Efficacy and Safety Study of BERIPLEX® P/N (Kcentra) Compared With Plasma in Patients With Acute Major Bleeding Caused by Anticoagulant Therapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety Study of BERIPLEX® P/N (Kcentra) Compared With Plasma in Patients With Acute Major Bleeding Caused by Anticoagulant Therapy (NCT00708435), a randomized phase 3 study. The primary outcome is Percentage of Participants Achieving Hemostatic Efficacy of Stopping an Ongoing Major Bleed.

2. Clinical Question

3. Trial Design

This was a Phase IIIb study with randomized allocation, no masking, and a parallel-group model. Its official title describes an open-label, randomized, multicenter study comparing BERIPLEX® P/N with plasma for rapid reversal of coagulopathy induced by coumarin derivatives in participants with acute major bleeding. The sponsor was CSL Behring. The registry lists enrollment of 216 and status as completed.

The registry records a study start of 2008-06 and primary completion of 2010-11. It identifies blood coagulation disorders and acute major bleeding as conditions. The interventions are BERIPLEX® P/N (Kcentra) and fresh frozen plasma. The arm descriptions contain no additional details about administration or treatment procedures, so those details are not reported in the registry record.

For the primary outcome, the registry reports 98 participants in the BERIPLEX® P/N group and 104 in the fresh frozen plasma group. These analysis-group counts should not be treated as interchangeable with the overall enrollment or safety denominators: the serious-adverse-event summaries use 103 and 109 participants, respectively. The primary population is described as the Intention-to-Treat Efficacy population, including randomized participants who received any study product, had acute major bleeding, and had an INR > 1.3 before infusion. The record says participants in this population were analyzed as randomized.

The study was open-label, but the primary hemostatic efficacy assessment was determined by a blinded independent board using prespecified definitions. The registry record does not report the randomization procedure, allocation concealment, the original sample-size justification, or a detailed protocol for treatment administration. It also does not report whether any interim analyses were planned or conducted.

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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Intention-to-Treat Efficacy (ITT-E) population included all randomized participants who had received any study product, presented with acute major bleeding, and had an international normalized ratio (INR) \> 1.3 prior to the infusion. Participants in the ITT-E population were analyzed 'as randomized'.

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 Intention-to-treat population comprised all subjects who were (1) eligible for the study and had (2) signed informed consent and were randomized to 1 of the 2 treatment groups regardless of whether the subjects received study product. In the ITT population, subjects were analyzed "as randomized".

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants Achieving Hemostatic Efficacy of Stopping an Ongoing Major Bleed, measured over At 1 and 4 hours after the end of infusion.

The primary endpoint is the percentage of participants who achieved hemostatic efficacy of stopping an ongoing major bleed. The outcome was assessed at 1 and 4 hours after the end of infusion. The registry describes visible or non-visible musculoskeletal bleeding assessments and a blinded independent board rating of excellent, good, or poor/none. Excellent or good counted as effective hemostasis; poor/none counted as non-effective hemostasis. Thus, the endpoint reduces a graded assessment to a binary participant-level outcome.

As a measure, the percentage makes the outcome easy to interpret as the proportion meeting the stated effectiveness definition in each group. The timing focuses on early hemostatic assessment after infusion, in keeping with the registry’s stated purpose of evaluating rapid reversal and control of acute bleeding. A binary endpoint also means that differences in the degree of improvement within the effective and non-effective categories are not represented in the percentage itself.

General statistical context: a binary endpoint can be summarized with a group percentage and a difference between group percentages. The difference describes the absolute separation between the observed proportions, while a confidence interval expresses uncertainty about that estimated separation. Neither summary removes the need to consider how the endpoint was defined, who entered the analysis population, and whether outcome assessments were complete. The registry record describes the endpoint definition and assessment timing, but does not report all details of missing-outcome handling.

7. Results Posted in the Registry

• Fresh Frozen Plasma: 65.4% (68/104) versus 72.4% (71/98) on control; risk difference -7.1 percentage points (95% CI -19.8 to 5.7), risk ratio 0.90 (0.75–1.09); unadjusted two-proportion z-test p = 0.279.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Percentage of Participants Who Had Hemostatic Efficacy for Visible or Non-visible Musculoskeletal Bleeding

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Fresh Frozen Plasma: 67.3% (70/104) versus 73.5% (72/98) on control; risk difference -6.2 percentage points (95% CI -18.7 to 6.4), risk ratio 0.92 (0.77–1.10); unadjusted two-proportion z-test p = 0.338.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Fresh Frozen Plasma and the control. The interval gives the range of effects that remain compatible with the data.

Transfusion of Red Blood Cells

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Fresh Frozen Plasma: mean 1.20 versus 1.40 on control; difference -0.20 (95% CI -0.66 to 0.26), standardized effect d = -0.12; z-test p = 0.397.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Fresh Frozen Plasma and the control. The interval gives the range of effects that remain compatible with the data.

Use of Other Blood Products and Hemostatic Agents

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Fresh Frozen Plasma: mean 0.30 versus 0.30 on control; difference 0.00 (95% CI -0.32 to 0.32), standardized effect d = 0.00; z-test p = 1.000.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Fresh Frozen Plasma and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists secondary outcome domains spanning hemostatic efficacy, coagulation-factor measures, INR correction, transfusions and other blood products, and 45-day all-cause mortality. The numerical secondary summaries include an additional hemostatic measure and measures of transfusion and other blood-product use. Across the posted comparisons, the binary hemostatic percentages are numerically higher in the BERIPLEX® P/N group; the mean for red blood cell transfusion is numerically higher in that group, while the reported means for other blood products are the same at the displayed precision. These directions are descriptive and do not establish a consistent overall advantage.

The secondary findings are related to the primary result because they give context on hemostatic response and resource use, but they are distinct endpoints with different definitions and scales. The secondary hemostasis assessment uses a different timing window from the primary outcome. Transfusion measures describe use over a specified period rather than the primary binary assessment of stopping an ongoing bleed. These outcomes should therefore not be treated as interchangeable replications of the primary endpoint.

The unadjusted recalculations for the posted secondary comparisons are p = 0.338 for the additional hemostatic outcome, p = 0.397 for red blood cell transfusion, and p = 1.0 for other blood products. General statistical context: when multiple outcomes are tested, the chance of at least one apparently notable result can increase if each test is considered separately without adjustment. Unadjusted secondary results therefore carry less weight than a clearly prespecified primary analysis, particularly when the registry does not report a multiplicity strategy.

The record does not report enough information to establish how all secondary outcomes were prioritized or whether the analyses were adjusted for multiple testing. The secondary summaries can describe patterns in this trial, but they do not independently settle the primary question or provide a substitute for the uncertainty in the primary comparison.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Percentage of Participants Who Had Hemostatic Efficacy for Visible or Non-visible Musculoskeletal Bleeding
• Incremental in Vivo Recovery (IVR) (Response) of Factors II, VII, IX, and X, Protein C, and Protein S for Beriplex
• Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S
• Percentage of Participants With INR Correction at Various Times After the Start of Infusion
• Percentage of Participants With INR Correction at Various Times After Randomization
• Transfusion of Red Blood Cells
• Use of Other Blood Products and Hemostatic Agents
• 45-Day All-cause Mortality

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary: each participant was classified as having effective or non-effective hemostasis using the registry’s stated rating categories. The reported group percentages are the proportions classified as effective at the specified assessments. The registry gives a 95% confidence interval for each group percentage and separately reports a sponsor comparison of the difference in effective hemostasis. Keeping these summaries distinct matters: an interval around each group percentage is not the same as an interval around the difference between groups.

What does a confidence interval describe?

General explanation: a confidence interval is a range of values that reflects sampling uncertainty under the statistical method used. It does not mean that the true value has a particular probability of lying inside this particular calculated interval. A wider interval indicates less precision than a narrower interval on the same scale and under comparable methods. The primary sponsor-reported interval runs from -5.8 to 19.9 percentage points for the difference, so the posted estimate is compatible with values below and above zero.

What is the risk difference?

General explanation: for a binary outcome, a risk difference is the percentage with the event in one group minus the percentage with the event in the other group. It is an absolute comparison, expressed in percentage points when the group results are percentages. Its sign depends on the order in which groups are subtracted. The sponsor reports the primary difference as 7.1 percentage points; the registry’s presentation does not give the calculation’s group-order wording alongside that result. The recalculated comparison identifies fresh frozen plasma as the comparison arm against BERIPLEX® P/N, but no extra recalculated difference is needed to interpret the sponsor-reported estimate.

Why distinguish the sponsor analysis from a recalculation?

The sponsor-reported analysis is identified as a 95% confidence interval for the difference in effective hemostasis and is categorized in the registry as a non-inferiority or equivalence type. Its reported difference is 7.1, with limits of -5.8 and 19.9, and no p-value is posted for that analysis. The simple unadjusted recalculation uses the posted group summaries and gives p = 0.279. A recalculated test based on summary statistics may not reproduce every feature of the sponsor’s analysis, which could use methods or assumptions not fully described in the registry record. The record does not report the non-inferiority margin or enough detail to reconstruct the complete sponsor method.

What does an unadjusted p-value mean?

General explanation: a p-value describes how unusual data at least as incompatible with a specified null hypothesis would be under that hypothesis and the test assumptions. It is not the probability that the null hypothesis is true, nor a measure of the size or clinical importance of a difference. An unadjusted p-value does not account for testing multiple outcomes or comparisons. The recalculated primary p-value is an unadjusted summary and should be read alongside the estimated difference and its interval, not on its own.

Why does the endpoint definition matter?

The endpoint groups excellent and good ratings together as effective, and poor/none as non-effective. This makes the outcome interpretable as a proportion meeting the stated threshold, but it does not show the distribution of ratings within those categories. A binary classification may also conceal variation in timing or degree of hemostatic response. The registry states that assessments occurred at 1 and 4 hours after the end of infusion and that the independent board used prespecified definitions. Details of the definitions themselves are not reported in the registry record.

How should the open-label design be considered?

The registry calls the study open-label and reports masking as none. It also says that the primary hemostatic efficacy determination was made by a blinded independent board. General explanation: blinding an outcome assessor can help reduce the influence of treatment knowledge on subjective classification, whereas open-label treatment assignment means participants and treatment personnel may know which intervention was given. The information in the registry establishes the assessor’s stated blinding but does not describe safeguards against other sources of bias or the board’s review process.

What is not recoverable from the posted method details?

The registry does not report the statistical analysis plan in enough detail to establish the model, covariate adjustment, missing-data procedure, or handling of repeated assessments for the primary comparison. It also does not report the original sample-size assumptions or a planned interim-analysis approach. Those omissions limit attempts to reconstruct the design rationale or determine whether the posted analysis follows a particular prespecified procedure. The statistical summaries can still be described as posted, but undocumented methods should not be inferred.

11. Confidence Intervals and Precision

The primary group percentages are accompanied by 95% confidence intervals: 72.4% with limits of 63.6% to 81.3% for BERIPLEX® P/N, and 65.4% with limits of 56.2% to 74.5% for fresh frozen plasma. These intervals show uncertainty around each group estimate. They should not be read as the interval for the difference between treatments.

For the sponsor-reported difference, the 95% confidence interval is -5.8 to 19.9 percentage points around a reported difference of 7.1. The interval includes zero, so the posted estimate does not precisely distinguish a positive difference from no difference or a difference in the opposite direction. Its upper and lower limits also leave room for materially different contrasts. The registry does not state the margin used for the non-inferiority or equivalence analysis, so the interval cannot be judged against that margin from this record alone.

General explanation: precision concerns the range of values compatible with the data under the method used, rather than whether a result is important. Intervals are influenced by sample size, event frequency, and the analysis method. The primary analysis includes 98 and 104 participants in the two groups, but those counts alone do not determine the interval or resolve uncertainty.

The percentages and interval are useful together: the percentages show the observed outcomes, while the interval communicates uncertainty in the estimated comparison. Neither implies certainty about future results. The record does not report a confidence level or interval for every secondary comparison, so precision should not be assumed to be the same across outcomes.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size figures are planning illustrations based on the observed effect, not the trial’s original design calculations. For the listed binary and continuous outcomes, the figures are participants per arm. The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is the stated fraction of the observed effect. The record notes that time-to-event tables give the total number of events, but the outcomes summarized in these planning figures are not time-to-event outcomes.

The 80% power column gives the illustrated number of participants per arm for a design with an 80% chance of detecting the specified effect under those assumptions, if the assumed effect and other assumptions hold. The 90% power column gives the corresponding per-arm planning figure for a design with a 90% chance under those assumptions. These are design calculations, not guarantees that a study of that size will find a result.

Rows that plan for a smaller fraction of the observed effect require more participants per arm than rows targeting the full observed effect. This reflects a general statistical principle: smaller differences are harder to distinguish from random variation, so detecting them with the same chosen power generally requires more information. The displayed values are illustrations using the observed effect as their starting point; they are not estimates of the sample size needed for a different protocol or population.

These figures are not observed power. Observed power is not a useful replacement for interpreting the estimated effect and its confidence interval. The trial’s own sample-size justification and original design assumptions are not reported in the registry record, so the planning illustrations should not be presented as the basis on which this study was designed.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.724; treatment proportion p₁ = 0.654; average p̄ = 0.689.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6545 = 1.2829.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6526 = 0.5493.
4. n = (1.2829 + 0.5493)² / (-0.0706)² = 672.6, rounded up to 673 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.724489795918367                          # control proportion
p1 <- 0.653846153846154                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(708435)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 673 (80% power), 900 (90% power)
 75% of observed effect: n per arm = 1,178 (80% power), 1,576 (90% power)
 50% of observed effect: n per arm = 2,607 (80% power), 3,489 (90% power)
power.prop.test: 672.6 
Simulated power at n = 673 per arm: 0.800 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Analyses Reported by the Sponsor

The sponsor-reported primary comparison gives a difference in effective hemostasis of 7.1 percentage points and a 95% confidence interval from -5.8 to 19.9. The registry classifies this as a non-inferiority or equivalence type of analysis, but does not report the non-inferiority margin or a p-value for the sponsor result. Consequently, the posted record does not allow the formal decision rule to be checked.

The simple unadjusted recalculation from posted summary statistics gives p = 0.279. It is a separate calculation and should not be substituted for the sponsor’s reported interval analysis. The registry marks the results as having no discrepancy, but that does not make the recalculation and sponsor analysis identical in purpose or method. One is a p-value from an unadjusted comparison reconstructed from summary statistics; the other is the sponsor-reported interval analysis.

The sponsor analysis takes precedence when a discrepancy is flagged. No discrepancy is flagged in this record. Even so, the sponsor’s analysis is the relevant reported analysis for interpreting the stated non-inferiority or equivalence framework, while the recalculation is a transparent unadjusted comparison. Without the analysis plan and margin, neither should be used to infer more about the formal decision than the registry reports.

15. Multiplicity, Missing Data and Analysis Populations

The registry lists 11 outcome measures and identifies a primary hemostatic efficacy endpoint, alongside secondary outcomes covering hemostasis, coagulation factors, INR correction, transfusion, other blood products, and mortality. It does not report whether a formal multiplicity adjustment was used, whether outcomes were tested in a hierarchy, or whether there were prespecified rules for interpreting secondary comparisons. The unadjusted recalculated p-values should therefore be understood as separate comparisons rather than as a multiplicity-controlled family of tests.

The primary analysis population is described: randomized participants who received any study product, had acute major bleeding, and had an INR > 1.3 before infusion. Participants in that population were analyzed as randomized. The record does not report the number of participants excluded from this population, reasons for exclusion, or how missing primary outcome assessments were handled. It also does not report whether the analysis used imputation, a missing-equals-failure rule, or another approach; none should be assumed.

For secondary outcomes, the registry record does not report a complete account of analysis populations or missing-data procedures. Some outcomes have different units and time windows, and the posted numerical summaries do not establish how every listed secondary outcome was analyzed. The record also does not report whether repeated observations, such as assessments at multiple times, were modeled jointly or separately.

The original sample-size justification, full statistical analysis plan, and any interim-analysis plan are not reported in the registry record. These omissions matter because analysis choices can affect uncertainty estimates and the interpretation of multiple results. They do not erase the posted estimates, but they limit independent assessment of whether all decisions were prespecified and how incomplete data or multiple testing may have influenced interpretation.

16. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cardiac failure congestive (3.7%), ischaemic stroke (2.9%), atrial flutter (1.9%), haemorrhage intracranial (1.9%), pneumonia (1.9%).

The serious-adverse-event summaries use denominators of 103 participants for BERIPLEX® P/N and 109 for fresh frozen plasma. Serious adverse events affected 32 participants in the BERIPLEX® P/N group and 26 in the fresh frozen plasma group. The registry also reports other adverse events affecting 46 and 40 participants, respectively. These counts are descriptive; the denominators differ from those in the primary efficacy analysis.

The listed serious-event terms and percentages are congestive cardiac failure, 3.7%; ischaemic stroke, 2.9%; atrial flutter, 1.9%; intracranial haemorrhage, 1.9%; pneumonia, 1.9%; and respiratory failure, 1.9%. The record does not identify the group attribution for these leading terms in the available summary, so they should not be assigned to either arm. The registry does not report death counts in the safety summary.

General statistical context: adverse-event counts describe events observed during the recorded study period, but they do not by themselves establish that an intervention caused an event. Differences in counts should be interpreted with attention to denominators, event definitions, follow-up, and the completeness of reporting. Detailed definitions and event-level information are not reported in the registry record.

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

The posted primary percentages describe effective hemostasis in 72.4% of participants in the BERIPLEX® P/N group and 65.4% in the fresh frozen plasma group. The sponsor-reported difference is 7.1 percentage points, with a 95% confidence interval from -5.8 to 19.9. These estimates summarize the trial’s observed results and their statistical uncertainty in the stated analysis population.

The confidence interval includes zero and spans values that could be interpreted as favoring either group. This means the result does not precisely establish the direction or size of the underlying difference. The record’s non-inferiority or equivalence classification cannot be fully evaluated because the margin and decision rule are not reported. The unadjusted recalculation is supplementary and does not replace the sponsor’s reported analysis.

The endpoint is a binary classification of an independent board’s rating at early post-infusion assessments. It does not capture every aspect of bleeding, the degree of response within each rating category, or longer-term outcomes. The registry lists other outcomes, including additional hemostatic assessment, coagulation-factor and INR measures, transfusions, and mortality, but these do not all answer the same question as the primary endpoint.

The study was open-label, although the primary outcome was determined by a blinded independent board. The primary analysis also included a defined subset of randomized participants rather than all enrolled participants. These features and the unreported details of missing-data handling, multiplicity, and original design assumptions constrain interpretation.

The results do not establish what will happen for every patient or in every setting, and statistical summaries alone cannot determine the clinical importance of a difference. They describe the evidence recorded for this trial, not a treatment recommendation. Safety counts are also descriptive and cannot, without fuller event definitions and context, establish causal effects.

18. Why This Trial Matters Statistically

This trial illustrates why an observed difference and its uncertainty should be considered together. The group percentages are numerically distinct, but the sponsor-reported interval for their difference includes zero and spans both directions. Reporting only the percentages would omit the uncertainty in the comparison; focusing only on a p-value would omit the size and range of plausible contrasts.

The registry also illustrates the value of distinguishing a sponsor’s analysis from an unadjusted recalculation. The sponsor reports an interval analysis categorized as non-inferiority or equivalence, while the recalculation gives an unadjusted p-value from summary statistics. These answer related but not identical statistical questions. The absent non-inferiority margin and analysis details are important limits on interpretation, not details that can safely be inferred.

Design and measurement are relevant to the statistical reading. Treatment allocation was randomized, the study was open-label, and the primary efficacy assessment was made by a blinded independent board. The primary endpoint converts graded ratings into a binary outcome, which supports a clear percentage comparison but necessarily simplifies the underlying assessment.

Finally, the registry’s secondary outcomes show how a trial can produce evidence on multiple dimensions, while also creating questions about multiplicity and emphasis. Unadjusted secondary comparisons are best read as descriptive context when the record does not establish a testing hierarchy or adjustment plan. The study is therefore a useful example of reading estimates, intervals, endpoint definitions, analysis populations, and reporting gaps together rather than treating a single statistic as a complete conclusion.

19. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

Several trial-specific limitations can be identified from the registry record. The study was open-label, so treatment assignment was not masked, although a blinded independent board determined primary hemostatic efficacy. The record does not describe the board’s procedures or the safeguards used to maintain blinding. The arm descriptions do not provide administration details.

The primary efficacy population was defined using receipt of study product, acute major bleeding, and INR > 1.3 before infusion. It is therefore important not to treat the reported primary counts as the entire enrolled population. The registry does not report screening numbers, reasons for exclusion, or missing primary outcome handling. Safety denominators also differ from primary efficacy denominators.

The registry labels the sponsor analysis as non-inferiority or equivalence but does not report the margin or decision rule. It does not report the original sample-size justification, full statistical analysis plan, interim-analysis details, or whether multiplicity was controlled. These gaps limit independent reconstruction of the planned analysis and formal interpretation of the sponsor’s framework.

Further, the primary endpoint combines excellent and good ratings and places poor/none in the other category. The resulting percentage does not show the distribution within those categories. The study’s early assessment times and the other listed outcome domains address different aspects of efficacy and resource use; they cannot be assumed to provide identical evidence. The registry record does not provide enough information to evaluate generalizability beyond the recorded study population and setting.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Efficacy and Safety Study of BERIPLEX® P/N (Kcentra) Compared With Plasma in Patients With Acute Major Bleeding Caused by Anticoagulant Therapy — NCT00708435.
• Registry record last updated 2014-02-03; status last verified 2013-09.
• Results first posted 2013-08-13.
• 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.

23. Record Summary

NCT00708435 is a completed, randomized, open-label, parallel-group Phase IIIb study sponsored by CSL Behring. The registry records enrollment of 216, a start date of 2008-06, and primary completion in 2010-11. It compared BERIPLEX® P/N (Kcentra) with fresh frozen plasma in participants with acute major bleeding associated with coumarin therapy.

The primary endpoint was the percentage achieving effective hemostasis, assessed at 1 and 4 hours after the end of infusion by a blinded independent board. The reported percentages were 72.4% and 65.4%, respectively. The sponsor-reported difference was 7.1 percentage points, with a 95% confidence interval from -5.8 to 19.9. The registry does not report the non-inferiority margin, original sample-size justification, or detailed missing-data and multiplicity procedures.

Secondary outcome domains included hemostasis, coagulation and INR measures, transfusion and other blood-product use, and 45-day all-cause mortality. Serious-adverse-event counts are reported with safety denominators of 103 and 109. The posted summaries are descriptive and should be interpreted alongside their definitions, analysis populations, and reporting limitations.