A Safety, Tolerability, and Pharmacokinetics Study of a Single Intravenous Injection of Recombinant Coagulation Factor VIII Fc - Von Willebrand Factor - XTEN Fusion Protein (rFVIIIFc-VWF-XTEN) (BIVV001) in Previously Treated Adults With Severe Hemophilia A (EXTEN-A): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Safety, Tolerability, and Pharmacokinetics Study of a Single Intravenous Injection of Recombinant Coagulation Factor VIII Fc - Von Willebrand Factor - XTEN Fusion Protein (rFVIIIFc-VWF-XTEN) (BIVV001) in Previously Treated Adults With Severe Hemophilia A (EXTEN-A) (NCT03205163), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During Advate Treatment Period.

2. Clinical Question

The clinical question is primarily about short-term safety and tolerability following single intravenous administrations, not about comparative clinical benefit. The study included two dose levels, with Advate followed by BIVV001 within the dose cohorts. The registry identifies pharmacokinetic outcomes such as maximum observed plasma concentration, half-life, total body clearance, and volume of distribution at steady state. These characterize how the drugs behave in the body; they are distinct from clinical outcomes such as bleeding control.

The recorded primary endpoint concerns participants with treatment-emergent adverse events and treatment-emergent serious adverse events during the Advate treatment period. Its stated observation window extends up to Day 3 for the Advate 25 IU/kg dose and up to Day 4 for the Advate 65 IU/kg dose. The posted adverse-event figures also list results for BIVV001 dose groups. The registry record does not establish a randomized comparison between those treatment periods, so differences in their counts should not be interpreted as causal treatment effects.

3. Trial Design

This was a phase 1/2a, open-label, non-randomized, sequential dose-escalation study. It enrolled 16 previously treated adults with severe hemophilia A and is recorded as completed. The listed start date is 2017-08-28, and primary completion is recorded as 2018-11-12. Bioverativ, a Sanofi company, is named as the sponsor.

Participants received Advate first and BIVV001 afterward in their dose cohort. The low-dose sequence used Advate 25 IU/kg followed by BIVV001 25 IU/kg. The high-dose sequence used Advate 65 IU/kg followed by BIVV001 65 IU/kg. Advate was administered as a single intravenous dose on Day 1. Its treatment period included a washout before BIVV001; for the high-dose cohort, the registry specifies a washout of at least 96 hours from the time of Advate dosing. The BIVV001 treatment period is described as 28 days. The registry description of the low-dose Advate period is truncated, so its full washout detail is not reported in the registry record.

Because treatment order was sequential rather than randomized, Advate was not a concurrent randomized control for BIVV001. The registry explicitly notes that the arms are not a like-for-like control comparison. Open-label conduct also means masking was absent. These features matter when interpreting adverse-event counts and pharmacokinetic comparisons: period, sequence, dose, and participant differences may affect observed results, and the record does not support attributing any difference solely to the drug given.

The primary safety endpoint was measured during the Advate treatment period, with different stated timeframes for the two dose levels. Secondary outcomes addressed pharmacokinetic measures for Advate and BIVV001 at both dose levels. The registry record does not report a detailed rationale for the sample size, a formal statistical analysis plan, or criteria for moving between dose levels.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: A total of 16 participants were enrolled, 7 participants to low dose cohort (LDC) and 9 to high dose cohort (HDC).

ATP (LDC: 3 Days; HDC: 4 Days)

Reasons for not completing this period:

BTP (LDC: 28 Days; HDC: 28 Days)

Analysis population for the primary outcome, as defined in the registry: Analysis was performed on safety analysis set which included all participants who received at least 1 dose of Advate.

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: Baseline population included all enrolled participants.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During Advate Treatment Period, measured over Up to Day 3 for Advate 25 IU/kg; up to Day 4 for Advate 65 IU/kg.

The primary endpoint counts participants with treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs) during the Advate treatment period. The registry defines an adverse event as an untoward medical occurrence after a participant received study drug; it need not have a causal relationship with treatment. A TEAE is an adverse event beginning on or after the single Advate dose and before the single BIVV001 dose.

The registry defines a serious adverse event as an event resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or another medically important event. The primary endpoint timeframe is up to Day 3 for Advate 25 IU/kg and up to Day 4 for Advate 65 IU/kg.

Counting participants is a direct way to describe how many people experienced an event in the observation period. It does not describe the number of separate episodes if a participant had multiple events, their duration, or their severity beyond the serious-event classification. General: safety endpoints are commonly used in early-phase studies to characterize observed harms and tolerability during defined exposure periods. They do not, by themselves, establish that a drug caused an event or quantify comparative risk when treatment assignment is not randomized.

The stated analysis population includes participants who received at least one dose of Advate. The registry record does not report further endpoint handling rules, such as how repeated events were treated or how missing safety observations were handled.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study’s statistical interpretation begins with its design. It was open-label, non-randomized, and sequential: participants received Advate before BIVV001 in their dose cohort. This structure is different from a randomized parallel-group comparison, where chance assignment is used to balance measured and unmeasured participant characteristics across treatments. Here, treatment and period are linked by design. Any contrast between Advate and BIVV001 counts therefore needs to be understood as descriptive rather than as an isolated causal treatment effect.

What does a participant count communicate?

The primary endpoint is a count of participants experiencing TEAEs and TESAEs during a defined period. A participant count expresses how many people in the safety analysis set met the event definition. It is not necessarily the same as an event count: one person can experience more than one event, while a participant-level endpoint generally counts that person once for the relevant category. The registry record does not report additional rules for handling repeated events.

The event window is bounded by the treatment sequence. TEAEs are defined as events that begin on or after the Advate dose and before the BIVV001 dose. This definition makes timing central to classification. The stated timeframe is up to Day 3 for the low-dose Advate cohort and up to Day 4 for the high-dose Advate cohort. Comparisons across windows of different lengths require care because participants have different stated observation periods.

Why distinguish serious from other adverse events?

The registry’s serious-event definition identifies events with specified consequences or medical importance, including death, immediate risk of death, hospitalization, persistent or significant disability, congenital anomaly or birth defect, or another medically important event. Seriousness is a regulatory classification, not a judgment that the study drug caused the event. The record explicitly defines an adverse event as not necessarily having a causal relationship with treatment. Counts of serious and other events should therefore be interpreted as events observed in the treatment periods, not automatically as drug-attributable harms.

General: presenting event counts alongside the number at risk helps readers understand the scale of the observed data. In a small study, each participant’s experience has a substantial influence on the group’s count. Statistical uncertainty can be considerable even when the observed count is low or zero. A zero count means no event was recorded in that group during the defined observation period; it does not prove that the underlying event risk is zero.

What can a confidence interval add?

General: a confidence interval describes the range of values compatible with the observed data under a specified statistical procedure. It communicates precision as well as the point estimate. Wider intervals indicate less precision, while narrower intervals indicate more precision. The registry record does not report confidence intervals for the adverse-event counts in the registry record listed. Without interval estimates or a specified inferential method, the posted counts alone do not show how uncertain an underlying event rate may be.

How should the pharmacokinetic outcomes be read?

The secondary outcomes name maximum observed plasma concentration, half-life, total body clearance, and volume of distribution at steady state for both products at the low and high dose comparisons. These are pharmacokinetic measures: they describe concentration and disposition over time rather than directly measuring clinical benefit. General: the interpretation of such outcomes depends on the sampling schedule, assay methods, analysis population, and model used. Those details and the numerical pharmacokinetic results are not reported in the registry record, so no conclusions about their magnitude or precision can be drawn from the outcome names alone.

What do the planning illustrations represent?

The sample-size assumptions are described as planning illustrations computed from an observed effect, rather than as the trial’s own design. They use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the target effect is a stated fraction of the observed effect. The record specifies that non-time-to-event illustrations are expressed as participants per arm, while time-to-event illustrations use a total number of events. These assumptions describe hypothetical planning calculations, not the design of this non-randomized sequential study. Any sample-size figure from that exercise is a planning illustration, not observed power and not evidence about the trial’s ability to detect an effect.

The registry record does not report the protocol’s statistical analysis plan, formal sample-size justification, interim-analysis procedures, inferential tests for the adverse-event outcomes, or model specifications for the pharmacokinetic analyses. These omissions limit the ability to reconstruct how the posted analyses were planned or to assess whether all intended analyses are represented. General: a complete statistical interpretation depends on knowing the outcome definitions, analysis populations, missing-data rules, and prespecified methods, especially when many outcomes are assessed.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 21 outcome measures and 16 analyses. It identifies multiple pharmacokinetic outcomes for Advate and BIVV001 at both dose levels, in addition to the safety endpoint. When many outcomes or comparisons are examined, the chance of at least one apparently notable result can increase if each is assessed separately. General: multiplicity procedures, such as controlling a family-wise error rate or using a hierarchical testing strategy, can address that issue, but the choice depends on the trial’s aims and prespecified analysis plan.

Any multiplicity strategy, including whether one was planned or used, is not reported in the registry record. The registry record also does not report a complete statistical analysis plan, a hierarchy among the outcomes, or which analyses were considered confirmatory versus exploratory. The number of listed outcomes and analyses alone does not reveal how multiplicity was handled.

The safety analysis population is described as participants who received at least one dose of Advate. The record does not report the number of participants with missing outcome data, the reasons for missingness, or rules for including participants with incomplete observations. A missing-data method or sensitivity analysis is not reported in the registry record. For the adverse-event summaries, the at-risk counts are stated by dose group, but the record does not explain differences in those counts across periods.

General: analysis populations define which participants contribute to a particular result. An intention-to-treat population is typically based on randomized assignment, whereas a safety population often includes participants who received study treatment. This study was not randomized, and the registry’s stated safety population is based on receiving Advate. Other analysis-population definitions are not reported in the registry record. These uncertainties mean that the posted counts should be read as descriptive of the recorded safety groups, without assuming unreported missing-data or multiplicity procedures.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: small intestinal obstruction (16.7%), contusion (14.3%), road traffic accident (14.3%), haemarthrosis (14.3%), tendonitis (14.3%).

The adverse-event figures give, for each dose group, the number of participants at risk and the number affected by serious or other adverse events. For Advate 25 IU/kg, the serious-event figures are 7 at risk and 1 affected; the other-event figures are 7 at risk and 1 affected. For Advate 65 IU/kg, the corresponding figures are 9 and 0 for serious events, and 9 and 1 for other events. No deaths are listed for either group.

For BIVV001 25 IU/kg, the figures are 6 at risk and 1 affected for serious events, and 6 at risk and 3 affected for other events. For BIVV001 65 IU/kg, they are 9 and 0 for serious events, and 9 and 6 for other events. No deaths are listed for either group. The record’s top serious adverse-event terms include small intestinal obstruction at 16.7%, and contusion, road traffic accident, haemarthrosis, and tendonitis at 14.3% each; their denominators are not reported in the registry record.

These counts describe events recorded in small groups and should not be treated as a randomized comparison. Seriousness does not itself establish causation, and a zero count does not establish absence of risk. The registry record does not provide confidence intervals or explain the differences in at-risk counts across some dose periods.

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

The posted results describe safety events observed after single doses of Advate and BIVV001 in a phase 1/2a study of previously treated adults with severe hemophilia A. They give participant counts by dose group for serious and other adverse events, as well as listed serious-event terms. The primary endpoint focuses on treatment-emergent adverse events and treatment-emergent serious adverse events during the Advate treatment period, with a specified observation window for each Advate dose level.

These data do not establish that an event was caused by either study drug. The registry’s adverse-event definition explicitly does not require a causal relationship, and the serious-event classification concerns the nature or consequence of an event. Likewise, the counts do not establish that a drug prevented events. No deaths are listed in the adverse-event groups, but zero recorded deaths in these groups is not evidence that the risk of death is zero.

The sequence was non-randomized and open-label, with Advate preceding BIVV001. Therefore, observed differences between dose groups or treatment periods cannot be interpreted as clean causal contrasts. The registry cautions that the arms are not a like-for-like control comparison. The study’s small enrollment and the group-level counts also limit precision; confidence intervals for these adverse-event results are not reported in the registry record.

The listed secondary outcomes concern pharmacokinetics, including maximum observed plasma concentration, half-life, total body clearance, and volume of distribution at steady state. Their numerical results are not reported in the registry record. The available information therefore does not establish the size or precision of any pharmacokinetic differences, nor does it directly establish comparative clinical benefit.

General: a study can provide useful descriptive safety and pharmacokinetic information without being designed to answer whether one treatment is clinically superior to another. The appropriate interpretation depends on the study’s design and what its reported outcomes measure. For this record, the strongest supported reading is a description of event counts in the stated groups and observation periods, not a definitive comparative conclusion.

13. Why This Trial Matters Statistically

Early-phase studies ask questions that are different from those in large randomized efficacy trials. This phase 1/2a study examined safety, tolerability, and pharmacokinetics after single intravenous doses in previously treated adults with severe hemophilia A. It also assessed Advate and BIVV001 at two dose levels in a sequential arrangement. The design makes the treatment sequence and observation windows central to interpreting any contrast.

Statistically, the record illustrates why the type of comparison matters as much as the reported count. Advate preceded BIVV001, allocation was non-randomized, and masking was absent. Those features limit causal interpretation of differences between the treatment periods. Reporting the number at risk alongside the number affected helps characterize the observed safety experience, while the lack of reported confidence intervals means that uncertainty around those counts is not quantified in the registry record.

The study also highlights the distinction between safety endpoints and pharmacokinetic endpoints. A count of participants with adverse events describes observed safety events under defined criteria. Measures such as maximum observed plasma concentration, half-life, total body clearance, and volume of distribution at steady state describe drug disposition. Neither type of measure alone answers every clinical question, and the numerical pharmacokinetic results are not reported in the registry record.

Finally, the registry lists multiple outcomes and analyses, but does not report the analysis plan, sample-size justification, missing-data approach, or multiplicity strategy. Those details are important for judging how planned analyses relate to reported results. The record is therefore most informative as a description of study structure and recorded adverse-event counts, with clear limits on comparative inference.

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 non-randomized, sequential design is a central limitation for comparative interpretation. Advate was administered before BIVV001, rather than assigned concurrently by randomization. Treatment, period, and sequence therefore cannot be separated using the posted counts alone. The registry also identifies the arms as not being a like-for-like control comparison. Open-label conduct adds the possibility that knowledge of treatment could influence event reporting or assessment; how that possibility was addressed is not reported in the registry record.

The study enrolled 16 participants, and the adverse-event groups include small at-risk counts. In small groups, a small number of participants can materially shape the descriptive pattern. Confidence intervals and inferential comparisons for the safety figures are not reported in the registry record, so their statistical precision cannot be assessed from the posted counts. A zero count in a group should not be interpreted as proof that the event cannot occur.

The stated primary endpoint applies to the Advate period, while adverse-event figures are also listed for BIVV001. The relationship between those additional summaries and the primary endpoint is not fully specified in the registry record. The at-risk counts differ across some dose-period groups, and an explanation is not reported. The registry’s serious-event terms include percentages, but the denominator and ranking basis for those terms are not stated.

Other limitations are gaps in the reported methods. A formal statistical analysis plan, sample-size justification, interim-analysis details, missing-data methods, multiplicity procedures, and detailed pharmacokinetic analysis methods are not reported in the registry record. The numerical pharmacokinetic results are also not reported in the listed details. These limits mean the record supports a descriptive account of recorded safety counts, but not a full reconstruction of the planned analysis or a precise comparative assessment.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Safety, Tolerability, and Pharmacokinetics Study of a Single Intravenous Injection of Recombinant Coagulation Factor VIII Fc - Von Willebrand Factor - XTEN Fusion Protein (rFVIIIFc-VWF-XTEN) (BIVV001) in Previously Treated Adults With Severe Hemophilia A (EXTEN-A) — NCT03205163.
• Registry record last updated 2022-04-19; status last verified 2022-03.
• Results first posted 2019-12-02.
• 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

NCT03205163 is a completed phase 1/2a, open-label, non-randomized, sequential dose-escalation study sponsored by Bioverativ, a Sanofi company. It enrolled 16 previously treated adults with severe hemophilia A. Participants received a single intravenous Advate dose followed by a single intravenous BIVV001 dose within a low-dose or high-dose cohort.

The primary endpoint counted participants with treatment-emergent adverse events and treatment-emergent serious adverse events during the Advate treatment period. The posted adverse-event figures list at-risk and affected participant counts for serious and other events across Advate and BIVV001 dose groups, with no deaths listed. Secondary outcomes addressed pharmacokinetic measures for both products. Numerical pharmacokinetic findings and several analysis details are not reported in the registry record.

The sequential non-randomized design does not support a like-for-like randomized comparison. The adverse-event counts are best read as descriptive observations within the reported groups and timeframes.