A Study of BAX 888 in Male Adults With Severe Hemophilia A: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of BAX 888 in Male Adults With Severe Hemophilia A (NCT03370172), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Participants With BAX 888-Related Adverse Events (AEs).

2. Clinical Question

Other listed outcomes address circulating plasma FVIII activity and antigen, annualized bleed rate, exogenous FVIII consumption, inhibitory and total binding antibodies to FVIII, immune responses to AAV8 and FVIII proteins, and AAV8 genome shedding. These outcomes describe a broader set of safety, biological-response, and clinical measures, but their presence in the record does not itself establish a result for any of them.

3. Trial Design

This was a Phase 1/2, global, open-label, multicenter study of BAX 888, described as an adeno-associated virus serotype 8 vector expressing B-domain deleted factor VIII. The intervention was administered as a single intravenous infusion. The study is marked completed in the registry record, with start listed as 2018-02-27 and primary completion listed as 2024-07-09.

Allocation was non-randomized, masking was absent, and the model was sequential. Participants were assigned to a dose cohort rather than randomized between a treatment and a control. Cohort 1 received 2.0*10^12 cp/kg, while Cohort 2 received 6.0*10^12 cp/kg. Each cohort had 2 participants enrolled in the posted adverse-event data. Total enrollment was 4.

That structure is consistent with describing experience at successive dose levels, but the record does not report the protocol rules used to escalate a dose, how decisions were made, or whether any dose was selected for later study. It also does not report a sample-size justification. The stated study aims concerned checking for side effects and determining a dose, but the posted information does not establish how those aims were operationalized beyond the listed endpoints and cohort descriptions.

Because the study was open-label and lacked randomized allocation, the cohort figures are descriptive rather than controlled comparative estimates. A difference between cohorts, if present, could not be attributed to dose alone from these data. The registry record lists the intervention as BAX 888 and reports single infusions on the day of dosing; it does not provide additional treatment details beyond the cohort dose descriptions.

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: Participants with severe Hemophilia A participated in the study to receive BAX 888.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Safety Set consisted of all participants who received any amount of investigational product.

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 Safety Set consisted of all participants who received any amount of investigational product.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With BAX 888-Related Adverse Events (AEs), measured over From first dose up to end of the study (approximately 6 years).

The primary endpoint counts participants with BAX 888-related adverse events. The registry defines an adverse event as an untoward medical occurrence in a participant administered an investigational product, whether or not it necessarily has a causal relationship with treatment. Serious adverse events are defined by outcomes including death, a life-threatening event, required or prolonged inpatient hospitalization, persistent or significant disability or incapacity, or congenital anomaly. The AE definition also includes serious and non-serious events, such as development of FVIII inhibitory antibodies and clinically significant changes in laboratory parameters, physical examination, or vital signs.

The endpoint is used to characterize safety experience during follow-up. A participant count gives a direct account of how many people in the safety set had an event meeting the endpoint definition; it is not, by itself, a measure of event severity, duration, or the certainty that BAX 888 caused an event. The record specifies follow-up from first dose to the end of the study, approximately 6 years.

The primary endpoint title refers specifically to BAX 888-related adverse events, while the general AE definition says an event need not necessarily have a causal relationship with treatment. The registry record does not provide the criteria for judging relatedness or a primary-endpoint count by cohort. It therefore does not allow the posted serious and other adverse-event figures to be treated automatically as the primary endpoint result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record describes a non-randomized, sequential study and lists a participant-count safety endpoint. It does not report a statistical analysis plan for that endpoint. The following explanations are general statistical context, not a description of methods confirmed to have been used by the study.

What does a participant count tell the reader?

For a binary outcome such as whether a participant had an event, a count records how many participants met the definition during the stated observation period. Such a count is easy to interpret as a description of the observed group. It does not convey the full pattern of events: a participant may have more than one event, and a participant count does not show event timing, duration, recurrence, or severity beyond any separate classification reported.

When a count is accompanied by the number at risk, the reader can see the size of the group from which the count arose. In this study the cohort-level safety figures are based on 2 participants in each cohort. With groups this small, one participant's outcome has a substantial influence on the apparent pattern. The counts should not be read as stable estimates of what would occur in a wider population.

Why are confidence intervals useful?

In general, a confidence interval expresses the statistical uncertainty around an estimate under the assumptions of the method used to construct it. It helps distinguish a point estimate from the range of values compatible with the data and method. A count alone does not supply that interval. The registry record does not report confidence intervals or an inferential estimate for the primary endpoint, so the precision of a population-level event rate cannot be assessed from the posted primary outcome information.

General statistical methods for binary outcomes may estimate a proportion or compare proportions, but those methods require a clearly specified analysis population, outcome definition, and handling of missing observations. A comparative method also requires attention to the design. Here allocation was non-randomized and the model sequential, so a simple comparison of cohort counts would not have the safeguards of a randomized comparison. Even a formal test would not remove the design limitations or make the cohorts exchangeable.

What does sequential allocation imply?

In general, sequential dose studies examine groups in an order, with later dose decisions potentially depending on earlier experience. The registry identifies this study's model as sequential and lists two dose cohorts, but does not report escalation criteria or decision rules. It is therefore not possible to assess from the record how the observed safety experience informed dosing, or whether a prespecified statistical boundary guided decisions.

Sequential designs can be useful for describing early experience across dose levels, but they are not automatically comparative trials. Cohorts may differ for reasons associated with their order, enrollment, or other features not captured in a summary count. Since randomization was not used and no control group is listed, the observed adverse-event counts do not estimate a dose effect in isolation.

How should the sample-size illustrations be understood?

General power calculations estimate how many participants might be needed to detect a specified effect under stated assumptions. The registry record's sample-size illustration is described as using a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. It is explicitly a planning illustration, not the trial's own design justification and not observed power. The record does not report the study's sample-size justification.

A planning calculation based on an observed effect is conditional on that effect estimate and its assumptions. It does not show the probability that this completed study detected a real effect, and it cannot replace a prespecified design rationale. No planning-result values are included in the registry record, so no sample-size estimate can be interpreted numerically. The study enrolled 4 participants; that enrollment is an observed design fact, not a power calculation.

What is not available for assessing the primary analysis?

The record lists 9 outcome measures and 0 analysis entries. It does not report a test, model, confidence interval, adjustment method, or missing-data procedure for the primary endpoint. It also does not state whether subgroup or sensitivity analyses were conducted. These omissions mean that readers cannot reconstruct an inferential analysis or evaluate whether analysis choices were prespecified.

General statistical interpretation depends on matching the analysis to the endpoint and study design. A binary participant outcome, repeated clinical measures, laboratory values, and time-to-event outcomes can require different methods. The secondary outcomes include several different kinds of measures, but the registry information does not specify analysis methods for them. No unreported model, test, or adjustment should be assumed.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Cohort 1: BAX 888 2.0*10^12 cp/kg", "Cohort 2: BAX 888 6.0*10^12 cp/kg")
n      <- c(2, 2)
events <- c(2, 2)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Cohort 1: BAX 888 2.0*10^12 cp/kg  2  2  100.0  15.8  100.0  34.2  100.0  29.2  99.2
ARM  Cohort 2: BAX 888 6.0*10^12 cp/kg  2  2  100.0  15.8  100.0  34.2  100.0  29.2  99.2

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists the primary adverse-event outcome and secondary outcomes covering FVIII activity, FVIII antigen, annualized bleed rate, exogenous FVIII consumption, antibodies, immune responses, and AAV8 genome shedding. It reports 9 outcome measures and 0 analysis entries. The record does not report a multiplicity strategy, such as a hierarchy among secondary outcomes or an adjustment for multiple statistical tests. Without an analysis plan or reported tests, it is not possible to assess how the study handled the chance of false-positive findings across several outcomes.

The record does not report how missing observations were handled, whether any outcomes were incomplete, or whether all participants completed follow-up. The primary endpoint timeframe extends from first dose to the end of the study, approximately 6 years, but participant-specific follow-up and censoring information are not reported in the registry record. The stated safety population consists of all participants who received any amount of investigational product. The adverse-event figures list 2 participants at risk in each cohort.

These details matter because outcome ascertainment and follow-up affect interpretation of event counts. A missing outcome cannot be treated as an event-free observation without an explicit rule, and unequal observation periods can make counts less directly comparable. The registry record does not say whether such issues arose or how they were addressed. Consequently, the reported counts can be described as posted, but a complete-case, imputed, or other analysis approach cannot be attributed to the study.

12. Safety Results

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

Deaths

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: hypophosphataemia (50.0%).

The serious adverse-event counts are 0 participants in Cohort 1 and 1 participant in Cohort 2; each cohort had 2 participants at risk. The registry reports 0 deaths in both cohorts. For other adverse events, 2 participants were reported in each cohort. These are participant counts, not counts of separate event episodes.

The registry identifies hypophosphataemia as the top serious adverse event term and gives 50.0%. The cohort assignment for this term is not reported in the registry record. The term percentage should not be taken to identify the percentage of participants with any serious event across the whole study, nor does it indicate the total burden of all adverse events.

The serious-event definition covers specified outcomes such as death, life-threatening events, hospitalization, significant disability or incapacity, and congenital anomaly. Seriousness is distinct from whether an event was judged related to BAX 888. The primary endpoint is specifically about BAX 888-related adverse events, but the registry record does not report that endpoint's count or explain the relatedness assessment. Thus, the serious and other AE figures describe the safety listings; they are not a substitute for an unreported primary-endpoint analysis.

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

The posted results establish that the registry reports adverse-event experience among a small group of participants treated in two sequential dose cohorts. The cohort counts indicate that serious adverse events were reported for 0 participants in Cohort 1 and 1 participant in Cohort 2; other adverse events were reported for 2 participants in each cohort. The record also reports no deaths in either cohort and lists hypophosphataemia at 50.0% as the top serious term, without identifying its cohort in the information presented.

Those observations do not establish that BAX 888 caused or prevented any event. The general adverse-event definition explicitly allows events without a necessary causal relationship to treatment, and the primary endpoint count for events judged related to BAX 888 is not reported. The record also provides no inferential analysis, confidence interval, or comparison against a control group.

The study's non-randomized, sequential design does not support a causal comparison of the two dose cohorts. The groups were small, and cohort membership was not assigned randomly. The observed counts should therefore not be interpreted as proof that one dose has a higher or lower risk than the other. The study record does not report a conclusion about a selected dose.

The broader outcome list signals that the study was intended to capture biological measures, bleeding, factor use, antibody development, immune responses, and vector shedding, in addition to safety. Their inclusion is not a report of their results. Those results are not reported in the registry record. The data discussed do not establish a treatment benefit, and they do not establish the absence of risks that might emerge with additional participants or longer observation.

In general, early-phase safety findings are interpreted alongside study design, follow-up, event definitions, and uncertainty. Here, the registry entries support a narrow descriptive reading of the counts. They do not provide sufficient information for a precise estimate of event risk, a reliable dose comparison, or a conclusion about clinical effectiveness.

14. Why This Trial Matters Statistically

This trial is statistically notable because it combines a safety-focused primary question with a very small, sequential dose-escalation design. The record gives a concrete description of the dose cohorts and the observed adverse-event counts, while also illustrating why descriptive counts should not be mistaken for comparative evidence. Enrollment was 4, with 2 participants in each cohort.

The distinction between safety description and causal inference is especially important in a non-randomized study. A count can summarize what happened among enrolled participants, but a comparison across cohorts does not automatically separate dose effects from other differences. The sequential model and absence of masking are part of the design context; the registry does not provide evidence that would overcome those constraints for a dose comparison.

The endpoint also raises a useful interpretive distinction. A general adverse event may occur during treatment without necessarily being caused by it, while the primary endpoint specifies BAX 888-related events. Because the related-event result and its assessment method are not reported, the overall adverse-event counts should not be substituted for that primary outcome.

Finally, the record lists a long follow-up timeframe and a broad set of secondary outcomes, but the statistical analysis entries are absent. This separates endpoint intent from analyzed evidence: defining an outcome does not establish a result, and a planning illustration is not observed power. The trial is therefore informative as a registry example of how design, endpoint definitions, analysis reporting, and sample size jointly limit the strength of statistical interpretation.

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.

Enrollment was 4, with 2 participants in each dose cohort. This small enrollment means the posted counts describe only a few participants and provide limited information about the range of possible safety experiences. The registry record does not report a sample-size justification, so the basis for the planned enrollment cannot be assessed.

The trial was non-randomized, sequential, and open-label, with no control arm listed. The registry explicitly notes that the arms are not a like-for-like control comparison. Differences between cohort counts cannot be attributed to dose alone, and no randomized contrast is available to estimate a treatment effect.

The primary endpoint is the number of participants with BAX 888-related adverse events, but that count and the method for judging relatedness are not reported in the registry record. Posted serious and other adverse-event counts do not resolve this gap. The record also does not provide event-level details, timing, participant-specific follow-up, or cohort attribution for the hypophosphataemia term.

Although the primary outcome timeframe is approximately 6 years, the record does not report follow-up completeness or missing-data handling. It lists secondary outcome definitions but does not provide their numerical results in the information. No inferential analysis, confidence interval, multiplicity approach, or analysis plan is reported. These omissions restrict assessment of precision, missingness, and the reliability of any outcome comparisons.

The population described is male adults with severe hemophilia A. Results from this small group should not be assumed to represent populations not described in the registry record. The record also does not report the protocol details needed to assess dose-escalation decisions or any dose-selection conclusion.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of BAX 888 in Male Adults With Severe Hemophilia A — NCT03370172.
• Registry record last updated 2025-09-11; status last verified 2025-08.
• Results first posted 2025-09-11.
• 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

NCT03370172 is a completed Phase 1/2, global, open-label, multicenter study of BAX 888 in male adults with severe hemophilia A. The study used non-randomized, sequential dose cohorts and a single intravenous infusion: Cohort 1 received 2.0*10^12 cp/kg, and Cohort 2 received 6.0*10^12 cp/kg. Enrollment was 4.

The primary endpoint was the number of participants with BAX 888-related adverse events over follow-up from first dose to the end of the study, approximately 6 years. The registry reports serious adverse events for 0 participants in Cohort 1 and 1 participant in Cohort 2; other adverse events were reported for 2 participants in each cohort, and no deaths were reported. Hypophosphataemia is listed as the top serious term at 50.0%.

The record lists 9 outcome measures and 0 analysis entries. It does not report a primary-endpoint analysis, sample-size justification, missing-data approach, multiplicity method, or results for the listed secondary outcomes. The cohort counts are descriptive and do not support a randomized or causal dose comparison.