BAX 826 Dose-Escalation Safety Study: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for BAX 826 Dose-Escalation Safety Study (NCT02716194), a non-randomized phase 1 study. The primary outcome is Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826.

2. Clinical Question

The clinical question is primarily about early safety and tolerability, not whether BAX 826 prevents bleeding or improves another clinical outcome. The registry also sets out pharmacokinetic comparisons with ADVATE and evaluation of immunogenicity of polysialic acid linked to Factor VIII. The listed secondary pharmacokinetic measures include exposure, elimination, distribution, and peak concentration measures.

The design uses dose escalation across low-, medium-, and high-dose cohorts. The cohort descriptions state that recruitment to the next dose level followed review of short-term safety. The detailed escalation criteria are not reported in the registry record. Because allocation was nonrandomized and the study was open label, treatment groups should not be treated as if they arose from a blinded randomized comparison. The primary safety question is therefore best read as a description of observed adverse events in the specified study groups and follow-up period.

3. Trial Design

This was a phase 1, prospective, open-label study with two periods, a fixed sequence, and dose escalation. Its model is recorded as crossover, but allocation was nonrandomized and masking was none. The registry lists BAX 826 and octocog alfa, also referred to as ADVATE. The study enrolled 40 participants and is recorded as completed. The listed start date is 2016-03-03 and the primary completion date is 2017-01-17.

Participants were assigned to three dose cohorts described as low, medium, and high. Each cohort description states a plan for 10 evaluable participants. Those planned evaluable counts are not the same as the at-risk counts in the posted adverse-event records: those records give group-specific denominators for ADVATE and BAX 826. The cohort descriptions also say that recruitment to the next dose level was contingent on review of short-term safety. The further criteria and operational details are not reported in the registry record.

In a fixed-sequence crossover design, treatment periods occur in a specified order rather than being assigned in a randomized order. That can make within-participant comparisons possible in principle, but the registry does not report the sequence details, washout information, or the statistical approach used to handle period or sequence effects. Those aspects should not be assumed. The primary safety outcome specifically includes participants in Cohorts 1, 2, and 3 in Period 2 receiving BAX 826, while the adverse-event listing also provides ADVATE group records.

Open-label status means treatment assignment was not masked. Nonrandomized allocation also means the groups do not constitute a like-for-like randomized control comparison. These design features are important when interpreting any observed differences: the record supports descriptive reporting of outcomes, but does not by itself establish that treatment assignment caused a difference. The protocol’s sample-size justification and any interim analysis plan 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: 44 participants signed informed consent. Of these, 4 participants were not treated (2 screen failures and 2 participants withdrew from study prior to receiving any dosing).

Period 1 - ADVATE

Reasons for not completing this period:

Period 2 - BAX 826

Analysis population for the primary outcome, as defined in the registry: Participants in Cohort 1, 2 and 3 in Period 2 (receiving BAX 826) are included.

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 Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826, measured over Up to 6 weeks ± 4 days post infusion with BAX826..

The primary endpoint is the number of serious and non-serious adverse events occurring after infusion with BAX 826. The specified population is participants in Cohorts 1, 2, and 3 during Period 2, when they received BAX 826. The follow-up window is up to 6 weeks ± 4 days after infusion. The endpoint is a count, rather than a measure of the probability of an event or a time-to-event outcome.

Adverse-event counts are used in safety studies to describe the types and frequency of events recorded during treatment and follow-up. Serious and non-serious events are distinguished because severity and regulatory classification are relevant aspects of safety monitoring. A count alone does not establish that an event was caused by the study product. It also does not necessarily describe how many individuals experienced an event if the record counts events and an individual could contribute more than one.

The posted adverse-event records give group-specific numbers at risk and affected, including records for ADVATE and BAX 826. Those records show no serious adverse events in the listed groups. They also record non-serious adverse-event counts in some groups. The primary endpoint’s stated scope remains BAX 826 in Period 2; the presence of ADVATE records does not change that definition. The registry does not report a formal statistical comparison for this endpoint, nor does it provide further detail on event coding or attribution.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The outcome is expressed as a count of adverse events. Count data differ from measurements such as a laboratory concentration: counts are whole-number events and can be zero. A count may describe the number of events, the number of affected participants, or both, depending on the registry’s definition and reporting structure. The primary outcome is explicitly labelled as a number of adverse events, while the group-level adverse-event records provide numbers at risk and affected. The registry does not give enough detail to determine whether repeated events in one participant are represented separately in every group count.

Why does the design matter for interpretation?

Randomization is intended to make treatment groups comparable on average with respect to measured and unmeasured factors. This study is recorded as nonrandomized, so that protection is not present. Differences in observed adverse-event counts may be associated with treatment, but may also relate to cohort composition, dose level, timing, or other factors. Open-label status means treatment was not masked; the registry does not report whether event assessment used any additional blinded procedures.

The study is described as a two-period fixed-sequence crossover. In general, crossover designs can compare measurements from the same participant under different treatments, which may reduce some between-person variability. Such comparisons require suitable handling of treatment order, period effects, and any carryover from one period to another. The registry record does not report the treatment sequence details, a washout description, or methods for assessing or adjusting for these effects. It therefore cannot be assumed that a particular crossover analysis was performed.

What can an event count tell the reader?

A count communicates the number of recorded events or affected individuals according to the registry’s reporting convention. A count by itself does not quantify uncertainty. Confidence intervals, when reported, describe a range of values compatible with the data and a specified statistical procedure; they do not remove design limitations or establish causality. No confidence intervals or formal comparative estimates for the primary outcome are reported in the registry record.

Counts also depend on the observation opportunity. The primary outcome’s follow-up is defined as up to 6 weeks ± 4 days after BAX 826 infusion. This is a bounded follow-up window, so the results describe that period rather than longer-term safety. Different group sizes and observation patterns can make raw counts difficult to compare directly. A rate or model that accounts for exposure time can sometimes help when follow-up differs, but no such analysis is reported in the registry record.

Why might a count model need extra care?

As a general statistical point, simple count models often assume that the variability in counts follows a particular relationship with their average. Over-dispersion occurs when observed variability is greater than that assumption allows; if ignored, uncertainty can be understated. Repeated events within the same participant may also be correlated rather than independent. Approaches that account for clustering or over-dispersion can be useful when appropriate, but the registry does not identify a count model or report whether these features were assessed. No model should be attributed to the study without that information.

Zero counts require careful reading as well. A recorded zero means no event was listed in that group for the outcome and reporting window; it is not proof that the underlying event risk is zero. The precision of an estimate based on zero observed events depends on the amount and structure of observation, and a formal interval or inferential analysis would need to be reported to quantify that uncertainty. No such interval is reported in the registry record.

What does the record say about planning calculations?

The registry describes sample-size planning illustrations using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The target effect is described as a stated fraction of the observed effect. These are planning assumptions, not evidence that the study was designed around a particular clinically meaningful effect. Specific planning outputs are not reported in the registry record. Any such sample-size illustration is not observed power: power is a design property under specified assumptions, not a probability calculated after seeing the observed result.

The registry records 21 outcome measures and zero analysis entries. This does not establish which analyses, if any, were conducted outside the entries in the registry. The specific statistical methods, handling of repeated events, treatment of missing observations, and inferential procedures are not reported in the registry record. Accordingly, the posted counts support descriptive interpretation, while a more detailed assessment of uncertainty or treatment contrasts would require analysis information that is not reported.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 21 outcome measures, including the primary safety outcome and pharmacokinetic measures. When a study evaluates multiple outcomes, multiple doses, or several contrasts, the chance of at least one apparently notable result can increase if each is tested separately. Statistical approaches can address multiplicity by defining a hierarchy, adjusting significance thresholds, or emphasizing estimation rather than isolated tests. The registry record does not report a multiplicity strategy, a hierarchy among outcomes beyond identifying the primary outcome, or a statistical analysis plan.

The record lists zero analysis entries. This is a statement about what is entered in the registry; it should not be interpreted as proof that no analyses were performed. Numerical results for the listed pharmacokinetic outcomes and immunogenicity objective are not reported in the registry record, and no formal comparative analysis of adverse events is reported.

Missing-data handling is not reported in the registry record. The record does not explain how participants with incomplete follow-up, unavailable measurements, or discontinuation would be handled in each analysis. The analysis populations are also not defined in detail beyond the primary outcome population: participants in Cohorts 1, 2, and 3 in Period 2 receiving BAX 826. Planned evaluable cohort sizes are stated, but the relationship between evaluability and the listed analysis population is not fully described. These omissions limit assessment of how complete and comparable the analyzed observations were.

In a crossover study, missing observations in one period can affect whether a within-participant comparison is possible. The record does not report how incomplete periods, sequence effects, or carryover would be treated. These matters are especially relevant when interpreting comparisons across the fixed sequence, but no particular method can be assumed.

11. 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 0% reporting threshold.

Most frequent non-serious adverse event terms

The adverse-event listing gives group-specific numbers at risk and affected. For serious adverse events, the recorded count is 0 in each listed group: Cohort 1, Cohort 2, and Cohort 3 for both ADVATE and BAX 826. No deaths are listed. The serious adverse-event term list is empty.

For non-serious adverse events, the listing records 3 affected in Cohort 1 - Low Dose ADVATE, 0 in Cohort 2 - Medium Dose ADVATE, and 4 in Cohort 3 - High Dose ADVATE. For BAX 826, it records 6 in Cohort 1 - Low Dose, 6 in Cohort 2 - Medium Dose, and 5 in Cohort 3 - High Dose. The corresponding at-risk counts are 11, 16, and 13 for ADVATE, and 10, 15, and 13 for BAX 826.

These are descriptive group records, not a randomized comparison. A zero indicates no event recorded in that group under the registry’s reporting, not proof of zero underlying risk. The listing does not establish causation, and the registry does not report confidence intervals or a formal statistical comparison. The primary safety outcome is defined for BAX 826 in Period 2, with follow-up up to 6 weeks ± 4 days after infusion; longer-term outcomes are not captured by that stated window.

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

The posted results support a limited conclusion about what the registry records: no serious adverse events or deaths are listed in the six ADVATE and BAX 826 groups, while non-serious adverse-event counts vary across the groups. The primary safety outcome is defined for participants receiving BAX 826 in Period 2, and the adverse-event records supply counts for each dose cohort. These observations are relevant to describing safety during the stated follow-up window.

They do not show that BAX 826 is safer or less safe than ADVATE. Allocation was nonrandomized, the study was open label, and the registry does not report a formal comparison or uncertainty estimates. Raw counts from groups with different at-risk numbers should not be treated as equivalent to adjusted treatment effects. Nor does an absence of recorded serious events prove that such events cannot occur.

The study’s aims also include pharmacokinetics and immunogenicity. The registry lists pharmacokinetic measures but does not report their numerical results. Immunogenicity is named as an objective, but its results are not reported in the registry record. The adverse-event counts therefore cannot answer questions about pharmacokinetic equivalence, immunogenicity, or clinical benefit.

The phase 1 dose-escalation setting is relevant: the design focuses on early assessment of safety and pharmacokinetics across dose cohorts. The cohort descriptions state that progression to a next dose level followed review of short-term safety. The full escalation rules and the sample-size justification are not reported. The findings are therefore best understood as descriptive evidence from this study’s recorded groups, not as a definitive estimate of comparative safety or effectiveness.

In general, a study can be informative even when it cannot establish causality. It can document observed events, identify areas for further evaluation, and describe how outcomes were collected in a particular study population. What it can support depends on the design, available follow-up, completeness of reporting, and statistical analyses. For this registry record, the posted adverse-event counts are the clearest numerical results, while important inferential details are not reported.

13. Why This Trial Matters Statistically

This trial is statistically notable because it combines dose escalation with a fixed-sequence crossover structure. Dose escalation organizes participants into low-, medium-, and high-dose cohorts, while the cohort descriptions state that movement to the next dose level followed review of short-term safety. A design of this kind raises questions about how dose cohorts are compared, what safety criteria guide escalation, and whether the analysis accounts for the different stages of recruitment. The registry does not report the full escalation criteria or statistical methods.

The crossover label also matters. In general, crossover designs can use within-participant information, but interpretation depends on treatment order, period effects, and possible carryover. Because allocation is nonrandomized and the sequence details are not reported, a reader should not assume the safeguards or analysis procedures of a randomized crossover trial. The registry’s designation of nonrandomized allocation is explicit and should guide interpretation of the ADVATE and BAX 826 group records.

Safety counts are useful but are not self-interpreting. The number at risk differs across the listed groups, and the record does not report a formal comparison, interval estimates, or adjustment for repeated events. This illustrates a broader biostatistical principle: a numerical outcome needs its design context and an appropriate analysis before it can support a causal or comparative claim.

The study also emphasizes the difference between planned cohort sizes and the group counts recorded for adverse events. The cohort descriptions state planned evaluable numbers, while the adverse-event records have their own group-specific denominators. Keeping those concepts separate helps prevent confusion between a planned target and the population contributing to an outcome.

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 trial-specific limitation is the nonrandomized, open-label design. The ADVATE records therefore do not function as a like-for-like randomized control group, and observed differences cannot be attributed to treatment from these counts alone. The fixed treatment sequence adds potential period and sequence considerations, but details needed to assess them are not reported in the registry record.

The primary safety outcome is limited to events after BAX 826 infusion in Period 2 and to follow-up up to 6 weeks ± 4 days. It does not describe longer-term safety. The posted records give counts by dose cohort, but the registry does not provide confidence intervals, a formal comparative analysis, or details sufficient to establish how repeat events within a participant were counted.

The record lists planned evaluable cohort sizes, but these are not identical to the group-specific at-risk numbers in the adverse-event listing. The relation between evaluability, outcome availability, and analysis populations is not fully described. Missing-data procedures and the handling of participants with incomplete follow-up are not reported in the registry record.

Although pharmacokinetic and immunogenicity outcomes are among the study aims, their numerical results are not reported in the registry record. The statistical analysis plan, multiplicity approach, and sample-size justification are also not reported. These gaps restrict interpretation to the design information and posted adverse-event counts; they prevent a fuller assessment of precision and comparative effects.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: BAX 826 Dose-Escalation Safety Study — NCT02716194.
• Registry record last updated 2021-05-25; status last verified 2021-05.
• Results first posted 2018-09-20.
• 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.

18. Record Summary

The registry describes a completed phase 1, prospective, open-label, nonrandomized, two-period fixed-sequence dose-escalation study of BAX 826 in previously treated patients with severe hemophilia A. It lists enrollment of 40, three dose cohorts, and ADVATE (octocog alfa) as the other intervention. The primary safety outcome is the number of serious and non-serious adverse events after BAX 826 infusion in Period 2, with follow-up up to 6 weeks ± 4 days.

The adverse-event listing records no serious events and no deaths in the listed groups. It records non-serious events across the dose cohorts, with the group-specific at-risk and affected counts reported in the registry. These findings are descriptive; allocation was nonrandomized, and no formal comparative estimates are reported. Numerical pharmacokinetic and immunogenicity results, analysis methods, missing-data procedures, and the multiplicity strategy are not reported in the registry record.