplied by 365.25 and divided by the number of treatment-period days. This makes the endpoint a rate-like measure on a common time scale, but it does not mean that every participant was observed for a full year. Annualized values can be more variable when follow-up periods are short or differ in length, and interpretation depends on how the observation periods and episodes were defined.

Why use a mean and standard deviation? The primary endpoint is identified as a mean of a continuous measure, with standard deviation as the dispersion statistic. The mean summarizes the arithmetic average of participant-level annualized counts. The standard deviation describes the spread of those values around the mean. General explanation: a mean and standard deviation are familiar summaries, but count-derived data can be asymmetric, with many low values and a smaller number of high values. In that setting, the mean can be influenced by high observations, and the standard deviation does not show whether the distribution is skewed or contains clusters. The registry record does not report additional distributional summaries or diagnostics.

Why might over-dispersion matter? General explanation: a simple count model may assume that variability follows a particular relationship to the mean. Over-dispersion means the observed variability is greater than that assumption allows. If present and not accommodated, standard errors and confidence intervals from a model may be too small, making results appear more precise than warranted. A participant-level annualized count and its mean do not by themselves establish whether over-dispersion was assessed. The statistical approach for assessing or modeling dispersion is not reported in the registry record.

What does the historical benchmark contribute? The study’s stated benchmark is the number of bleeding episodes observed in study GENA-01 among patients receiving Human-cl rhFVIII on demand. The registry says the study was considered to show efficacy if the annualized number during Phase II was reduced by 50% compared with that historical number. General explanation: a historical comparison uses an outcome from a separate study rather than a concurrently randomized control group. This can provide context, but the interpretation depends on whether populations, outcome definitions, observation, and study procedures are sufficiently comparable. The record does not report the historical endpoint value or the details needed to evaluate comparability. No adjustment method for between-study differences is reported in the registry record.

What would a confidence interval add? General explanation: a confidence interval expresses uncertainty around an estimate under a specified method and its assumptions. It can show which effect sizes remain compatible with the data, rather than presenting only a point estimate. For a historical comparison, uncertainty in both the prophylaxis estimate and the historical benchmark may matter, depending on the analysis. The registry record does not report a confidence interval for the primary endpoint or explain how uncertainty in the historical rate was handled. Without those details, the precision of the comparison cannot be assessed.

What does a p-value answer? General explanation: a p-value is calculated relative to a particular null hypothesis and statistical model; it is not the probability that the null hypothesis is true and does not measure clinical importance. A p-value cannot substitute for an effect estimate and uncertainty interval. The primary endpoint p-value and the test used for the historical comparison are not reported in the registry record. The record also does not report whether any analysis was adjusted for covariates.

How should planning illustrations be understood? The planning illustration assumptions described for the page use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a stated fraction of the observed effect. The record characterizes these as planning illustrations based on the observed effect, not the trial’s own design. They are not observed power. The study itself is listed as single-group, so the equal-allocation two-arm setup is an illustration rather than a description of how participants were assigned in this trial. The illustration’s numerical sample-size outputs are not reported in the registry record.

What information is needed to reproduce the analysis? Reproduction would require the endpoint values, analysis population size, handling of incomplete observations, and the statistical method used for the historical comparison. Definitions and time windows for the endpoint are partly described, but the actual primary result and analysis details are not. The registry record does not report whether the analysis used a particular distributional model, how uncertainty was calculated, or whether sensitivity analyses were conducted. Those omissions limit independent evaluation of the result.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Human-cl rhFVIII")
n   <- c(66)
m   <- c(3.05)
sp  <- c(13.43)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Human-cl rhFVIII  66  3.050  13.430  -0.252  6.352

11. Multiplicity, Missing Data and Analysis Populations

The registry lists five outcome measures and two analyses, including the primary annualized number of bleeding episodes and several secondary outcomes concerning spontaneous bleeding, participants with two or fewer treatments per week, dosing interval, and weekly dosage. The record does not report a multiplicity strategy for interpreting several outcomes. In general, testing many outcomes can increase the chance of at least one apparently notable result when each is considered separately. Adjustments, outcome hierarchies, or a prespecified focus can address that issue, but whether any such approach was used is not reported in the registry record.

The primary endpoint population was defined as participants who received at least 1 dose of Human-cl rhFVIII in Phase II and had any data collected after treatment. Enrollment was 66, but the number contributing to the primary analysis is not reported in the registry record. The record does not describe missing-data methods, reasons for missing endpoint observations, or sensitivity analyses for missing data. It is therefore not possible to assess from this record whether missing observations could have affected the endpoint estimate.

General explanation: excluding participants without post-treatment data can make the analyzed population differ from the enrolled population. If the likelihood of missing data is related to bleeding experience or treatment, a complete-case summary may not represent all enrolled participants. This is a general concern, not evidence that such a pattern occurred in this study. The registry record does not report enough information to assess it.

The record identifies the primary endpoint population but does not report a complete analysis-population flow or a statistical analysis plan. The handling of protocol deviations, withdrawals, and any other analysis populations is not reported in the registry record. The record also does not report interim analyses or a sample-size justification. These missing details constrain assessment of prespecification and robustness.

12. 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 3% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: haematemesis (1.5%), fracture of lower leg (1.5%), tenotomy of muculus gastrocnemius medialis (1.5%), appendicitis acuta (1.5%), wound inflammation due to surgery (1.5%).

The registry lists 66 participants at risk for serious adverse events and 5 affected by at least one serious adverse event in the Human-cl rhFVIII group. For other adverse events, it lists 66 at risk and 24 affected. These are separate registry summaries; they should not be added together, because the record does not state whether participants could appear in both categories. A death count is not reported in the registry record.

The serious adverse-event terms listed include Haematemesis, Fracture of Lower Leg, Tenotomy of muculus gastrocnemius medialis, Appendicitis Acuta, wound inflammation due to surgery, and Pain of lumbar spine. Each listed term is shown with 1.5%. The record does not give further clinical details, timing, outcome, or an attribution assessment for these terms. The term-level percentages should not be interpreted as a treatment-caused risk without those details and an appropriate comparison.

General explanation: an affected-participant count is different from an event count because one participant may experience more than one event. A serious adverse event is a reporting category, not by itself a statement that the event was caused by treatment. These safety figures are descriptive summaries from a single-group study, not estimates of a difference against a concurrent control. The registry record does not report a comparative safety analysis.

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

The record establishes the study’s design and the question it set out to address: bleeding during individually tailored Human-cl rhFVIII prophylaxis, with comparison to a historical on-demand rate. It defines the primary measure, the endpoint timeframe, the treatment approach, and the stated benchmark criterion. It also provides descriptive adverse-event counts for the treatment group.

The record does not report the primary endpoint mean or standard deviation, the historical bleeding rate, or a confidence interval or p-value for the primary comparison. It therefore does not establish from the information recorded whether the stated 50% reduction criterion was met, nor how precise any observed contrast was. The design is single-group and open-label, so the historical reference is not equivalent to a randomized concurrent control. Any contrast would need to be interpreted in light of possible differences between the study populations and circumstances.

General explanation: a result can be statistically uncertain even when a point estimate appears large, and a precisely estimated difference does not by itself establish that a treatment caused it. Effect size, uncertainty, outcome definition, and design all matter. In this record, the absence of primary numerical results prevents evaluation of effect size and precision, while the nonrandomized historical comparison limits causal interpretation.

The safety summaries report affected participants in the serious and other adverse-event categories, alongside selected serious terms. They do not provide a randomized safety comparison, and the record does not report a death count. Those summaries should be understood as descriptive rather than as evidence that events were or were not caused by the intervention.

Accordingly, the trial’s record is informative about its planned clinical question and methods as described, but the numerical primary outcome and key inferential details are not reported in the registry record. No conclusion about the magnitude, precision, or causal meaning of a treatment effect can be drawn from the endpoint information recorded.

14. Why This Trial Matters Statistically

Statistically, this trial illustrates the difference between describing outcomes in a treated group and estimating a treatment contrast. The study is listed as prospective, open-label, multicenter, and single-group. Its primary comparison uses a historical on-demand rate rather than a concurrent randomized control. That distinction matters because a historical comparison relies on the assumption that the two study experiences can be meaningfully compared, an assumption that cannot be evaluated from the endpoint definition alone.

The primary outcome also illustrates the challenges of summarizing count-derived data. Each participant’s total bleeding episodes were annualized using treatment-period duration, and the group measure was specified as a mean with standard deviation. This makes the endpoint interpretable on a common time scale, while leaving questions about distribution, variability, and the influence of unusually high counts. The registry record does not report analyses that would answer those questions.

The stated 50% reduction criterion makes the historical benchmark central to interpretation. But without the primary estimate, the benchmark value, or uncertainty measures, the record does not show how close the data were to that criterion or how stable the comparison might be. This highlights why an endpoint definition and a decision threshold are not substitutes for reporting the observed result and its precision.

The record also makes the analysis population important: the primary population required treatment exposure and post-treatment data, while the enrolled count alone does not identify how many participants contributed to the endpoint. Missing-data handling and multiplicity procedures are not reported in the registry record. These details affect how readers assess representativeness and the strength of conclusions. The trial is therefore a useful example of why design, estimand, analysis population, uncertainty, and reporting completeness must be considered together.

15. 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 most consequential limitation for interpreting the primary outcome is that the numerical result is not reported in the registry record. The record gives the endpoint definition and a historical efficacy benchmark, but not the observed mean, standard deviation, historical rate, confidence interval, or p-value. This prevents assessment of effect magnitude and precision.

The single-group design has no concurrent randomized comparator. The historical reference comes from patients receiving on-demand treatment in study GENA-01, but details needed to judge comparability are not reported in the registry record. Differences in populations, follow-up, measurement, or study conduct could affect a cross-study contrast. The record does not report an adjustment strategy for such differences.

The study was open-label, and masking was listed as none. The primary endpoint included bleeding episodes whether treated or not, while surgery-related episodes were excluded. The definition is described, but the record does not provide further detail on how episodes were identified or adjudicated. The implications of open-label assessment for event ascertainment cannot be evaluated from the record.

Although enrollment was 66, the primary endpoint population required treatment exposure and post-treatment data. The number analyzed, missing-data approach, reasons for missing observations, and sensitivity analyses are not reported in the registry record. The statistical plan, multiplicity approach, and interim analyses are also not reported in the registry record. These gaps limit assessment of prespecification and robustness.

Finally, adverse-event summaries are descriptive and do not include a concurrent comparison. The registry record does not report a death count or detailed context for the listed serious-event terms. These reporting limitations do not establish that unreported events or analyses occurred; they mean those details are not available in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Assess the Safety and Efficacy of Individually Tailored Prophylaxis With Human-cl rhFVIII in Patients With Severe Haemophilia A — NCT01863758.
• Registry record last updated 2018-01-30; status last verified 2017-07.
• Results first posted 2018-01-30.
• 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.

19. Record Summary

NCT01863758 is a completed Phase 3b, prospective, open-label, multicenter, single-group study of individually tailored intravenous Human-cl rhFVIII prophylaxis in previously treated adults with severe haemophilia A. Enrollment was 66. The record lists a start date of 2013-08 and a primary completion date of 2015-01.

The primary endpoint was the annualized number of total bleeding episodes during Phase II, described as 6 months. Episodes related to surgery were excluded. The stated benchmark was a 50% reduction compared with the historical on-demand bleeding rate in study GENA-01, NCT00989196. The primary numerical result and its uncertainty are not reported in the registry record.

The registry lists 5 participants with serious adverse events and 24 with other adverse events, with 66 at risk in each category. A death count is not reported in the registry record. The record does not report a concurrent randomized comparison, missing-data methods, or the statistical plan for the primary historical comparison.