Non-interventional Post-authorisation Study to Document the Immunogenicity, Safety, and Efficacy of NUWIQ: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Non-interventional Post-authorisation Study to Document the Immunogenicity, Safety, and Efficacy of NUWIQ (NCT02962765), a registered phase not stated study. The primary outcome is Number of Patients With FVIII Inhibitors.

2. Clinical Question

The study was designed to collect additional clinical data and assess whether long-term experience in routine practice was consistent with outcomes from earlier pre-authorisation studies. The registry summary identifies immunogenicity, particularly inhibitor development, alongside general safety and efficacy as areas of interest. The primary endpoint is a participant count, not a comparison of assigned treatments.

The clinical question is descriptive: among the patients followed in this setting, how many had inhibitor development identified under the study’s stated clinical and laboratory approach? Because testing could be carried out at the physician’s discretion, the outcome depends on clinical observation and whether suspicion led to testing. The registry record does not report the number of patients with FVIII inhibitors, so the primary question cannot be answered from the posted outcome information.

3. Trial Design

This was a prospective, multinational, non-interventional post-authorisation study of NUWIQ in patients with Hemophilia A treated in routine clinical practice. Octapharma is listed as the sponsor. The registry reports a start date of 2015-01, primary completion on 2020-08-20, a COMPLETED status, and enrollment of 80 participants.

In a non-interventional study, treatment is not allocated by the study protocol in the way it would be in a randomized trial. Clinical care proceeds in routine practice, and the study collects information about outcomes in that setting. Accordingly, the record does not describe a randomized treatment contrast. It also does not state an allocation method, and no like-for-like control group is described. The registry record does not report a protocol-defined treatment assignment or a comparator arm.

The stated primary measure is the number of patients with FVIII inhibitors. The timeframe runs from screening through study completion, with a minimum of 1.7 months and a maximum of 31.6 months. The description says that testing could occur at any time at the physician’s discretion; clinical symptoms suggesting inhibitor development were to prompt investigation by laboratory testing. This means the outcome ascertainment approach combines clinical observation and laboratory confirmation.

The registry summary describes the study as collecting additional clinical data and assessing long-term immunogenicity, safety, and efficacy in routine practice. Its listed secondary outcomes concern annualized breakthrough-bleed rates during prophylactic treatment, efficacy assessments for treatment of bleeding episodes, and physicians’ overall assessment of surgical prophylaxis. The record reports six outcome measures, while the listed secondary outcome descriptions do not account for all of them; further details are not reported in the registry record.

The registry does not report the planned sample-size justification, a detailed statistical analysis plan, or interim analyses. Nor does it describe how treatment patterns or differences among clinical settings were to be handled analytically. Those omissions limit conclusions about the intended inferential framework beyond the stated outcomes and study design.

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: FVIII inhibitor testing could be carried out at any time at the physician's discretion. Patients were checked for clinical symptoms suggesting FVIII inhibitor development, any suspicion of inhibitor formation was to be investigated by FVIII inhibitor testing. No symptoms led to suspicion of inhibitor formation in any patient treated with Nuwiq®. Within the FAS population, inhibitor levels were tested in 40 patients at screening, 44 between screening and completion and 21 at study completion.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Number of Patients With FVIII Inhibitors, measured over Screening through to study completion (minimum 1.7 months; maximum 31.6 months).

The primary endpoint is the number of patients with FVIII inhibitors, expressed as a count of participants. It measures how many patients were identified with this immunogenicity outcome during the period from screening through study completion. The registry specifies a minimum timeframe of 1.7 months and a maximum of 31.6 months.

The endpoint is used because the study’s stated focus includes inhibitor development. Inhibitors are addressed through clinical observation and laboratory testing: symptoms suggesting inhibitor development were to be investigated, and suspected cases were to be confirmed by FVIII inhibitor testing. The registry says that testing could be carried out at the physician’s discretion, rather than reporting a fixed testing schedule for all participants.

As a participant count, the measure describes the number identified, but by itself does not express the timing of onset or account for differences in follow-up duration. A proportion would require a clearly specified denominator and calculation; neither a primary outcome count nor a primary effect estimate is reported in the registry record. Therefore, the endpoint definition is available, but the posted information does not establish how many patients experienced the endpoint.

In general, a clearly defined endpoint helps readers understand what an outcome represents and how it is ascertained. Here, the clinical trigger and laboratory confirmation are described, while the registry does not report a primary endpoint result or an estimate of its precision.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What kind of outcome is the primary measure?

The primary outcome is a participant count: the number of patients with FVIII inhibitors. In general, this is a binary outcome at the participant level. Each person is classified according to whether the event was identified or not, and the total count depends on both the number meeting the endpoint and the number assessed. A count is not itself a rate or a treatment effect. To interpret a count across studies or populations, readers also need a clearly stated denominator and an understanding of follow-up and outcome ascertainment.

The registry record describes a clinical and laboratory process for identifying the event. Symptoms suggesting inhibitor development were to lead to investigation, and laboratory FVIII inhibitor testing was used to confirm the diagnosis. Testing could occur at the physician’s discretion. In general, when testing is prompted by clinical suspicion, outcome identification can depend on both the underlying event and the opportunity to detect it. The record does not report test frequency or a uniform testing schedule.

What would an estimate of precision mean?

In general, a confidence interval describes a range of values compatible with the observed data under the statistical model used. It helps distinguish a precise estimate from one with substantial uncertainty. For a binary outcome, the interval would be interpreted alongside the number assessed and the event count. The registry record does not report the primary event count, a confidence interval, or another measure of precision, so none can be interpreted for inhibitor development in this study.

A p value, in general, evaluates how compatible data are with a specified null hypothesis under a chosen analysis. It does not measure the size or clinical importance of an effect. No p value or primary endpoint analysis is reported in the registry record. There is also no described randomized comparison for which a between-group hypothesis test could be interpreted.

How does the study design affect statistical interpretation?

This is a prospective, non-interventional study in routine clinical practice. In general, prospective data collection can specify what outcomes are to be followed, but it does not by itself remove confounding or create treatment groups that are comparable. Without a described comparator and allocation method, the study is not a randomized comparison. Its design is suited to documenting observations in the studied setting, but causal conclusions require more than a count of outcomes in a single observed group.

The stated outcome timeframe varies from a minimum of 1.7 months to a maximum of 31.6 months. In general, unequal follow-up can affect how counts are interpreted: participants observed for different lengths of time may have different opportunities for an event to be detected. Time-to-event or person-time methods can address some follow-up differences when appropriately specified, but the registry record does not report such an analysis for the primary endpoint.

What do the planning assumptions describe?

The record’s planning assumptions describe illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They state that the effect to detect is a specified fraction of the observed effect. These are planning assumptions, not evidence that the study assigned participants to two arms. The study is described as non-interventional and no comparator is reported. Any sample-size illustrations are planning quantities, not observed power and not a substitute for the missing primary result.

The assumptions also distinguish total event counts for time-to-event illustrations from participants per arm for other illustrations. In general, these quantities answer different planning questions: an event total concerns the number of observed events needed under a time-to-event model, while a per-arm participant count concerns enrollment under a specified group comparison. The registry record does not report the study’s own sample-size justification or enough outcome results to interpret a numerical planning illustration as an observed trial finding.

What statistical information is unavailable?

The registry reports six outcome measures and zero analyses. It does not report the analysis methods used for the primary endpoint, the handling of missing data, or a multiplicity procedure. It also does not report a primary endpoint estimate, its uncertainty, or the analysis population used for that endpoint. These omissions mean readers cannot determine whether the intended analysis was purely descriptive or included additional inferential methods, beyond what is stated in the outcome definition.

In general, statistical methods should match the design, endpoint, and observation process. A binary count, a rate of bleeding episodes, and a time-to-event outcome may require different summaries and models. The listed secondary outcomes include an annualized rate and efficacy assessments, but the registry record does not report how they were analyzed. It would therefore be inappropriate to infer a particular model, adjustment strategy, or testing procedure from the outcome names alone.

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("FVIII Inhibitors Detected at Screening in Patients", "FVIII Inhibitors Detected Between Screening and Co", "FVIII Inhibitors Detected at Completion in Patient")
n      <- c(40, 44, 21)
events <- c(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  FVIII Inhibitors Detected at Screening in Patients  40  0  0.0  0.0  8.8  0.0  8.8  0.1  8.6
ARM  FVIII Inhibitors Detected Between Screening and Co  44  0  0.0  0.0  8.0  -0.0  8.0  0.1  7.9
ARM  FVIII Inhibitors Detected at Completion in Patient  21  0  0.0  0.0  16.1  -0.0  15.5  0.1  15.4

11. Multiplicity, Missing Data and Analysis Populations

The registry reports six outcome measures, including the primary count of patients with FVIII inhibitors and listed secondary assessments of breakthrough bleeds, bleeding-episode treatment, and surgical prophylaxis. It reports zero analyses. A multiplicity strategy for interpreting several outcomes is not reported in the registry record. In general, when many outcomes are tested, the chance of at least one apparently unusual result can increase; a prespecified testing hierarchy or adjustment can help manage that issue. No such approach can be attributed to this study from the posted information.

The registry record does not report how missing outcome data were handled, whether any imputation was used, or how participants with incomplete follow-up were included in the primary analysis. It reports enrollment of 80 and a safety population of 78, but does not explain the difference or identify the primary endpoint analysis population. The primary population description says that testing could occur at the physician’s discretion; it does not provide a complete account of missing tests or outcome status.

The safety population is identified for the serious adverse event figures, but other analysis populations are not described in the registry record reported for the study. The statistical analysis plan, including population definitions and any missing-data sensitivity analyses, is not reported in the registry record. These gaps limit assessment of how complete the outcome data were and how robust any intended analyses might have been.

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 0% reporting threshold.

For the Nuwiq® (Human-cl rhFVIII) safety population, the registry reports 78 participants at risk for serious adverse events and 0 participants affected. It separately reports 1 death. These figures should be read as registry safety counts, not as a comparison with another treatment group: no comparator is described.

The zero serious adverse events figure means that no participants are recorded as affected in that specific registry category. It does not establish that no adverse events of any kind occurred, because the posted information concerns serious adverse events. The record lists no top serious adverse event terms. It also does not state the cause of the death or its relationship to treatment, so neither should be inferred from the count alone.

The safety population count differs from the enrollment count of 80, but the registry record does not explain why. The serious adverse event counts do not provide a measure of treatment effect, and the single death should not be assumed to be either treatment-related or unrelated. In general, safety counts are most informative when interpreted with the population definition, duration of observation, event definitions, and attribution information. Some of those details are not reported in the registry record.

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

The registry record documents a prospective, multinational, non-interventional study of NUWIQ in routine clinical practice, with a stated focus on long-term immunogenicity, safety, and efficacy. It identifies the primary outcome as the number of patients with FVIII inhibitors and describes a clinical and laboratory approach to identifying cases. It also gives enrollment and selected serious adverse event figures.

What the record does not establish is the frequency of FVIII inhibitor development: the primary endpoint count is not reported. Nor does it establish a comparative treatment effect, because no comparator group or randomized allocation is described. The listed safety counts do not answer the immunogenicity question, and the death count alone does not establish cause or treatment relationship.

In general, evidence from routine-practice observation can describe what was recorded in a particular setting, but interpreting it requires attention to who was followed, how outcomes were ascertained, how long participants were observed, and whether data were complete. For this study, follow-up duration is reported as ranging from a minimum of 1.7 months to a maximum of 31.6 months, and testing could occur at the physician’s discretion. The registry record does not report enough detail to assess consistency of testing or missing primary outcome data.

The posted information should therefore be understood as a partial account of a completed study, rather than a complete statistical results report. Enrollment, design, outcome definitions, and safety counts are available; the primary result, statistical uncertainty, and analysis methods are not reported in the registry record. Conclusions about efficacy or the rate of inhibitor development would go beyond these data.

14. Why This Trial Matters Statistically

This study is statistically relevant because it addresses outcomes collected in routine clinical practice rather than a randomized treatment comparison. Such studies can contribute descriptive evidence about care outside a controlled allocation setting. At the same time, the design makes it especially important to distinguish observation from causal comparison. The registry record describes no comparator and no allocation method, so its stated purpose should not be mistaken for a randomized efficacy test.

The primary outcome also illustrates how endpoint definition and ascertainment shape interpretation. The measure is a count of patients with FVIII inhibitors, but identification involves clinical observations and laboratory testing, with testing at the physician’s discretion. In general, a count can reflect both the occurrence of an outcome and the process used to detect it. Reporting testing practices and complete outcome results would help readers assess what the count represents.

The registry lists enrollment of 80 and a safety population of 78, while reporting no primary outcome result and zero analyses. This contrast highlights why sample size and a completed study status do not, on their own, demonstrate that a statistical question has been answered. A result and a measure of its precision are needed to assess what the data can support.

The record also names several clinical outcomes beyond immunogenicity, including bleeding and surgical prophylaxis assessments. Their presence signals a broad descriptive scope, but without reported analyses or results they cannot support conclusions about the outcomes themselves. Statistically, this case underscores the importance of transparent outcome reporting, clear analysis populations, and a distinction between planned questions and posted results.

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.

A central limitation is that the primary endpoint result is not reported in the registry record. The number of patients with FVIII inhibitors, any estimate of uncertainty, and any analysis details are unavailable. As a result, the study’s primary immunogenicity question cannot be evaluated from the posted information.

The non-interventional design and absence of a comparator limit comparative interpretation. The registry does not state an allocation method, and it does not describe a like-for-like control group. Observations in routine practice cannot be treated as a randomized estimate of treatment effect. The record also does not report how potential confounding or differences among clinical settings were addressed.

Outcome ascertainment may depend on clinical recognition and physician-directed testing. The record describes symptoms prompting investigation and laboratory confirmation, but does not report how many participants were tested, testing frequency, or whether testing was consistent across participants. Follow-up ranges from a minimum of 1.7 months to a maximum of 31.6 months; the registry does not report an analysis accounting for differing observation time for the primary count.

The relationship between enrollment of 80 and the safety population of 78 is not explained. The record does not report the primary analysis population, missing-data handling, or a sample-size justification. It lists six outcome measures and zero analyses, without reporting a multiplicity approach or results for the listed secondary outcomes. These limitations restrict both the interpretation of the available safety figures and the assessment of the study’s planned statistical questions.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Non-interventional Post-authorisation Study to Document the Immunogenicity, Safety, and Efficacy of NUWIQ — NCT02962765.
• Registry record last updated 2021-10-21; status last verified 2021-09.
• Results first posted 2021-09-28.
• 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

This completed, prospective, multinational, non-interventional post-authorisation study assessed NUWIQ in routine clinical practice among patients with Hemophilia A. The registry lists Octapharma as sponsor, enrollment of 80, a start date of 2015-01, and primary completion on 2020-08-20.

The primary outcome was the number of patients with FVIII inhibitors, assessed from screening through study completion over a reported range of 1.7 to 31.6 months. The registry describes clinical observation and laboratory confirmation, with testing at the physician’s discretion. The primary outcome result and statistical analyses are not reported in the registry record.

The safety population included 78 participants at risk for serious adverse events; 0 were affected, and 1 death was reported separately. The record does not report the death’s cause or treatment relationship. No comparator is described, and the study is not a randomized comparison.