Pharmacokinetic, Efficacy and Safety of BT524 in Patients With Congenital Fibrinogen Deficiency: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pharmacokinetic, Efficacy and Safety of BT524 in Patients With Congenital Fibrinogen Deficiency (NCT02065882), a na phase 3 study. The primary outcome is Single-dose Pharmacokinetics (PK) of BT524: Terminal Elimination Half-life (t1/2) for Fibrinogen Antigen.

2. Clinical Question

In practical statistical terms, the study asked how the concentration of fibrinogen antigen changed over time after infusion, with the terminal half-life serving as the primary pharmacokinetic summary. The study also investigated BT524’s pharmacokinetic and pharmacodynamic properties, efficacy, and safety in the treatment or prophylaxis of bleeding. Those broader aims do not turn the design into a controlled treatment comparison: no randomized comparator is described, and the parts of the study served different purposes.

3. Trial Design

This was a prospective, open-label, multicenter, Phase I/III study. The registry record gives the study model as sequential and allocation as not applicable. Participants and investigators were not masked. The record reports enrollment of 67, a start in 2013-03, primary completion on 2020-05-18, and completed status.

The study had two parts. Part I used a single intravenous infusion of BT524 to assess pharmacokinetic and pharmacodynamic properties. Part II used a single or repetitive intravenous infusion or infusions for on-demand prophylaxis or treatment of bleeding events. The design therefore combined a single-dose assessment with an investigation involving bleeding-event management. The registry record does not report a randomized allocation or a separate untreated or active-control group.

Because the parts had different purposes and dosing approaches, their participant groups are not a like-for-like comparison. Differences between their reported observations could reflect differences in the parts’ objectives, treatment exposure, or participants, among other factors. The registry record does not provide a design that would isolate a causal contrast between BT524 and another intervention.

The enrollment figure describes the study record, not necessarily the number included in every outcome analysis. For the primary endpoint, the stated analysis population was the PK Set: all patients in Part I with pharmacokinetic data. The size of that set and the number contributing to the primary endpoint are not reported in the registry record. A sample-size justification, interim-analysis plan, and detailed statistical analysis plan are also 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.

Part I: PK/PD

Reasons for not completing this period:

Part II: Clinical Efficacy

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: PK Set: consists of all patients of part I with PK data.

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: Part I: Baseline characteristics were assessed in all participants who received any portion of BT524 (n=27). Part II: Baseline characteristics were assessed in all participants who received any portion of BT524 (n=36).

6. Primary Endpoint

The registry lists the primary outcome as Single-dose Pharmacokinetics (PK) of BT524: Terminal Elimination Half-life (t1/2) for Fibrinogen Antigen, measured over Pre-dose on Dosing Day 0, at the end of the infusion and 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240 and 336 hours post-dose.

The primary endpoint was the terminal elimination half-life, written as t1/2, for fibrinogen antigen after a single dose of BT524. It was measured in hours. The endpoint was defined from fibrinogen-antigen concentration-time profiles based on samples taken before dosing on Day 0, at the end of infusion, and at 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240, and 336 hours after dosing.

As a general pharmacokinetic concept, a terminal half-life describes the time associated with a decline in concentration during the terminal portion of a concentration-time profile. It condenses that part of the profile into a summary measure; it does not by itself describe every feature of the profile or establish a clinical effect. The registry record says the estimate was derived using the study’s time-concentration data and an adapted methodology, which could involve non-compartmental analysis, compartment analysis, or population modeling, as appropriate or required.

The endpoint is useful for characterizing the time course of fibrinogen antigen after a single infusion. The record specifies a mean as the summary parameter and standard deviation as the dispersion measure. However, the observed mean and standard deviation, and any confidence interval for the endpoint, are not reported in the registry record. The endpoint definition and schedule therefore describe what was intended to be measured, not the size or precision of an observed estimate.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The main statistical task for the primary endpoint was to summarize a continuous pharmacokinetic measure: terminal elimination half-life for fibrinogen antigen, in hours. The registry record specifies the mean and standard deviation. It also describes estimation from time-concentration profiles using an adapted approach that could be non-compartmental analysis, compartment analysis, or population modeling, as appropriate or required. The specific approach used for the reported primary result is not reported in the registry record.

What does a mean and standard deviation tell the reader?

General: a mean is a measure of the center of observed values. A standard deviation describes how dispersed those values are around the mean. They answer different questions: the mean describes an average, while the standard deviation describes variability among observations. A standard deviation is not the same as a standard error or a confidence interval. Confidence intervals, in general, communicate uncertainty about an estimated quantity; the registry record does not report one for the primary endpoint.

The record identifies the PK Set as all patients in Part I with pharmacokinetic data. This definition clarifies the intended analysis population, but it does not give the number included in that set or explain how many had usable endpoint data. The primary endpoint’s actual mean and standard deviation are also not reported in the registry record. Consequently, no estimate of its central value, observed spread, or precision can be assessed from the record.

Why were samples collected over time?

The endpoint depends on a concentration-time profile rather than a single measurement. Samples were scheduled before dosing on Day 0, at the end of the infusion, and at 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240, and 336 hours post-dose. General: repeated measurements help characterize the time course and the terminal part of a profile. The adequacy of the estimated terminal phase depends on the observed data and analytic choices, not just on the planned schedule. The registry record does not report the individual profiles, the data handling rules, or diagnostic assessments used to support the primary estimate.

The record allows for different analytic approaches—non-compartmental analysis, compartment analysis, or population modeling—according to what was appropriate or required. General: non-compartmental methods summarize observed exposure and related quantities without specifying a detailed compartment structure. Compartment models represent concentration changes using a defined mathematical structure. Population modeling can account for variation across participants while estimating shared and participant-level features. These approaches make different assumptions and can produce estimates whose interpretation depends on model specification and data availability. Which approach generated the primary endpoint estimate is not reported in the registry record.

What do the other pharmacokinetic and pharmacodynamic outcomes add?

The registry record lists secondary pharmacodynamic outcomes for fibrinogen activity, including terminal half-life, time to maximum concentration, maximum concentration, areas under the curve, mean residence time, and clearance. These outcomes are complementary summaries of concentration or activity over time. General: maximum concentration describes a peak, time to maximum concentration locates that peak, and area under the curve summarizes exposure across a specified interval. Clearance and mean residence time describe other aspects of disposition. The outcome list does not establish which estimates were observed, how they were analyzed, or how uncertainty was quantified.

The primary endpoint concerns fibrinogen antigen, whereas the listed secondary pharmacodynamic measures concern fibrinogen activity. Antigen concentration and activity are not interchangeable endpoints. Interpreting one does not automatically determine the other, and the record does not provide numerical results for these measures in the registry record.

Why does the design matter for statistical interpretation?

The study was open-label, sequential, and had allocation recorded as not applicable. General: randomization and a suitable concurrent comparator can help distinguish an intervention’s effect from other explanations for a difference. Since this record does not describe a like-for-like control comparison, results from its two parts should be read in light of their different purposes and treatment approaches. Part I assessed single-dose properties, while Part II involved dosing for on-demand prophylaxis or treatment of bleeding events. A difference between parts would not, on its own, estimate a randomized treatment contrast.

The record reports 28 outcome measures and one analysis. These counts do not reveal the full inferential plan. The statistical plan, including any approach to multiplicity, missing observations, model selection, or interim analyses, is not reported in the registry record. General: when many outcomes are evaluated, multiplicity can increase the chance of finding apparently notable results by chance if testing is repeated without an appropriate plan. Whether and how that issue was addressed cannot be established from the outcome count alone.

The record also includes sample-size planning assumptions: a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with planning based on a stated fraction of an observed effect. Those assumptions are described as planning illustrations, not as the trial’s own design. The record identifies the study as not being a randomized comparison, so the illustration should not be read as evidence that the study was designed around a two-arm controlled test. A trial-specific sample-size justification is not reported in the registry record.

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("BT524 (Human Fibrinogen Concentrate)")
n   <- c(27)
m   <- c(67.9)
sp  <- c(15.3)
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  BT524 (Human Fibrinogen Concentrate)  27  67.900  15.300  61.848  73.952

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 28 outcome measures and one analysis. It does not report a statistical analysis plan detailing a primary testing hierarchy, a multiplicity adjustment, or how secondary outcomes were to be interpreted alongside the primary endpoint. The number of listed outcomes alone does not show that every measure was tested or that a particular adjustment was or was not used. Any multiplicity procedure is not reported in the registry record.

General: multiplicity matters when several hypotheses or outcomes are examined because the chance of at least one apparently unusual result can increase across repeated tests. Prespecifying a primary outcome and an analysis strategy can help distinguish confirmatory questions from exploratory ones. Here, the primary endpoint is identified, but the detailed testing strategy and any control of multiplicity are not reported in the registry record.

The primary analysis population is defined as the PK Set, consisting of all Part I patients with pharmacokinetic data. The number in that set, the number contributing to the primary endpoint, and the handling of incomplete or unusable profiles are not reported in the registry record. The registry record also does not report an imputation method, missing-data assumptions, sensitivity analyses, or reasons for missing endpoint data. This means the effect of missing observations on the estimate cannot be assessed from the recorded details.

Other analysis populations for the additional outcomes are not described in the registry record. The record does not report an interim-analysis plan, stopping boundaries, or other interim statistical procedures. These omissions do not establish that such methods were absent; they mean their use and rationale are not reported in the registry record.

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: pain in extremity (3.7%), hypertensive encephalopathy (3.7%), post streptococcal glomerulonephritis (3.7%), iron deficiency anaemia (2.8%), pancreatitis (2.8%).

The registry record lists serious and other adverse-event figures separately for PK/PD Part I and Part II. For PK/PD Part I, it reports 27 at risk for the serious-event listing and 2 affected; for other events, it reports 27 at risk and 10 affected. For Part II, the corresponding serious-event figures are 36 at risk and 7 affected, while the other-event figures are 36 at risk and 25 affected. The record reports 0 deaths in PK/PD Part I and 1 in Part II.

These are descriptive counts from different study parts, not a randomized comparison. The parts had different roles and exposure approaches, so their figures should not be interpreted as a controlled estimate of comparative safety. The record does not provide enough detail to infer causality or to assess how event ascertainment and follow-up affected the counts.

Reported serious-event terms include pain in extremity, hypertensive encephalopathy, and post streptococcal glomerulonephritis, each listed as 3.7%; iron deficiency anaemia, pancreatitis, and portal vein thrombosis are each listed as 2.8%. The denominator for these percentages is not reported in the registry record. These event listings describe what was recorded; they do not establish that BT524 caused an event or indicate its comparative frequency against a control group.

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

The study record describes an investigation of BT524’s pharmacokinetic and pharmacodynamic properties, efficacy, and safety in patients with congenital fibrinogen deficiency. Its primary endpoint was the terminal elimination half-life of fibrinogen antigen after a single dose in Part I. The endpoint definition, unit, sampling schedule, and stated summary statistics are reported, but the primary endpoint’s observed mean and standard deviation are not reported in the registry record. Its magnitude and precision therefore cannot be evaluated from the recorded information.

The study’s design is also important to what can be concluded. It was open-label, sequential, and had no like-for-like control comparison. Part I assessed single-dose properties; Part II involved single or repetitive infusions for on-demand prophylaxis or treatment of bleeding events. Comparisons between the parts would not constitute randomized evidence of a treatment effect. The registry record does not report a controlled efficacy estimate or its uncertainty.

The record’s adverse-event figures can be read as descriptive safety information for the listed groups. They do not establish whether an event was caused by BT524, and they cannot provide a controlled comparison of event risk. Some serious-event terms are listed with percentages, but the denominator for those percentages is not reported in the registry record. The listed figures should therefore be interpreted within the limits of their reported definitions and design.

In general, pharmacokinetic endpoints characterize how measured substances change over time, while clinical outcomes address events or effects that matter to patients. These types of outcomes answer different questions. A pharmacokinetic estimate alone does not establish clinical benefit, and a study purpose that includes efficacy and safety does not substitute for numerical outcome results. The registry record does not report the primary endpoint estimate or the detailed inferential results needed to judge its precision.

Thus, the record supports an account of the study structure, the planned primary measurement, and certain adverse-event counts. It does not support a conclusion about the size or precision of the primary pharmacokinetic result, or a causal comparison with another treatment. Such conclusions require the corresponding results and analysis details, which are not reported in the registry record.

14. Why This Trial Matters Statistically

This trial is statistically notable for combining a single-dose pharmacokinetic assessment with a separate part addressing on-demand prophylaxis or treatment of bleeding events. That structure gives the study more than one kind of question, but it also makes it important to distinguish the parts rather than treat them as interchangeable groups. Part I’s primary endpoint concerns a concentration-time property; Part II’s stated purpose concerns management of bleeding events.

The primary endpoint illustrates how a continuous pharmacokinetic outcome is constructed from repeated measurements. Terminal half-life is derived from a profile over time, and its estimate may depend on the method used to characterize the terminal phase. The registry record allows several analytic approaches but does not report which was used for the primary result. Without the estimate, variability, and uncertainty information, readers cannot assess the numerical finding or its precision.

The record also highlights the difference between describing an outcome and reporting its result. It specifies the endpoint, measurement schedule, summary parameter, and analysis-population definition, but does not report the primary endpoint’s observed mean or standard deviation. The endpoint is therefore identifiable as the planned primary measure, while its observed statistical result remains unavailable in the registry record.

Finally, the safety figures are presented by study part rather than as a controlled comparison. This supports a descriptive reading but not an inference that differences between the groups reflect a treatment effect. The combination of a non-comparative design, multiple outcomes, and unreported analysis details makes cautious interpretation essential. The statistical value of the record lies in clarifying what was measured and where the interpretive limits arise.

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 primary limitation for interpreting the main pharmacokinetic question is that the registry record does not report the terminal half-life estimate, its standard deviation, or an uncertainty interval. Although the endpoint definition and sampling schedule are described, the numerical result cannot be assessed for magnitude, variability, or precision.

The study was open-label and did not use a like-for-like control comparison. Part I and Part II had different aims and dosing approaches, so contrasts between them cannot be treated as randomized comparisons. This design limits causal interpretation of efficacy or safety differences and does not provide a controlled estimate against another intervention.

The record describes the primary analysis population as the Part I PK Set but does not report the size of that set or the number with usable primary endpoint data. The missing-data approach, reasons for missing measurements, sensitivity analyses, and analysis populations for other outcomes are not reported in the registry record. The impact of incomplete data is therefore unknown.

The primary endpoint could be estimated using non-compartmental analysis, compartment analysis, or population modeling, as appropriate or required. The specific method used, model diagnostics, and assumptions supporting the estimate are not reported in the registry record. A detailed statistical analysis plan, including multiplicity procedures and interim analyses, is also not reported.

For safety, the record gives counts by study part and lists several serious-event terms with percentages, but the denominator for those term percentages is not reported. The design and available summaries do not establish causality or comparative risk. These limitations apply to interpretation of the registry record; they do not determine what additional analyses or information may exist outside it.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Pharmacokinetic, Efficacy and Safety of BT524 in Patients With Congenital Fibrinogen Deficiency — NCT02065882.
• Registry record last updated 2025-07-03; status last verified 2025-06.
• Results first posted 2025-07-03.
• 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

NCT02065882 is a completed, prospective, open-label, multicenter Phase I/III study of BT524 in patients with congenital afibrinogenemia or severe congenital hypofibrinogenemia. The study used a sequential model and had no like-for-like control comparison. Part I assessed single-dose pharmacokinetic and pharmacodynamic properties; Part II involved single or repetitive intravenous infusions for on-demand prophylaxis or treatment of bleeding events.

The primary endpoint was terminal elimination half-life of fibrinogen antigen, measured in hours and summarized as a mean with standard deviation. The primary analysis population was the Part I PK Set. The endpoint estimate and its precision are not reported in the registry record. The record lists adverse-event counts by part, but these are descriptive and do not establish comparative risk or causality. Detailed missing-data, multiplicity, and statistical-analysis procedures are not reported in the registry record.