Safety and Efficacy of Nonacog Beta Pegol (N9-GP) in Previously Untreated Patients With Haemophilia B: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Nonacog Beta Pegol (N9-GP) in Previously Untreated Patients With Haemophilia B (NCT02141074), a na phase 3 study. The primary outcome is Number of Participants With Incidence of Inhibitory Antibodies Against Coagulation Factor IX (FIX) (50 Exposure Days).

2. Clinical Question

3. Trial Design

This was an open-label, single-arm, multicentre phase 3a trial investigating nonacog beta pegol in previously untreated patients with haemophilia B. The phase field records phase 3, while the official title identifies it as phase 3a. The study is described as global. Enrollment is recorded as 54; that figure is not the number reported as analyzed for the primary endpoint.

The intervention was nonacog beta pegol. The trial investigated prophylaxis and treatment of bleeding episodes. Its primary outcome concerns inhibitory antibodies against factor IX after 50 exposure days. The specified assessment timeframe is when a minimum of 20 previously untreated patients have reached at least 50 exposure days, up to 156 weeks. This describes the endpoint’s timeframe, not a reported outcome or a guarantee that the threshold was reached.

There was no randomized comparator: allocation is listed as not applicable and the model as single group. Masking is listed as none. The safety information is organized into pre-prophylaxis and prophylaxis groups, but the registry explicitly cautions that these are not like-for-like control arms. Changes between those periods cannot be interpreted as a randomized treatment contrast.

The registry lists the study status as completed, with a start date of 2014-07-02 and a primary completion date of 2022-10-27. It records 16 outcome measures and no analyses. A sample-size justification, interim analysis plan, and detailed statistical plan are 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.

Before assignment: Trial consists of main phase including pre-prophylaxis \& prophylaxis, extension phase \& prophylaxis period until end of treatment. Pre-prophylaxis was optional and allowed participants to receive treatment until 24 months of age/upon reaching 20EDs, whichever came first. Other participants directly started on prophylaxis treatment at visit 1.

Pre-prophylaxis

Reasons for not completing this period:

Prophylaxis

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety analysis set included all participants exposed to nonacog beta pegol. Overall Number of Participants Analyzed = participants with available data for this outcome measure.

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: all participants exposed to study drug. Participants switched from pre-prophylaxis treatment to prophylaxis treatment. Other participants directly started on prophylaxis treatment at visit 1. Pre-prophylaxis and Prophylaxis arms are not mutually exclusive so the data in this section is provided for all participants that started the study.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Incidence of Inhibitory Antibodies Against Coagulation Factor IX (FIX) (50 Exposure Days), measured over When minimum 20 previously untreated patients (PUPs) have reached at least 50 exposure days (ED) (up to 156 weeks).

The primary endpoint is the number of participants with incidence of inhibitory antibodies against coagulation factor IX after 50 exposure days. It is a participant-count outcome, rather than a continuous measurement such as a laboratory value averaged across the group. The endpoint definition requires an inhibitory antibody titre greater than or equal to 0.6 Bethesda unit at two consecutive tests performed at the central laboratory, together with a positive test for nonacog beta pegol binding antibodies.

The endpoint focuses on an immune response relevant to the study’s investigation of safety. Requiring the threshold at consecutive tests makes the registry definition more specific than a single positive test; requiring a positive binding-antibody test adds a further condition. These are features of the stated endpoint definition, not evidence that any participant did or did not meet it.

The stated timeframe is when a minimum of 20 previously untreated patients have reached at least 50 exposure days, up to 156 weeks. The safety analysis set includes all participants exposed to nonacog beta pegol, while the overall number analyzed for this outcome is defined as participants with available data. The analyzed number and the number meeting the endpoint are not reported in the registry record. The primary outcome result is also not reported in the registry record, so the endpoint’s observed frequency and its precision cannot be described.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies this as a single-group, open-label trial and lists no analyses. The explanations below distinguish the general statistical concepts relevant to such a design from what is actually documented. The primary endpoint definition and analysis-population descriptions are available, but the endpoint result and detailed analysis methods are not reported in the registry record.

What does a single-group design estimate?

In general, a single-group study describes outcomes observed among participants who received the intervention. Because there is no concurrent randomized control group, it cannot directly estimate a treatment contrast protected by random allocation. Randomization is a design method that helps make groups comparable with respect to both measured and unmeasured characteristics on average. Without it, an apparent difference across periods or subgroups may reflect differences in who was observed, when they were observed, or other factors, rather than an intervention effect.

That distinction matters for the safety figures labeled pre-prophylaxis and prophylaxis. They are not randomized arms, and the registry specifically says they are not a like-for-like control comparison. The labels alone do not establish comparable follow-up, comparable risk, or a causal contrast. General statistical practice would require clear information about observation time, eligibility, and analysis methods before interpreting such groups comparatively; these details are not reported in the registry record.

What does the primary endpoint count?

The primary outcome is a count of participants who meet the stated inhibitory-antibody definition after 50 exposure days. It is not simply a count of positive laboratory tests: the definition requires a titre greater than or equal to 0.6 Bethesda unit at two consecutive central-laboratory tests and a positive test for nonacog beta pegol binding antibodies. This rule determines which observations qualify as endpoint events. The registry states that the outcome is assessed when a minimum of 20 previously untreated patients reach at least 50 exposure days, up to 156 weeks.

For a participant-count endpoint, the denominator is consequential. The safety analysis set includes all participants exposed to the intervention, while the endpoint-specific analyzed group is defined as participants with available data. The number with available data, the endpoint count, and any approach for handling participants without endpoint data are not reported in the registry record. The enrollment figure should not be substituted for the endpoint denominator.

How should uncertainty be understood?

In general, a point estimate summarizes the observed data, while a confidence interval describes uncertainty around that estimate under the chosen model and assumptions. With a binary participant outcome, uncertainty depends in part on the event count and the number analyzed. If events are uncommon, estimates can be imprecise, and a small change in the event count can materially affect the estimate. These are general statistical considerations, not findings about this trial.

No endpoint estimate or confidence interval is reported in the registry record, so the observed frequency and its precision cannot be evaluated. The registry also lists no analyses. No statistical model, interval method, hypothesis test, or adjustment procedure for the primary endpoint is reported in the registry record. It is therefore not possible to assess whether any estimate accounted for follow-up differences, missing data, or other analysis choices.

What do the planning calculations mean?

General sample-size calculations estimate how much information a proposed design might need under specified assumptions. They are planning tools, not results from the trial. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. The illustration describes participants per arm for 80% power and other specified planning scenarios, except that time-to-event calculations use the total number of events.

These assumptions describe an illustrative comparison and do not describe this study’s actual design, which is single-group. The registry record does not report that this was the trial’s own sample-size plan or that those assumptions informed enrollment. Calculated planning requirements should not be called observed power: observed power is not a substitute for an estimate and its uncertainty, and it cannot recover a primary result that is not reported.

Why can event counts differ from event rates?

In general, a count records how many participants or events were observed, while a rate accounts for time at risk. If participants contribute different amounts of observation time, raw counts can be difficult to compare. Over-dispersion is a general statistical issue that arises when observed variation exceeds what a simple model assumes; accounting for it can affect standard errors and uncertainty. The registry includes annualised bleeding rate among secondary outcomes, but does not report its result or the statistical method used to analyze it. The listed serious-event figures do not, by themselves, provide person-time rates.

Overall, the registry documents the design, endpoint definition, analysis-population wording, and some safety counts. It does not document the primary endpoint result or the inferential methods needed to assess an estimate. Statistical interpretation should remain within those limits.

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("Pre-prophylaxis", "Prophylaxis")
n      <- c(34, 28)
events <- c(2, 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  Pre-prophylaxis  34  2  5.9  0.7  19.7  1.6  19.1  1.8  19.2
ARM  Prophylaxis  28  0  0.0  0.0  12.3  0.0  12.1  0.1  11.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 16 outcome measures, including the primary inhibitory-antibody endpoint and secondary safety and bleeding outcomes. It lists no analyses. A multiplicity procedure for interpreting several outcomes or tests is not reported in the registry record. No hierarchy of secondary outcomes, family-wise error approach, or other adjustment strategy is reported either. Without analysis results and a prespecified testing strategy, the record does not support claims based on statistical significance across outcomes.

The primary endpoint population is described as participants with available data for that outcome. The safety analysis set is described as all participants exposed to nonacog beta pegol. These are different population definitions: an outcome-specific available-data group need not include every exposed participant. The number analyzed for the primary endpoint and the number with missing endpoint data are not reported in the registry record.

Methods for missing observations are not reported in the registry record. It is not stated whether missing endpoint values were excluded, imputed, or handled in another way, nor is a sensitivity analysis described. General statistical practice treats missingness as potentially important because results based only on observed data may not represent participants without measurements, depending on why data are missing. The record does not provide enough detail to assess that issue.

No statistical analysis plan, interim-analysis plan, or sample-size justification is reported in the registry record. The trial is marked completed, but that status does not explain how multiplicity or missing data were handled and does not replace the absent endpoint analysis.

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: pneumonia (7.8%), factor ix inhibition (5.9%), haemorrhage intracranial (5.9%), dental caries (3.9%), anaphylactic reaction (2.9%).

The registry reports serious adverse-event figures for two labeled periods. In the pre-prophylaxis group, 9 of 34 at-risk participants are recorded as affected; in the prophylaxis group, 19 of 51 at-risk participants are recorded as affected. The corresponding figures for other adverse events are 22 of 34 and 46 of 51. One death is recorded in each group. These counts should be read as registry safety summaries, not as randomized comparisons or proof of a causal relationship.

The record cautions that the groups are not a like-for-like control comparison. Their labels do not establish equivalent observation time or comparable participants, and the displayed counts cannot be used to infer that one period had greater or lesser risk. Details on person-time and the timing of individual events are not reported in the registry record.

The serious-event terms listed with percentages are pneumonia, 7.8%; Factor IX inhibition, 5.9%; haemorrhage intracranial, 5.9%; dental caries, 3.9%; anaphylactic reaction, 2.9%; and bronchiolitis, 2.9%. The denominator and calculation details for these term percentages are not reported in the registry record. A listed term does not establish that the event was caused by the intervention.

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

The registry record establishes that a global, open-label, single-group phase 3a trial investigated nonacog beta pegol in previously untreated patients with haemophilia B. It specifies a primary safety endpoint based on inhibitory antibodies against factor IX after 50 exposure days, along with safety and bleeding outcomes. It also records adverse-event summaries for pre-prophylaxis and prophylaxis periods.

However, the primary endpoint result is not reported in the registry record. The available information therefore does not establish how many participants met the antibody definition, how frequently the endpoint occurred, or how precise an estimate would be. Enrollment of 54 does not reveal the number with available endpoint data. The completed status likewise does not supply an unreported result.

The design also sets limits on what can be concluded. With no randomized control group, observations cannot be interpreted as a controlled treatment effect. The pre-prophylaxis and prophylaxis safety groups are explicitly not like-for-like controls. The counts and listed event terms are descriptive registry information, not evidence by themselves that an event was caused by the intervention or that risks differ between periods.

Absence of a reported endpoint result is not evidence that the endpoint did not occur. It is also not evidence that the intervention was effective or ineffective. It means the registry record does not support a conclusion about the primary endpoint’s observed frequency or precision. The record’s stated aim and outcome definitions describe what the trial set out to investigate, not what the missing result would show.

For readers assessing the evidence, the distinction between design information, observed safety counts, and an analyzed primary outcome is central. The first two are documented to some extent; a primary-endpoint estimate, uncertainty interval, and statistical analysis are not reported in the registry record.

14. Why This Trial Matters Statistically

This trial is statistically notable because it focuses on a clearly specified immunogenicity endpoint in previously untreated patients, while the registry record does not report the endpoint result. The definition is precise about the laboratory criteria: a titre greater than or equal to 0.6 Bethesda unit at two consecutive central-laboratory tests, plus a positive test for nonacog beta pegol binding antibodies. Such specificity helps define what counts as an endpoint event, but it does not replace the observed count or its uncertainty.

The record also illustrates why design labels matter. The study is open-label and single-group, and its safety summaries divide observations into pre-prophylaxis and prophylaxis periods. Because the registry says those groups are not like-for-like controls, a numerical contrast between them would not be equivalent to a randomized comparison. Statistical interpretation depends not only on the outcome measure but also on how participants and observations are organized.

The analysis population is another important issue. The safety set includes all exposed participants, while the primary outcome population is described as participants with available data. Since the analyzed number is not reported, enrollment alone cannot establish the denominator used for the endpoint. This limits assessment of both the event frequency and potential missing-data effects.

Finally, the registry lists many outcomes but no analyses. That gap highlights the difference between registering what will be measured and reporting what was observed. Without results, methods, and uncertainty estimates, readers cannot assess the primary endpoint’s magnitude or precision. These distinctions are useful when interpreting registry records across clinical research: endpoint definitions, design, analyzed populations, and reported results each answer different statistical questions.

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 design is open-label and single-group, with allocation listed as not applicable and no concurrent randomized control. This prevents a direct randomized comparison. The registry also cautions that the pre-prophylaxis and prophylaxis safety groups are not like-for-like controls, so their counts should not be treated as evidence of a comparative effect.

The primary outcome is defined using laboratory criteria after 50 exposure days, with assessment when a minimum of 20 previously untreated patients reach that exposure threshold, up to 156 weeks. The primary result and the number analyzed are not reported in the registry record. The endpoint-specific population is defined by data availability, but the handling of missing measurements is not reported. These omissions prevent assessment of the observed endpoint frequency, its precision, and the effect of missing data.

Although the trial status is completed and enrollment is recorded as 54, those details do not identify the analyzed population or establish that all planned outcomes were reported. The record lists 16 outcome measures and no analyses. A statistical analysis plan, multiplicity approach, interim analyses, and sample-size justification are not reported in the registry record.

For safety, the registry gives counts by period, a death count for each period, and percentages for selected serious-event terms. It does not report the person-time context or the calculation details for the term percentages. The record also does not establish whether the event terms represent distinct participants. These limitations prevent interpretation of the listed figures as comparative rates or causal estimates.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Efficacy of Nonacog Beta Pegol (N9-GP) in Previously Untreated Patients With Haemophilia B — NCT02141074.
• Registry record last updated 2025-12-23; status last verified 2025-12.
• Results first posted 2023-12-29.
• 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

The registry record describes a completed, global, open-label, single-group phase 3a trial of nonacog beta pegol in previously untreated patients with haemophilia B. Enrollment is recorded as 54. The primary endpoint counts participants meeting a specified inhibitory-antibody definition after 50 exposure days, with assessment up to 156 weeks. The primary endpoint result and the number analyzed are not reported in the registry record.

The record lists 16 outcome measures and no analyses. It includes adverse-event summaries for pre-prophylaxis and prophylaxis periods, while cautioning that these are not like-for-like control groups. The statistical analysis plan, handling of missing data, multiplicity approach, and sample-size justification are not reported in the registry record.