An Open-label, Multinational, Multicenter, Follow-up Study to Evaluate the Long-term Safety and Efficacy of Brivaracetam: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for An Open-label, Multinational, Multicenter, Follow-up Study to Evaluate the Long-term Safety and Efficacy of Brivaracetam (NCT00761774), a na phase 3 study. The primary outcome is Percentage of Subjects With at Least One Treatment-emergent Adverse Event (TEAE) During the Evaluation Period From Entry Visit 1 Through End of Treatment (up to 9 Years).

2. Clinical Question

The registry describes a follow-up study intended to explore the long-term safety and efficacy of brivaracetam and to permit continued access to treatment for people from a previous epilepsy study. The primary endpoint is a safety measure: whether a participant had at least one treatment-emergent adverse event during the evaluation period, which could last up to 9 years.

The registry also lists secondary outcomes concerning continuous brivaracetam monotherapy for specified durations during an evaluation period of up to 9 years. Those outcomes address treatment exposure over time, rather than providing a comparison with another treatment. The record does not report a control group or a randomized comparison, so the study does not directly answer how the observed outcomes would differ under another treatment or under no brivaracetam.

The primary endpoint result itself is not reported in the registry record. The posted adverse-event information includes counts for serious and other adverse events, but those entries do not state the primary endpoint result as a percentage with at least one treatment-emergent adverse event.

3. Trial Design

This is a completed Phase 3, open-label, multinational, multicenter follow-up study of brivaracetam. The registry identifies the design as single-group, with no allocation to comparative arms and no masking. Enrollment was 108. The study began in 2008-11, and primary completion was recorded as 2017-03.

Participants were aged 16 years or older and had epilepsy. The study permitted continued access to brivaracetam for people who had participated in a previous epilepsy study. Brivaracetam was given at a flexible dose up to a maximum of 200 mg/day. Because there was no comparator group, the study describes outcomes among participants receiving brivaracetam rather than estimating a randomized difference between treatments.

The primary outcome concerns treatment-emergent adverse events during the evaluation period, from Entry Visit 1 through the end of treatment, up to 9 years. The registry defines these as untoward medical occurrences during administered study treatment, whether or not they were related to treatment. This definition is important: an event counted as treatment-emergent is not necessarily judged to have been caused by brivaracetam.

Secondary outcomes concern the percentage of participants on continuous brivaracetam monotherapy for at least 3 months, at least 6 months, and at least 12 months during the evaluation period. The record does not provide the methods used to assess efficacy beyond listing these outcomes. Details such as the dosing changes participants actually received, the schedule of assessments, and the handling of treatment discontinuation are not reported in the registry record.

The open-label, single-group structure is suited to describing follow-up experience in this cohort, but it does not provide a like-for-like control comparison. Differences between people who remain in follow-up and those who do not could also affect the observed experience over time; the registry record does not report methods for assessing that possibility.

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: Participant Flow refers to the Safety Set, which consisted of all subjects who took at least 1 dose of study drug.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Safety Analysis Set consisted of all subjects 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 subjects who received at least 1 dose of study medication.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Subjects With at Least One Treatment-emergent Adverse Event (TEAE) During the Evaluation Period From Entry Visit 1 Through End of Treatment (up to 9 Years), measured over During the Evaluation Period (up to 9 years).

The primary endpoint is the percentage of participants with at least one treatment-emergent adverse event during the evaluation period, from Entry Visit 1 through the end of treatment, up to 9 years. It is a binary participant-level outcome: for this endpoint, a participant either had at least one qualifying event or did not. The registry identifies the unit as percentage of participants and describes the analysis population as the Safety Analysis Set, comprising participants who took at least 1 dose of study drug.

This kind of endpoint is used to describe how commonly participants experience at least one event during treatment exposure. It gives a broad summary of safety experience, but it does not describe the number of events per participant, their duration, their severity, or whether they were caused by treatment. The registry definition explicitly includes events whether or not they are related to study treatment.

Long follow-up can capture events occurring during extended treatment, but a percentage alone does not convey when events occurred or how long participants were observed. Interpretation of such a percentage depends on the observation period and on who remains under observation. The registry record does not report the primary endpoint result, a confidence interval for it, or the detailed analysis method. The posted counts of serious and other adverse events are not, by themselves, a reported result for the primary endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The design and the endpoint determine what statistical conclusions are available. This study is identified as single-group, open-label, with no allocation to a comparison arm. Its primary endpoint is a percentage of participants with at least one treatment-emergent adverse event. The posted record therefore supports a descriptive framing, rather than a treatment-effect estimate from a randomized comparison.

What does a participant-level percentage describe?

In general, a participant-level percentage summarizes the proportion of an analysis population that meets a binary definition. For an outcome such as at least one event, each participant is classified according to whether the event definition was met during the specified observation period. This type of summary does not tell how many total events occurred, whether one participant had multiple events, or how long each participant was observed.

For this study, the endpoint is defined over the evaluation period from Entry Visit 1 through the end of treatment, up to 9 years. The Safety Analysis Set is described as all participants who took at least 1 dose of study drug. The registry record does not report a primary endpoint percentage, its confidence interval, or the method used to calculate it. It is therefore not possible to assess the precision of the primary endpoint estimate from the record.

What does a confidence interval add?

In general, a confidence interval expresses the statistical uncertainty around an estimate under the assumptions of the analysis. A narrow interval indicates greater precision than a wide interval, while neither width nor the interval alone resolves possible bias or confounding. A confidence interval for a percentage would help readers understand how much uncertainty surrounds the observed proportion. No confidence interval for the primary endpoint is reported in the registry record.

Why does the design matter?

A single-group follow-up study can describe outcomes among participants who receive the study treatment. It cannot, on its own, separate the contribution of treatment from other explanations for what was observed. In general, a comparator group can provide context for estimating a between-group contrast, while randomization helps make groups comparable on average. Neither a comparator nor random allocation is listed for this study. The posted data should therefore not be interpreted as a randomized estimate of benefit or harm.

Open-label status is also relevant. In general, when treatment is known, reporting or assessment of outcomes can be influenced by expectations, especially for outcomes requiring judgment. The registry does not report whether any endpoint assessments were independently adjudicated or whether other safeguards were used. Those details are not reported in the registry record.

How should the adverse-event counts be read?

The registry lists serious adverse events for 26 participants among 108 at risk and other adverse events for 81 among 108 at risk. These figures are counts of participants with the listed event category, not counts of every event. In general, multiple events can occur in one participant, and a participant may have events in more than one category. The record does not explain overlap between these categories. It also does not provide person-time, so the counts cannot be interpreted as rates per duration of exposure.

Seriousness and treatment-emergence are not the same as treatment causality. The primary endpoint definition includes untoward occurrences whether or not they are related to study treatment. The record lists serious event terms and one death, but does not report causal attribution or enough details to connect the death to a particular event or treatment.

What do the planning assumptions mean?

In general, a sample-size planning illustration estimates the number of participants that might be needed under stated statistical assumptions; it does not describe the number actually observed and is not observed power. The planning assumptions associated with the analysis use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They describe an effect to detect as a stated fraction of an observed effect. Those assumptions do not match the registry’s single-group design, which has no two-arm randomized comparison. No planning sample-size values or an effect estimate for such calculations are reported in the registry record, so no numerical planning conclusion can be drawn.

More generally, a planning calculation depends on the target effect, outcome variability, analysis method, and design assumptions. If the underlying effect estimate is uncertain or not reported, the resulting planning exercise is illustrative rather than a firm statement about what a future study requires. The registry record does not report the original sample-size justification or protocol planning rationale.

Over-dispersion is a general statistical issue that arises when observed variability exceeds what a model assumes. For count outcomes, ignoring over-dispersion can make uncertainty appear too small. The primary endpoint is described as a participant-level percentage, and the record does not report a model-based analysis or an over-dispersion assessment. No claim about such an assessment can be made from 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("Brivaracetam (SS)")
n      <- c(108)
events <- c(98)
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)  108  98  90.7  83.6  95.5  83.8  94.9  83.8  94.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary safety outcome and secondary outcomes concerning continuous brivaracetam monotherapy for at least 3 months, at least 6 months, and at least 12 months during an evaluation period of up to 9 years. It does not report a multiplicity strategy for interpreting these outcomes together. When several outcomes are examined, a general concern is that the chance of at least one apparently notable result can increase unless the analysis accounts for multiple testing. The record does not state whether any adjustment or hierarchy was prespecified.

The registry record lists 0 analyses. It does not report a statistical analysis plan, methods for missing data, or rules for censoring or discontinuation. In a long-term follow-up study, participants may have different durations of observation; in general, that can affect the interpretation of percentages based on whether an event occurred during follow-up. The record does not provide enough detail to assess how that issue was handled.

The Safety Analysis Set is described as all participants who took at least 1 dose of study drug. The record does not report the number included in the primary endpoint analysis, whether all participants in that set had complete endpoint information, or how missing endpoint data were treated. It also does not report a separate efficacy analysis population or an approach for handling missing values for the monotherapy outcomes.

Without these details, the analysis population and the treatment of incomplete follow-up cannot be fully evaluated. No conclusion about the direction or size of missing-data bias can be drawn from the registry record.

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 (4.6%), angina pectoris (2.8%), atrial fibrillation (1.9%), cholelithiasis (1.9%), contusion (1.9%).

The registry lists serious adverse events for 26 participants among 108 at risk, and other adverse events for 81 participants among 108 at risk. It also lists 1 death. These are descriptive figures; the record does not report a comparison group or a statistical test for them. The categories should not be added together because the record does not say whether participants could be counted in both.

The serious terms listed include Convulsion at 4.6%, Angina pectoris at 2.8%, and Atrial fibrillation, Cholelithiasis, Contusion, and Grand mal convulsion at 1.9% each. These percentages are registry-reported frequencies for listed serious event terms. The record does not give further detail on timing, recurrence, participant-level overlap among terms, or treatment attribution.

A serious adverse event is not necessarily caused by the study treatment. Likewise, the primary endpoint definition includes treatment-emergent events whether or not they were related to treatment. The registry record does not explain the circumstances or cause of the death, so it should not be attributed to treatment based on these figures.

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

The study’s record describes long-term follow-up experience among participants treated with flexible-dose brivaracetam, with dosing up to a maximum of 200 mg/day. It establishes the study’s safety question and reports descriptive counts of serious and other adverse events. It also lists serious event terms and records 1 death. These details can help characterize what the registry reports about the cohort.

The record does not report the result of the primary endpoint: the percentage of participants with at least one treatment-emergent adverse event during the evaluation period. It therefore does not give a direct estimate for that primary question, nor does it provide a confidence interval for such an estimate. The listed adverse-event counts should not be substituted for the missing primary endpoint result.

Even if an endpoint percentage were available, the single-group, open-label design would still limit causal interpretation. Without a comparison group, the study cannot establish how event frequency or other outcomes would compare under another treatment or no study treatment. The event definition also includes occurrences not judged related to treatment, so temporal association and causation must remain distinct.

The registry lists monotherapy-duration outcomes as secondary measures, but does not report their results in the record. It also does not report a statistical analysis plan, missing-data methods, or a multiplicity approach. These omissions limit assessment of the precision and robustness of any unreported analyses.

Accordingly, the posted record supports a descriptive account of study design and selected safety information, not a definitive comparative conclusion about brivaracetam. The event counts do not establish that treatment caused an event, and the absence of a reported primary endpoint result should not be treated as evidence that events did not occur. The record is incomplete for evaluating the primary safety endpoint and the secondary outcomes.

14. Why This Trial Matters Statistically

This trial matters statistically because it illustrates the distinction between describing outcomes during treatment and estimating a treatment effect. The registry identifies an open-label, single-group follow-up study, so its design can document events and treatment experience in the enrolled cohort but does not provide a randomized contrast with a control group.

The long evaluation period, up to 9 years, also makes follow-up time relevant to interpretation. A simple percentage of participants with an event does not show when events occurred or how long each participant was observed. In general, differences in observation time can affect the opportunity to experience and record an event. The registry record does not report participant-level follow-up durations or event timing.

The endpoint definition is another important statistical detail. It includes treatment-emergent adverse events whether or not they are related to study treatment. That broad definition captures occurrences during treatment but does not by itself establish causality. Keeping the endpoint definition separate from causal attribution is essential when reading safety summaries.

The record also demonstrates why completeness of reporting matters. Although the primary endpoint is specified and adverse-event counts are listed, the primary endpoint result, its uncertainty, analysis details, missing-data methods, and multiplicity approach are not reported in the registry record. Without those details, readers cannot fully evaluate the primary endpoint estimate or judge how robust analyses may be to incomplete follow-up.

Finally, planning calculations should be interpreted in relation to their design assumptions. A two-arm illustration with equal allocation does not describe this single-group follow-up study. Such an illustration is a planning aid, not evidence of observed power and not a substitute for the trial’s own design rationale, which is not reported in the registry 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.

Interpretation is limited first by the absence of a comparator. This open-label, single-group study describes outcomes among people receiving brivaracetam but cannot estimate a randomized difference against another treatment. The observed event counts therefore cannot establish treatment causality or comparative safety.

The primary endpoint result is not reported in the registry record, despite the endpoint definition being available. The record also does not report its confidence interval or detailed calculation method. The listed serious and other adverse-event counts are not identified as the primary endpoint calculation.

The record covers an evaluation period of up to 9 years but does not report actual observation time for participants, event timing, or the handling of discontinuations. These details would matter when interpreting event occurrence over extended follow-up. The record does not report how missing data were handled or whether incomplete follow-up affected outcome summaries.

The registry lists secondary monotherapy-duration outcomes but does not report their results in the record. A multiplicity strategy, statistical analysis plan, sample-size justification, and interim analysis approach are not reported in the registry record. The record also does not provide details on the treatment attribution of serious events or the death.

Finally, the Safety Analysis Set is defined as participants who took at least 1 dose, but the record does not state how many participants contributed data to each endpoint analysis or whether analysis populations differed by outcome. These reporting gaps restrict evaluation of precision, potential bias, and generalizability beyond the enrolled follow-up cohort.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: An Open-label, Multinational, Multicenter, Follow-up Study to Evaluate the Long-term Safety and Efficacy of Brivaracetam — NCT00761774.
• Registry record last updated 2018-07-11; status last verified 2018-03.
• Results first posted 2018-04-23.
• 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 Phase 3, open-label, single-group follow-up study of flexible-dose brivaracetam in people aged 16 years or older with epilepsy. The dose could be adjusted up to a maximum of 200 mg/day. Enrollment was 108, with study start recorded as 2008-11 and primary completion as 2017-03.

The primary endpoint was the percentage of participants with at least one treatment-emergent adverse event during the evaluation period, from Entry Visit 1 through end of treatment, up to 9 years. The endpoint result is not reported in the registry record. The record lists 26 participants with serious adverse events, 81 with other adverse events, and 1 death. It also lists secondary outcomes related to durations of continuous brivaracetam monotherapy, but their results are not reported in the record.

Because the study had no comparator group, its safety counts are descriptive and do not establish treatment causality or comparative effects. Statistical analysis, missing-data, and multiplicity methods are not reported in the registry record.