A Study to Assess the Efficacy and Safety of Brivaracetam as Treatment for Increased Seizure Activity in an Epilepsy Monitoring Unit Setting: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Assess the Efficacy and Safety of Brivaracetam as Treatment for Increased Seizure Activity in an Epilepsy Monitoring Unit Setting (NCT03021018), a randomized phase 2 study. The primary outcome is Time to Next Seizure (Per Clinical Observation With Electroencephalogram [EEG] Confirmation) or Rescue Medication.

2. Clinical Question

The study was designed to assess the efficacy and safety of intravenous brivaracetam compared with intravenous lorazepam in the specific setting of increased seizure activity during monitoring-unit evaluation. It was randomized, open-label, and parallel-group, with the two brivaracetam doses compared separately with the active-control arm. The registry lists 46 participants enrolled overall. The primary-outcome population includes 15 participants in each arm, but the registry record does not provide a complete set of primary endpoint summaries or a reported inferential comparison. As a result, the central clinical question is clear, but the posted primary results do not support a complete quantitative comparison of time to next seizure or rescue medication.

3. Trial Design

This completed phase 2 study was randomized, open-label, parallel-group, and active-controlled. It compared intravenous brivaracetam at 100 mg and 200 mg with intravenous lorazepam in people with epilepsy being evaluated in an Epilepsy Monitoring Unit who experienced seizures requiring prompt treatment. The registry lists 46 participants enrolled. In the primary Intent-to-Treat as Randomized population, 15 participants are listed in each of the three arms.

The brivaracetam 100 mg dose was described as two 5 ml vials administered intravenously over a 2-minute period. The 200 mg dose was described as four 5 ml vials administered over a 4-minute period. Lorazepam was given as a bolus according to the patient leaflet or package insert, at a rate not exceeding 2.0 mg/min; the investigator determined the dose according to clinical judgment. Because masking was listed as none, the study was open-label rather than blinded.

The primary endpoint was time to next seizure, defined as a clinically observed seizure with electroencephalogram confirmation starting within 12 hours after the end of study-drug administration, or rescue medication. The stated timeframe extended during the treatment period on Day 1 until the safety follow-up visit on Day 2. Secondary outcomes included seizure-free status and rescue-medication use at specified follow-up times, as well as time to next seizure or rescue medication.

The registry record does not report the sample-size justification, detailed allocation procedure, prespecified statistical analysis plan, interim analyses, or handling of missing outcome data. The study is listed as completed, with a start date of 2017-02-06 and primary completion date of 2018-04-27.

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 Intent-to-Treat as Treated (ITT-T) Set.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Intent-to-Treat as Randomized (ITT-R) Set consisted of all randomized subjects who received the investigational medicinal product (IMP) for qualifying seizures.

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 Intent-to-Treat as Treated Set which consisted of subjects who were treated with investigational medicinal product (IMP) regardless of qualifying seizure status.

6. Primary Endpoint

The registry lists the primary outcome as Time to Next Seizure (Per Clinical Observation With Electroencephalogram [EEG] Confirmation) or Rescue Medication, measured over During the Treatment Period (Day 1) until Safety Follow-Up Visit (Day 2).

The primary endpoint was time to the next seizure, per clinical observation with electroencephalogram confirmation, or rescue medication. Time was measured in hours during the treatment period on Day 1 until the safety follow-up visit on Day 2. The registry defines a qualifying next seizure as the first seizure that was clinically observed, confirmed by electroencephalogram, and started within 12 hours after the end of investigational medicinal product administration.

A time-to-event measure describes how long participants remain without the specified event, rather than simply whether an event occurred at a single scheduled assessment. Combining seizure activity and rescue medication in the endpoint reflects the study’s focus on prompt treatment during monitoring-unit evaluation. The registry wording names both next seizure and rescue medication, but does not provide a fuller account of how these events were handled analytically.

The registry identifies the summary measure as a median with a 95% confidence interval. A median time can describe the point by which half of the relevant observations have experienced the event, subject to the analysis definition and estimability. A confidence interval conveys uncertainty around an estimate; it does not guarantee that the true value lies within the reported limits. The posted primary results do not include the median or the upper confidence limit for any arm. Only lower limits are listed: 5.55 hours for lorazepam, 6.93 hours for brivaracetam 100 mg, and 4.33 hours for brivaracetam 200 mg. With the central estimates and the remaining limits absent, the primary endpoint cannot be interpreted as a complete set of arm-level time-to-event results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Time-to-event endpoints and binary outcomes answer different questions. The primary endpoint is framed as elapsed time until the next seizure or rescue medication, whereas the secondary seizure-free outcomes ask whether participants were seizure-free at specified follow-up times. A time-to-event summary retains information about when an event occurs; a single-time-point percentage reduces the outcome to status at that assessment. These measures can complement one another, but they are not interchangeable.

What a median time means

For a time-to-event outcome, the median is a summary of the event-time distribution. In general, it identifies the time by which half of the observations have experienced the event, under the analysis definition. The registry identifies the primary parameter as a median and specifies a 95% confidence interval. A confidence interval communicates uncertainty in an estimated quantity: a wider interval generally indicates less precision, while a narrow interval indicates greater precision. It is not a probability statement that the particular interval contains the true value.

Here, the registry lists only lower confidence limits for the primary endpoint and does not provide the medians or upper limits. The missing components prevent readers from assessing the full estimates, their precision, or differences between the three arms. It would not be appropriate to infer the absent values from the lower limits. The registry record also does not report details such as the time-to-event estimation method, how participants without an observed event were handled, or the exact treatment of rescue medication within the endpoint.

How to read the secondary comparisons

For seizure-free status, the posted comparison measure is a risk difference: the proportion seizure-free in a brivaracetam arm minus the proportion in the lorazepam arm. A positive estimate means the observed percentage was higher in the brivaracetam arm; a negative estimate would mean it was lower. The risk-difference confidence intervals give a range of values compatible with the data under the calculation method. Every interval reported for these comparisons includes zero, so the data are compatible with no difference as well as with differences in either direction. The intervals are broad, reflecting limited precision in summaries based on 15 participants per arm.

The p-values are unadjusted. In general, a p-value describes how unusual the observed data, or more extreme data, would be under a specified null model. It does not measure the probability that a treatment effect is true, and it does not indicate clinical importance. A p-value also does not convey the size or precision of an effect; the estimate and confidence interval are needed for that context. The registry record lists no reported analyses for these secondary outcomes, so the posted unadjusted calculations should not be mistaken for a documented sponsor analysis.

Multiplicity and repeated outcomes

When several outcomes, time points, or treatment comparisons are examined, the chance of obtaining an apparently notable result by chance can increase. In general, multiplicity procedures control or describe that issue, but the registry record does not report whether any adjustment or hierarchy was planned for these outcomes. The secondary comparisons should therefore be read as exploratory descriptions, not as a single confirmatory test. This is especially important because there are three assessment times and two comparisons with lorazepam at each time.

Planning illustrations are not trial results

Sample-size planning illustrations use the observed effects as inputs, under stated assumptions: a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The displayed scenarios consider planning for 100%, 75%, or 50% of the observed effect. These are illustrations of how sample sizes might change under those assumptions; they do not describe the study’s actual design rationale, and they are not observed power. The registry record does not report the trial’s own sample-size justification. The small realized groups also mean the secondary estimates are imprecise; planning calculations do not remove that uncertainty or change the results already observed.

10. Multiplicity, Missing Data and Analysis Populations

The registry record identifies a primary endpoint and several secondary outcomes, but does not report a detailed statistical analysis plan. In particular, it does not report a multiplicity strategy, a hierarchy among secondary outcomes, or whether any secondary result was intended to support a confirmatory claim. The available seizure-free results cover multiple time points and compare each brivaracetam dose with lorazepam. Their p-values are unadjusted, and the record lists no reported analyses. They should be interpreted as descriptive comparisons rather than as a family of controlled confirmatory tests.

Missingness and analysis-population details also limit interpretation. For the primary endpoint, the registry defines the Intent-to-Treat as Randomized set as randomized participants who received the investigational medicinal product for qualifying seizures, and lists 15 participants in each arm. The registry does not describe how participants with incomplete follow-up, no observed event, or other missing endpoint information were handled. It also does not explain why the central primary estimates and upper confidence limits are absent. Those omissions prevent assessment of whether the reported summaries represent all participants in the stated population or how incomplete observations might affect them.

The safety summaries use an ITT-T population, while the efficacy summaries use ITT-R. The registry gives 16 participants at risk for lorazepam safety outcomes and 15 for each brivaracetam safety outcome. These population labels and denominators should not be treated as interchangeable. No further explanation of population construction or missing safety observations is reported.

In general, prespecified analysis methods and transparent missing-data handling help readers judge how results were generated and how robust they may be. The registry record does not report those details, so it is not possible to determine whether the posted summaries follow a particular missing-data strategy or a multiplicity adjustment.

11. 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: seizure cluster (6.2%).

The registry reports serious adverse events among participants in the ITT-T safety population. The lorazepam group had 1 serious adverse event among 16 participants at risk; the brivaracetam 100 mg and 200 mg groups each had 0 among 15 participants at risk. The recorded number of deaths was 0 in every group. These are observed counts in the listed safety populations; they do not establish that an event cannot occur or provide a precise estimate of comparative safety.

Other adverse events affected 4 participants in the lorazepam group, 6 in the brivaracetam 100 mg group, and 3 in the brivaracetam 200 mg group. The registry also lists seizure cluster as a serious adverse-event term at 6.2%. The record does not provide enough context in these summaries to interpret that term as a comparative treatment effect.

Safety counts are descriptive. With the small denominators, a difference in counts can be unstable, and a zero count should not be read as proof of no risk. The registry record does not report further detail needed to evaluate timing, severity distribution, relationship to study drug, or a formal comparative safety analysis. These figures describe reported events in the listed groups, not a recommendation about treatment.

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

The registry record establishes that a randomized, open-label, active-controlled phase 2 study evaluated intravenous brivaracetam at two doses against intravenous lorazepam in a monitoring-unit setting. It also reports seizure-free percentages at selected follow-up times and counts of adverse events. Those data allow a limited description of the participants and outcomes recorded in the registry.

The main primary endpoint cannot be fully interpreted from the posted results. Although the endpoint is defined as time to next seizure or rescue medication and the registry lists lower confidence limits for the three arms, it does not provide the median times or upper confidence limits. There is no reported primary analysis comparing arms. The secondary seizure-free estimates are based on 15 participants per arm and have broad unadjusted confidence intervals that include zero for the risk differences. They do not establish a difference, nor do they establish equivalence.

The posted data therefore do not show that one study drug is superior, inferior, or equivalent to another. Absence of a clearly demonstrated difference in these summaries is not proof of equal effects. The incomplete primary results and limited size of the analyzed groups leave substantial uncertainty. In addition, the registry record does not report a detailed analysis plan, multiplicity adjustment, or missing-data method, which further limits confidence in interpretation of the secondary comparisons.

These findings apply to the study setting and populations described in the record. They do not settle how the treatments compare in other settings or populations. The safety counts likewise describe only the events recorded in the listed safety groups and do not establish comparative safety. The study’s purpose was to assess efficacy and safety; the posted results provide an incomplete basis for answering that purpose quantitatively.

13. Why This Trial Matters Statistically

This study illustrates why a clearly specified endpoint and complete reporting matter as much as the choice of statistical method. Time to next seizure or rescue medication is clinically framed as a duration, but the registry reports only lower confidence limits for the primary endpoint. Without the median estimates and the remaining interval limits, readers cannot judge the central results or their precision. A recognizable endpoint definition does not substitute for a complete result.

The study also shows how secondary outcomes can provide context without resolving the primary question. Seizure-free percentages at fixed follow-up times describe observed status, while the primary endpoint concerns event timing. The two perspectives are related but not interchangeable. In this record, the secondary comparisons are based on small groups, and their unadjusted confidence intervals include zero. The absence of reported analyses and multiplicity details means those results should not be treated as definitive evidence of a difference.

Finally, randomized allocation does not by itself guarantee precise estimates. The listed primary population has 15 participants per arm, and the secondary comparisons likewise use 15 per arm. Planning illustrations based on observed effects highlight how sample-size needs can depend on the effect one aims to detect, but they are not the study’s design justification and are not observed power. The registry record does not report its own sample-size rationale. This trial is therefore statistically informative as an example of the distinction between a study’s question, its observed summaries, and the strength of evidence those summaries can support.

14. 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 limitations specific to this record constrain interpretation. The most important is incomplete reporting of the primary endpoint: the registry lists a lower confidence limit for each arm but no median time or upper confidence limit. It also provides no reported primary comparison. The endpoint is described as time to next seizure or rescue medication, but the registry record does not explain the analysis method or how these event types were combined in the analysis.

The randomized, open-label design means treatment assignment was not masked. Clinical observation is part of the outcome definition, and the seizure event also required electroencephalogram confirmation. The record does not describe additional safeguards or adjudication procedures. The active-control lorazepam dose was determined by investigator judgment, as described in the registry, rather than as one fixed listed dose.

The available secondary results are limited to seizure-free status at 6, 8, and 12 hours. Although additional secondary outcomes are listed, their results are not reported in the registry record. The available comparisons are unadjusted, and no reported analyses or multiplicity plan are listed. The small arm sizes and broad confidence intervals make the secondary comparisons imprecise.

The registry record does not report the sample-size justification, detailed statistical analysis plan, interim analyses, or missing-data handling. It also does not provide enough detail to assess the full composition of the analysis populations beyond their definitions and listed denominators. The safety results are counts from the ITT-T population and are not a formal comparative safety analysis. These limitations mean that the registry summaries are useful for describing what was posted, but insufficient for a complete evaluation of efficacy or comparative safety.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study to Assess the Efficacy and Safety of Brivaracetam as Treatment for Increased Seizure Activity in an Epilepsy Monitoring Unit Setting — NCT03021018.
• Registry record last updated 2020-12-16; status last verified 2020-11.
• Results first posted 2019-05-28.
• 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.

18. Record Summary

NCT03021018 is a completed phase 2 randomized, open-label, parallel-group, active-controlled study of intravenous brivaracetam for increased seizure activity during Epilepsy Monitoring Unit evaluation. It compared brivaracetam 100 mg and 200 mg with intravenous lorazepam. The registry lists 46 enrolled participants and 15 participants per arm in the primary Intent-to-Treat as Randomized population.

The primary endpoint was time to next seizure, confirmed by electroencephalogram, or rescue medication. The registry reports only lower confidence limits and does not provide the medians, upper limits, or a primary comparison. Secondary seizure-free percentages are available at 6, 8, and 12 hours, but the unadjusted comparisons are imprecise and the record lists no reported analyses. Safety summaries show few serious events and no deaths in the listed groups; these counts are descriptive and based on small denominators.

The registry record does not report the trial’s sample-size rationale, detailed analysis plan, multiplicity strategy, or missing-data handling. The posted evidence therefore supports limited descriptive interpretation, not a definitive comparative conclusion.