Brivaracetam Safety and Efficacy Follow-up Study in Subjects With Epilepsy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Brivaracetam Safety and Efficacy Follow-up Study in Subjects With Epilepsy (NCT01339559), a na phase 3 study. The primary outcome is Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE).

2. Clinical Question

3. Trial Design

This was a Phase 3, open-label, multicenter, noncomparative follow-up study of brivaracetam used as adjunctive treatment in people aged 16 years or older with epilepsy. The registry describes its model as single group and its allocation as NA. There was no randomized comparison, and masking was recorded as none. The study is titled as a safety and efficacy follow-up, with long-term follow-up identified in its description.

Enrollment is recorded as 767. The study began on 2011-05-11, and its primary completion date is 2019-04-18; its status is completed. The primary endpoint timeframe runs from the entry visit (Month 0) until the last visit, up to 84 months. These dates and the endpoint timeframe describe the study record and do not establish that every participant was followed for the full timeframe.

Brivaracetam was the listed intervention, with a maximum dose of 200 mg/day. The primary endpoint concerns TEAEs in the Safety Set, defined as participants who took at least one dose of study drug. The adverse-event summary records 766 participants at risk. The registry does not explain the difference between this safety-summary denominator and the enrollment figure.

Secondary outcomes listed in the record concern partial onset seizure frequency per 28 days during the evaluation period, percentage change in that frequency from the previous study baseline, and responder rate. The study description identifies the trial as noncomparative; these outcomes should therefore be read as follow-up observations, not as randomized estimates of a treatment difference. Details of the protocol, including the basis for the follow-up schedule, 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: Participants Flow refers to the Safety Set (SS).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Safety Set (SS) consisted of all participants who took at least 1 dose of study drug.

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: Baseline Characteristics refer to the Safety Set which consisted of all participants who took at least 1 dose of study medication.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE), measured over From Entry Visit (Month 0) until the Last Visit (up to 84 months).

The primary endpoint is the percentage of participants with at least one TEAE during the period from the entry visit (Month 0) until the last visit, up to 84 months. It is a participant-level binary outcome: each participant either had at least one event meeting the definition during the stated period or did not. Counting participants rather than counting every event makes the measure a summary of how many people experienced an event, not how often events occurred or how long they lasted.

The registry definition includes events that started on or after the first dose of investigational medicinal product and events whose severity worsened on or after the first dose of study medication. The definition explicitly does not require a causal relationship with treatment or its use. Thus, the endpoint records events arising or worsening during the defined treatment period; it is not by itself a measure of events proven to have been caused by brivaracetam.

This kind of endpoint is used in safety follow-up because it gives a direct participant-level summary over the observation period. Its interpretation depends on the population assessed, the event definition, and the time during which participants were observed. The registry record defines the Safety Set as participants who took at least one dose. It does not report the numerical result for the primary endpoint, so the percentage itself cannot be interpreted from this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary participant-level measure: whether each person in the Safety Set experienced at least one TEAE during the stated observation period. The study description and endpoint definition determine what counts as an event for this measure. The endpoint includes new events beginning on or after the first dose and events that worsened in severity on or after the first dose. It does not require the investigator to determine that treatment caused the event.

What does a percentage of participants measure?

A percentage for a binary endpoint is the number of participants meeting the endpoint divided by the number of participants assessed, expressed as a percentage. It answers how many participants experienced at least one qualifying event in the population and time window used for the analysis. It does not measure the total number of event episodes, the duration of events, or the severity of every event. The registry record gives the endpoint definition and defines the Safety Set, but the primary endpoint percentage is not reported in the registry record.

The denominator matters because it identifies the people represented by the estimate. The Safety Set consists of participants who took at least one dose of study drug. The adverse-event summary separately records 766 participants at risk, while enrollment is recorded as 767. The registry does not explain the relationship between these figures. A reader should not assume that the enrollment count is the denominator for every endpoint or that the record explains why the values differ.

How should uncertainty be considered?

A point estimate alone describes the observed result but not how precisely it estimates the underlying event percentage. In general, a confidence interval communicates uncertainty around an estimate under the assumptions of the selected statistical method. Wider intervals indicate less precision, while narrower intervals indicate greater precision. Such intervals do not account for every source of uncertainty: they cannot correct a noncomparative design, resolve missing information about follow-up, or show that an event was caused by treatment.

No confidence interval for the primary endpoint is reported in the registry record. No recalculated estimate is available in the record, and the listed number of analyses is 0. The information therefore does not support an assessment of the endpoint's statistical precision or a comparison of a recalculated result with a sponsor analysis.

What does the single-group design permit?

In general, an uncontrolled single-group study can describe outcomes observed among enrolled participants during treatment and follow-up. It cannot separate treatment-associated events from events that might have occurred because of the underlying condition, other treatments, or other circumstances. Open-label conduct also means the treatment was not masked. The registry does not report a randomized control group, so a treatment-effect estimate against a concurrent comparator is not available from this design.

The record identifies brivaracetam as adjunctive treatment and gives a maximum of 200 mg/day. That description does not establish that all participants received the maximum dose or the same dose throughout follow-up. Dose-level results and detailed exposure summaries are not reported in the registry record.

How should planning illustrations be read?

General sample-size planning estimates ask how many participants might be needed under specified assumptions to detect a chosen effect with a chosen statistical procedure. They are planning illustrations, not observed results and not observed power. The registry's planning description specifies a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It also describes effects as fractions of the observed effect. The specific planning values and the observed effect are not reported in the registry record.

Those assumptions describe a hypothetical two-arm planning exercise; they do not turn this single-group, noncomparative follow-up into a two-arm trial. The planning description says that time-to-event illustrations give a total number of events, while other illustrations give participants per arm. No specific sample-size figure is reported in the registry record, so none can be interpreted as a design target or as evidence of the study's power.

In general, over-dispersion means that observed variability exceeds what a simpler statistical model assumes. It can make model-based uncertainty too small if ignored. The registry record does not report a model for the primary endpoint, an over-dispersion assessment, or a statistical analysis plan. It is therefore not possible to say whether such issues were assessed or how they were handled.

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("Brivaracetam (SS)")
n      <- c(766)
events <- c(643)
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  Brivaracetam (SS)  766  643  83.9  81.1  86.5  81.2  86.4  81.2  86.4

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists six outcome measures overall and identifies secondary outcomes concerning partial onset seizure frequency per 28 days, percentage change from the previous study baseline, and responder rate. The listed number of analyses is 0. Numerical analyses for the primary and secondary outcomes are not reported in the registry record.

When a study examines several outcomes, repeated comparisons can increase the chance that at least one result appears notable by chance. In general, multiplicity methods can address this issue by adjusting how results are evaluated or by specifying a hierarchy of outcomes in advance. The registry record does not report a multiplicity procedure, an outcome hierarchy, or details of a prespecified statistical analysis plan. It is not possible to determine from the record whether multiplicity was addressed in a separate analysis document.

Missing-data handling is also not reported in the registry record. The primary endpoint timeframe extends from the entry visit through the last visit, up to 84 months, but the record does not describe how incomplete follow-up, withdrawal, or unavailable event information was handled. It does not report how many participants contributed to each outcome analysis or whether any imputation method was used.

The Safety Set is defined as participants who took at least one dose of study drug. The adverse-event summary lists 766 at risk; enrollment is 767. The record does not reconcile these figures or describe other analysis populations. Therefore, the displayed safety summary should be understood within the reported safety denominator, not assumed to represent every enrolled participant or every outcome population.

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: convulsion (2.0%), status epilepticus (1.4%), epilepsy (0.9%), suicide attempt (0.9%), pneumonia (0.7%).

The safety summary lists 140 participants affected by serious adverse events and 421 affected by other adverse events, with 766 participants at risk. It also lists 5 deaths. These figures are descriptive counts in the registry record. They do not show whether the same participant could be included in more than one category, and the record does not establish that the deaths or other events were caused by brivaracetam.

The listed serious-event terms include Convulsion (2.0%), Status epilepticus (1.4%), Epilepsy (0.9%), Suicide attempt (0.9%), Pneumonia (0.7%), and Suicidal ideation (0.7%). These term-specific percentages should be read as entries in the registry's adverse-event summary, not as a comparison with another treatment group. The record does not describe the event-level coding or explain whether a participant could contribute to multiple terms.

The primary TEAE endpoint is broader than serious adverse events: it concerns any qualifying treatment-emergent adverse event, without requiring a causal link. Its percentage is not reported in the registry record. The serious-event counts and term percentages do not substitute for that missing primary endpoint result.

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

The record documents a completed Phase 3, open-label, single-group follow-up study of adjunctive brivaracetam in people aged 16 years or older with epilepsy. It defines a primary safety outcome based on whether participants experienced at least one TEAE during follow-up and provides adverse-event summary counts and selected serious-event term percentages. These details help clarify what was measured and the population represented in the safety summary.

The numerical result for the primary endpoint is not reported in the registry record. The record therefore does not establish the percentage of participants who experienced at least one TEAE, nor does it provide an estimate of that percentage's precision. The adverse-event counts and listed term percentages are descriptive; they do not establish that events were caused by treatment.

The study's single-group, noncomparative design does not support a randomized estimate of how brivaracetam compares with another treatment or with no treatment. Outcomes observed during follow-up can reflect multiple influences, including the underlying epilepsy and other circumstances. Without a comparator and the relevant analysis, the record cannot attribute differences in event experience or seizure outcomes to brivaracetam.

The registry lists seizure-related secondary outcomes, but their numerical results are not reported in the record. Consequently, the study description and adverse-event summaries do not establish the magnitude or precision of seizure-frequency changes or responder rates. The record also does not report missing-data procedures, multiplicity handling, or a statistical analysis plan. These omissions limit the conclusions that can be drawn from the recorded results.

Overall, the record supports a description of the study design, endpoint definitions, and selected safety summaries. It does not, by itself, provide the primary endpoint estimate, a controlled treatment comparison, or evidence that an observed adverse event was treatment-caused.

14. Why This Trial Matters Statistically

Long-term follow-up raises statistical questions that differ from those in a short, controlled comparison. The stated primary endpoint covers the period from the entry visit through the last visit, up to 84 months. Over a long observation period, the interpretation of a participant-level adverse-event percentage depends on how long participants were observed, how events were recorded, and how incomplete follow-up was handled. The registry record defines the endpoint and the Safety Set but does not report the primary percentage or missing-data procedures.

The study also illustrates the distinction between describing safety experience and estimating a comparative treatment effect. Its open-label, single-group design can summarize events in the treated group, but does not supply a randomized comparator. That distinction matters when interpreting adverse-event counts, deaths, and serious-event terms: descriptive records are not causal contrasts.

Another statistical issue is denominator clarity. Enrollment is recorded as 767, while the safety summary lists 766 participants at risk. The registry does not explain the difference. Reporting the endpoint population and denominator is essential because a percentage is meaningful only in relation to the participants included and the observation period applied.

Finally, the record shows why endpoint definitions and analysis transparency matter. It defines TEAEs by timing or worsening after the first dose and explicitly notes that an event need not be causally related to treatment. Yet the primary endpoint estimate, its uncertainty, analysis details, and handling of missing observations are not reported. Those distinctions help readers separate what the record documents from what it cannot establish.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The primary endpoint is defined, but its numerical percentage is not reported in the registry record. The record also does not report a confidence interval or other measure of precision for that endpoint. As a result, the primary safety estimate cannot be assessed for magnitude or uncertainty from the recorded information.

The study is described as open-label, noncomparative, and single group, with allocation recorded as NA. There is no randomized comparator. This limits interpretation to outcomes observed in the study group and prevents a like-for-like estimate of differences against another treatment group. The design also cannot establish that an event was caused by brivaracetam; the TEAE definition explicitly does not require a causal relationship.

Enrollment is recorded as 767, whereas the safety summary lists 766 participants at risk. The registry record does not reconcile these numbers. It also does not report how missing observations, withdrawals, or differing follow-up durations were handled. Although the endpoint timeframe extends up to 84 months, the record does not establish that every participant was observed for that full period.

Statistical-analysis details are limited: the record lists 0 analyses and does not report a statistical analysis plan, multiplicity procedure, or endpoint-specific uncertainty estimates. Numerical results for the listed seizure-related secondary outcomes are not reported in the registry record. The safety summary provides event counts and selected term percentages, but does not explain potential overlap among categories or provide a causal attribution analysis.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Brivaracetam Safety and Efficacy Follow-up Study in Subjects With Epilepsy — NCT01339559.
• Registry record last updated 2021-08-17; status last verified 2021-08.
• Results first posted 2020-06-04.
• 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

NCT01339559 is a completed Phase 3, open-label, multicenter, noncomparative, single-group follow-up study of brivaracetam as adjunctive treatment for epilepsy in people aged 16 years or older. Enrollment is recorded as 767. The study began on 2011-05-11, with primary completion on 2019-04-18.

The primary endpoint is the percentage of participants with at least one TEAE from the entry visit through the last visit, up to 84 months. The Safety Set consists of participants who took at least one dose of study drug. The primary endpoint percentage is not reported in the registry record.

The adverse-event summary lists 766 at risk, 140 participants affected by serious adverse events, 421 affected by other adverse events, and 5 deaths. Selected serious-event terms and percentages are listed, but the record does not establish causality. Seizure-related secondary outcomes are identified; their numerical results are not reported in the registry record.