Safety and Efficacy of Turoctocog Alfa (N8) in Prevention and On-demand Treatment of Bleeding Episodes in Subjects With Haemophilia A: An Extension to Trials NN7008-3543, NN7008-3545, NN7008-3600, NN7008-3893 and NN7008-4015: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Turoctocog Alfa (N8) in Prevention and On-demand Treatment of Bleeding Episodes in Subjects With Haemophilia A: An Extension to Trials NN7008-3543, NN7008-3545, NN7008-3600, NN7008-3893 and NN7008-4015 (NCT00984126), a non-randomized phase 3 study. The primary outcome is Frequency of Development of FVIII Inhibitors (Greater Than or Equal to 0.6 Bethesda Units (BU)/mL).

2. Clinical Question

3. Trial Design

NCT00984126 is a completed Phase 3 trial of turoctocog alfa in haemophilia A. It was registered as a non-randomized, unmasked, parallel-model study, with enrollment of 214. The trial began on 2009-10-26 and had a primary completion date of 2016-06-28. These dates and the completed status describe the trial record; they do not establish how long each participant was followed.

The study was described as an extension to trials NN7008-3543, NN7008-3545, NN7008-3600, NN7008-3893 and NN7008-4015. Its stated aim was to investigate safety and efficacy of turoctocog alfa in haemophilia A, including prevention and on-demand treatment of bleeding episodes. The brief summary identifies trial activity across Asia, Europe, Japan, Oceania, North America and South America. Country-level enrollment and participant distribution are not reported in the registry record.

Non-randomized allocation means treatment was not assigned through random allocation as described in the record. The absence of masking means the trial was not blinded according to its masking entry. General statistical context: random allocation can help make treatment groups comparable at baseline, while masking can reduce some differences in assessment or reporting. Neither design feature can be assumed. Because the record identifies both intervention entries as turoctocog alfa and supplies no distinct control description, group differences would not support a clean treatment-versus-control interpretation.

The record does not state the treatment regimen, criteria for entering the extension, reasons for choosing a regimen, or participant retention. It also does not give a protocol-based sample-size rationale or a description of interim analyses. These omissions limit what can be concluded about design choices beyond the recorded trial structure and stated objectives.

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: Subjects completing 1 of the trials NN7008-3543 (NCT00840086),NN7008-3545 (NCT01138501),NN7008-3600 (NCT01238367),NN7008-3893 (NCT01365520) and NN7008-4015 (NCT01692925) could continue treatment with turoctocog alfa in the extension trial (NN7008-3568). Both new subjects and those from main trial (NN7008-3568) could enter the on-demand sub-trial.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full analysis set

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: Full analysis set includes all dosed patients with data after dosing.

6. Primary Endpoint

The registry lists the primary outcome as Frequency of Development of FVIII Inhibitors (Greater Than or Equal to 0.6 Bethesda Units (BU)/mL), measured over After 90 months.

The primary endpoint was the frequency of development of FVIII inhibitors at or above 0.6 Bethesda Units per mL. It was measured in subjects and specified for assessment after 90 months. The registry record defines frequency as the number of participants with inhibitors during the trial divided by the number of participants in the trial. The endpoint population is the full analysis set.

FVIII inhibitors are antibodies that interfere with factor VIII activity. In a treatment study involving factor VIII, recording inhibitor development is relevant to the safety and treatment-response profile because it documents an immune response directed against the factor. This is general clinical-statistical context; the registry record does not explain the rationale for choosing this threshold or provide further laboratory procedures.

The endpoint is binary at the participant level: each participant either met the stated inhibitor criterion or did not, according to the trial’s assessment. A frequency can communicate how common the recorded event was in the defined population, but interpretation depends on a clear numerator, denominator, assessment window and handling of missing observations. The registry definition supplies the basic numerator and denominator concept, but the actual primary endpoint count and frequency are not reported in the registry record. A confidence interval, statistical comparison, and further details on testing or repeated measurements are also not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies a participant-level binary primary outcome and gives a simple frequency definition. It does not report a detailed statistical analysis plan, inferential model, or uncertainty interval for the primary endpoint. The explanations below describe general statistical concepts and distinguish those concepts from methods documented for this trial.

What does a binary endpoint represent?

General explanation: a binary endpoint classifies each participant according to whether an event meeting the specified definition occurred. For this trial, the event was development of FVIII inhibitors at or above 0.6 Bethesda Units per mL. The registry definition calls for counting participants meeting the criterion and relating that count to the number of participants in the trial. The actual count and frequency are not reported in the registry record.

A frequency is descriptive. It tells readers how much of the defined group experienced the event, provided the numerator, denominator and observation period are known. It does not by itself show why the event occurred, nor does it establish a treatment effect. The record specifies a full analysis set for the primary endpoint, but the eligibility rules and number of participants in that set are not reported. The distinction between the registered enrollment and the analyzed denominator therefore cannot be resolved from the record.

Why does uncertainty matter?

General explanation: an estimate from a finite group is subject to sampling uncertainty. A confidence interval expresses a range of values compatible with the data under a specified statistical procedure and assumptions. It helps readers assess precision as well as the point estimate. No primary endpoint confidence interval or point estimate is reported in the registry record. Without the underlying event count and denominator, neither can be reconstructed.

General explanation: a hypothesis test can assess compatibility between observed data and a stated null hypothesis, but its meaning depends on the question, analysis population, model and assumptions. A p-value does not measure the size or clinical importance of an effect. The registry record does not report a primary endpoint p-value, a hypothesis, or a specified testing procedure. It would be inappropriate to infer one from the endpoint description alone.

What can be inferred from the study structure?

The trial is recorded as non-randomized, unmasked and parallel-model. These terms describe design characteristics, not an analysis method. General explanation: random assignment can balance known and unknown prognostic factors on average, while a non-randomized design may leave groups different before treatment. Masking can limit influences on care or outcome assessment; no masking is recorded. The record lists turoctocog alfa for both intervention entries and does not provide a distinct comparator description, so a contrast between arms cannot be interpreted as a randomized treatment comparison.

The primary endpoint is a count-based binary outcome at the participant level, but the record does not identify a regression model, adjustment variables, stratification, or repeated-measures method. Nor does it report whether estimates were adjusted for age, prior treatment, or other characteristics. These methods are not assumed. The number of analyses is listed as one, but this alone does not describe what was tested or how the analysis was conducted.

How should planning illustrations be read?

The sample-size assumptions describe planning illustrations based on the observed effect, rather than the trial’s own design. They specify a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. For time-to-event outcomes, the illustration is based on total events using the Schoenfeld method; other illustrations refer to participants per arm.

General explanation: a planning calculation estimates the sample size or event count that would be needed under specified assumptions for a future design. It is not an observed outcome, and it is not observed power. Here, the trial is non-randomized and the record warns that arms are not a like-for-like control comparison. A planning illustration based on an observed effect should therefore not be read as evidence that the trial was designed to detect a specified causal effect. The record does not report a protocol sample-size justification, and no specific planning results are stated in the registry record.

Why do event definitions and follow-up matter?

General explanation: event counts are interpretable only alongside consistent definitions, surveillance, and follow-up. Participants followed for different lengths of time may have different opportunities for an event to be observed. Time-to-event methods can account for timing and censoring when the required information and assumptions are available; no such primary endpoint method is reported. The phrase “after 90 months” gives the stated timeframe, but participant-level follow-up and censoring details are not reported in the registry record.

General explanation: over-dispersion is relevant when count data vary more than a chosen statistical model expects, and can make standard errors too small if ignored. The primary endpoint in this record is described as a participant count for a binary event, not as a repeated count of episodes. The registry record does not report an over-dispersion assessment or a model for recurrent bleeding events. It lists annualised bleeding rate as a secondary outcome for the prevention period, but its analysis method and result are not reported in the registry record.

10. Exact Estimates for Each Arm

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

R code and output

arm    <- c("Small Children (0 - <6 Years)", "Older Children (6 - <12 Years)", "Adolescents (12 - <18 Years)", "Adults (≥18 Years)")
n      <- c(27, 28, 23, 135)
events <- c(0, 0, 0, 0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Small Children (0 - <6 Years)  27  0  0.0  0.0  12.8  0.0  12.5  0.1  12.3
ARM  Older Children (6 - <12 Years)  28  0  0.0  0.0  12.3  0.0  12.1  0.1  11.9
ARM  Adolescents (12 - <18 Years)  23  0  0.0  0.0  14.8  0.0  14.3  0.1  14.2
ARM  Adults (≥18 Years)  135  0  0.0  0.0  2.7  0.0  2.8  0.0  2.7

11. Multiplicity, Missing Data and Analysis Populations

The record lists four outcome measures overall: the primary inhibitor endpoint and secondary outcomes concerning adverse events, annualised bleeding rate during the prevention period, and haemostatic response to treatment of bleeds. The secondary outcomes cover distinct questions and may involve different populations or observation periods. The record does not report whether a multiplicity adjustment was planned or used, how outcomes were prioritized beyond the designation of a primary endpoint, or whether any analyses were exploratory. Without a stated multiplicity strategy, a reader cannot determine how the chance of false-positive findings across several tests was handled.

Missing-data rules are not reported in the registry record. The full analysis set is named for the primary endpoint, but its membership, inclusion criteria, exclusions and handling of participants without endpoint assessment are not described. The record does not state whether missing observations were imputed, treated as non-events, excluded, or addressed through sensitivity analyses. These choices can affect a binary frequency because the analyzed denominator and event classification may change.

The relationship between the stated 90-month timeframe and each participant’s available follow-up is also not explained. Censoring rules and the handling of withdrawal or loss to follow-up are not reported in the registry record. No interim analyses, stopping rules, or monitoring procedures are reported. These absences do not show that a procedure was or was not used; they mean that the posted record does not describe it. Consequently, readers cannot evaluate robustness to missingness, assess endpoint-specific analysis populations, or determine whether all planned outcome analyses are represented.

12. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: forearm fracture (7.1%), gastrointestinal haemorrhage (4.3%), haematuria (4.3%), haemorrhage intracranial (4.3%), optic neuritis (4.3%).

The serious adverse-event information is grouped by age. The registry lists 27 small children at risk, with 5 affected; 28 older children at risk, with 9 affected; 23 adolescents at risk, with 6 affected; and 135 adults at risk, with 21 affected. These are counts, not evidence of a causal relationship with turoctocog alfa. The registry record does not report event-level exposure time, the number of recurrent events, or a comparative analysis.

The listed serious-event terms are forearm fracture at 7.1%, gastrointestinal haemorrhage at 4.3%, haematuria at 4.3%, intracranial haemorrhage at 4.3%, optic neuritis at 4.3%, and road traffic accident at 4.3%. The denominators behind these percentages, whether terms overlap within participants, and the period over which they were collected are not reported in the registry record. They should therefore be read as the percentages attached to listed terms, not as directly comparable risks across all age groups.

The record also gives counts for other events, but does not define that category in the posted information. Death data are not reported in the registry record. General explanation: safety counts are most informative when paired with event definitions, exposure duration, severity, attribution procedures and a suitable comparison. Those details are not available.

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

The registry record describes an extension study intended to investigate safety and efficacy of turoctocog alfa in haemophilia A, including prevention and on-demand treatment of bleeding episodes. It establishes that development of FVIII inhibitors at or above 0.6 Bethesda Units per mL was the primary endpoint, with assessment described after 90 months. However, the primary result itself—the event count and calculated frequency—is not reported in the registry record. The information therefore does not quantify how often the primary event occurred.

The listed adverse-event counts provide descriptive information by age group. They do not establish that the treatment caused the events, and the listed percentages do not provide a clear denominator or comparable risk estimate in the posted record. No distinct control treatment is described, and the study was non-randomized. Accordingly, the record does not support a like-for-like comparison of treatment groups or a causal claim about treatment benefit or harm.

General explanation: a study can contribute information about outcomes observed during follow-up without providing a controlled estimate of what would have happened under another treatment. Extension studies can describe experience among participants who continue from earlier studies, but interpretation depends on entry criteria, follow-up and completeness of outcome reporting. The registry record does not provide enough detail to assess those features fully.

The record also does not report the primary endpoint’s uncertainty interval, test result, missing-data handling or analysis-population rules. Without these details, neither precision nor robustness can be assessed. The completed status indicates the trial is marked completed in the record; it does not replace the missing outcome result. The responsible interpretation is limited to the stated design, endpoint definition and posted descriptive safety counts, while acknowledging that the primary endpoint estimate and comparative conclusions are unavailable.

14. Why This Trial Matters Statistically

This trial is statistically notable because it combines a long extension context with a primary endpoint focused on inhibitor development. For an outcome defined by whether a participant crossed a laboratory threshold, the numerator, denominator and assessment period are essential to understanding the observed frequency. The registry record describes these features in broad terms, but does not post the primary result or its uncertainty. That makes the distinction between a well-specified question and an answerable result especially important.

The non-randomized structure also matters. Extension studies can collect additional safety and treatment-experience information, but they do not automatically provide a controlled estimate of treatment effects. The registry record explicitly identifies the arms as not being a like-for-like control comparison. That warning should govern interpretation of any apparent group difference and discourage causal conclusions from arm contrasts.

The age-stratified safety counts show why denominators and exposure context matter in safety reporting. Counts across age groups are not directly comparable without considering group sizes, follow-up duration, event definitions and ascertainment. Although at-risk counts are listed, the record does not provide person-time, event-level detail, or a comparative analysis. Percentages attached to serious-event terms also lack a stated denominator in the posted information.

Finally, the record illustrates a reporting distinction between trial completion and result completeness. A completed trial record can identify the endpoint and design while leaving the primary outcome estimate unavailable. Statistical interpretation depends not only on the planned question, but also on transparent outcome counts, analysis populations, uncertainty estimates and missing-data methods. Those absent details constrain what readers can conclude from this record.

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.

Several trial-specific limitations constrain interpretation. The primary outcome result is not reported in the registry record: no inhibitor count, frequency, confidence interval or inferential test is posted. Although the endpoint is defined as a frequency and is assigned to the full analysis set, the analysis-set size and membership rules are not described. The stated enrollment of 214 therefore cannot be assumed to be the primary endpoint denominator.

The non-randomized allocation and lack of a distinct comparator description limit causal and between-arm interpretation. The record lists turoctocog alfa in both intervention entries and does not give informative arm descriptions. It is not possible to determine from the posted information how treatment regimens differed, whether they did differ, or how participants came to receive particular regimens. Baseline characteristics and treatment exposure are not reported in the registry record.

Although the endpoint timeframe is given as after 90 months, the record does not provide participant-level follow-up, censoring, withdrawal, or missing-observation details. The eligibility and retention criteria for the extension are also not reported. These omissions make it difficult to assess whether participants had comparable opportunities for outcome detection.

For safety, adverse-event counts are grouped by age, but event definitions, ascertainment procedures, exposure duration and attribution are not reported. Denominators for the serious-event term percentages are also not specified. The record does not report death information. Multiplicity handling, sensitivity analyses, interim monitoring and the detailed statistical analysis plan are not reported in the registry record. Together, these gaps limit assessment of precision, bias, completeness and the meaning of any apparent group differences.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Efficacy of Turoctocog Alfa (N8) in Prevention and On-demand Treatment of Bleeding Episodes in Subjects With Haemophilia A: An Extension to Trials NN7008-3543, NN7008-3545, NN7008-3600, NN7008-3893 and NN7008-4015 — NCT00984126.
• Registry record last updated 2017-07-27; status last verified 2017-06.
• Results first posted 2017-07-27.
• 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

NCT00984126 is a completed Phase 3, non-randomized, unmasked extension trial of turoctocog alfa in haemophilia A, with enrollment listed as 214. It was intended to investigate safety and efficacy in prevention and on-demand treatment of bleeding episodes and extended earlier trials. The primary endpoint was development of FVIII inhibitors at or above 0.6 Bethesda Units per mL, assessed after 90 months in the full analysis set.

The registry record does not report the primary endpoint count or frequency, an uncertainty interval, or an inferential result. It lists serious adverse-event counts by age group and several serious-event terms with percentages, but does not report key denominator and exposure details. Because allocation was non-randomized and no distinct control is described, the arms are not a like-for-like comparison. Missing-data methods, multiplicity handling and detailed analysis procedures are not reported in the registry record.