Safety and Tolerability of Intravenous Brivaracetam (Infusion or Bolus) as Adjunctive Antiepileptic Therapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Tolerability of Intravenous Brivaracetam (Infusion or Bolus) as Adjunctive Antiepileptic Therapy (NCT01405508), a randomized phase 3 study. The primary outcome is Number of Subjects With at Least One Treatment-emergent Adverse Event During the Study (Maximum 40 Days).

2. Clinical Question

The trial asked whether the number of participants experiencing at least one treatment-emergent adverse event differed among four treatment sequences involving brivaracetam tablets or placebo tablets followed by intravenous brivaracetam. The intravenous treatment was given by bolus or infusion. The registry describes the study as evaluating safety and tolerability, rather than as a test of seizure control or another measure of treatment efficacy.

3. Trial Design

This was a phase 3, randomized, open-label, parallel-group, multicenter trial with four treatment groups. The registry lists enrollment of 105 participants and a completed status. The study started in 2011-08, and primary completion was recorded as 2012-07. The registry does not report the number of participating centers.

The four sequences combined a one-week tablet period with 4.5 days of intravenous treatment. Two sequences began with placebo tablets and then used brivaracetam by bolus or infusion. The other two began with brivaracetam tablets and then used brivaracetam by bolus or infusion. The brief summary describes repeated intravenous dosing of 100 mg per administration twice daily. The official title gives an age range of 16 to 70 years, while the brief summary describes adults with epilepsy.

Allocation was randomized, but the study had no masking. Participants and study personnel could therefore know the assigned treatment; the registry does not report further details about who was aware of assignment or how the randomization sequence was generated. The record identifies the sponsor as UCB Pharma. It does not report the original sample-size justification, allocation ratio assumptions, or further operational details about trial conduct.

The primary endpoint was a safety count: the number of participants with at least one treatment-emergent adverse event during the study, with a maximum timeframe of 40 days. The stated population was participants who took at least one dose of study drug. Two secondary outcomes are listed: withdrawal due to a treatment-emergent adverse event, and at least one injection-related treatment-emergent adverse event during the evaluation period. Results for those secondary outcomes 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: Participant Flow refers to the Randomized Set (RS).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Population consisting 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 Characetristics refer to the Safety Population consisting of all subjects who took at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Number of Subjects With at Least One Treatment-emergent Adverse Event During the Study (Maximum 40 Days), measured over 40 days.

The primary endpoint counts participants who experienced at least one treatment-emergent adverse event during the study, over a maximum of 40 days. An adverse event is defined in the registry as an untoward medical occurrence after administration of a pharmaceutical product. The event need not be caused by the treatment; the definition includes an unfavorable or unintended sign, symptom, or disease that occurs in temporal association with use of the product, whether or not a causal relationship is established.

The outcome is a participant count, not a count of all events. A participant with several events still contributes to the endpoint as a participant with at least one event. This kind of outcome is used to describe how many people in each treatment group experienced an event, and it permits comparison of the proportions with an event between groups. The registry defines the analysis population as the safety population: all participants who took at least one dose of study drug.

In this trial, the endpoint addresses the stated safety and tolerability question during the study period. It does not by itself identify the cause, seriousness, duration, or clinical importance of each event, and it does not measure treatment efficacy. The registry separately lists withdrawal due to an adverse event and injection-related adverse events as secondary outcomes; their results are not reported in the registry record.

7. Results Posted in the Registry

• Placebo Tablets / Brivaracetam Infusion: 73.1% (19/26) versus 76.9% (20/26) on control; risk difference -3.8 percentage points (95% CI -27.4 to 19.7), risk ratio 0.95 (0.69–1.30); unadjusted two-proportion z-test p = 0.749.
• Brivaracetam (BRV) Tablets / BRV Bolus: 77.8% (21/27) versus 76.9% (20/26) on control; risk difference 0.9 percentage points (95% CI -21.7 to 23.4), risk ratio 1.01 (0.76–1.35); unadjusted two-proportion z-test p = 0.941.
• Brivaracetam (BRV) Tablets / BRV Infusion: 76.9% (20/26) versus 76.9% (20/26) on control; risk difference 0.0 percentage points (95% CI -22.9 to 22.9), risk ratio 1.00 (0.74–1.35); unadjusted two-proportion z-test p = 1.000.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: each participant either had at least one treatment-emergent adverse event during the stated timeframe or did not. The posted group results are counts of participants with an event and the number at risk in each group. This outcome differs from a total event count, because repeat events in the same participant do not add extra participants to the primary endpoint.

What does a risk difference express?

A risk difference compares the event proportions in two groups by subtracting one group’s proportion from the other. A value of zero represents equal observed proportions. Negative and positive values indicate opposite directions according to the comparison’s group order. The comparison estimates are given as risk differences, with the placebo-tablets-then-bolus group as the reference. The risk difference is an absolute contrast, rather than a relative measure such as a risk ratio.

For placebo tablets followed by infusion, the estimated risk difference is -0.038. For brivaracetam tablets followed by bolus, it is 0.009. For brivaracetam tablets followed by infusion, it is 0.0. Their uncertainty is described by the corresponding confidence intervals. These estimates are based on the posted summary counts and do not adjust for other participant characteristics.

How should the p-values be read?

The unadjusted p-values are 0.749, 0.941, and 1.0 for the three comparisons, respectively. A p-value describes how compatible the observed data are with a specified null model of no difference, under the statistical test and its assumptions. It is not the probability that the null hypothesis is true, nor does it quantify the size or clinical importance of a difference. The p-values are unadjusted; a multiplicity adjustment is not reported in the registry record.

General statistical explanation: a p-value is sensitive to both the observed effect and the amount of information in the data. With small groups, a sizeable uncertainty range may accompany an estimate close to zero. A large p-value therefore does not establish that two treatment groups are the same. To support a claim of equivalence, an appropriate margin and a design and analysis aimed at equivalence would be needed; such a margin or analysis is not reported in the registry record.

What does the confidence interval add?

A confidence interval gives a range of values reasonably compatible with the observed data under the method used to calculate it. In repeated use of the same method, intervals constructed in this way have a stated coverage property; for an individual interval, it is not a probability statement that the true effect lies within its endpoints. The intervals in the posted comparisons all cross zero and extend in both directions. They therefore show that the estimates do not distinguish precisely between possible decreases, no difference, and possible increases in the event proportion.

General statistical explanation: wider intervals indicate less precision than narrower intervals. Precision depends on factors such as the number of participants and the variability of the outcome. A binary outcome has uncertainty in both the estimated event proportion and the difference between proportions. The registry record reports no adjusted model or covariate-based analysis for this endpoint, so the comparisons described are unadjusted contrasts rather than estimates adjusted for baseline factors.

The trial is described as randomized, which is intended to support comparability between groups at assignment. Randomization does not guarantee exact balance in a small trial, and this record does not provide baseline characteristics or details about the sequence-generation and concealment procedures. The design was open-label, with masking listed as none. The registry does not report whether outcome assessment involved any additional safeguards against knowledge of assignment.

The endpoint is defined for the safety population, which includes participants who took at least one dose. The registry does not report how many randomized participants did not enter that population, how missing endpoint information was handled, or whether any participants were excluded from the endpoint analysis. It also does not report the statistical plan for the primary comparison, the handling of multiple comparisons, interim analyses, or a sponsor analysis set. The three comparison results should therefore be read as the posted unadjusted summaries rather than as evidence of a fully specified inferential framework.

General statistical explanation: over-dispersion is relevant when outcome variability is greater than a chosen model expects, which can make model-based uncertainty too small if not addressed. The primary endpoint is a participant-level binary count, and the registry record does not describe a model for over-dispersion or a repeated-event analysis. The endpoint does not count multiple adverse events per participant, so methods for recurrent event counts are not established by these primary results.

10. Confidence Intervals and Precision

The confidence intervals describe substantial uncertainty around each estimated risk difference. For placebo tablets followed by infusion versus placebo tablets followed by bolus, the estimate is -0.038 and the interval runs from -0.274 to 0.197. For brivaracetam tablets followed by bolus versus the reference group, the estimate is 0.009 and the interval runs from -0.217 to 0.234. For brivaracetam tablets followed by infusion versus the reference, the estimate is 0.0 and the interval runs from -0.229 to 0.229.

All three intervals include zero, and each also spans values on both sides of zero. Thus, the estimates alone do not establish which direction any underlying difference takes. The intervals permit no difference as well as differences in event risk in either direction. Their width matters: the available data do not tightly constrain the size of the possible group difference. This uncertainty is consistent with a trial enrolling 105 participants across four groups, with 26 or 27 participants in each listed primary endpoint group.

General statistical explanation: a confidence interval is an uncertainty range derived using a statistical method. Its endpoints reflect both the estimate and its precision; they should not be treated as observed outcomes or as a range containing every participant’s experience. A confidence interval that includes zero does not prove equality. Conversely, the fact that an interval includes possible differences does not show that those differences occurred.

The intervals are unadjusted comparisons, and the registry does not report an adjustment for multiple comparisons. Their interpretation should therefore remain tied to the individual contrasts and methods represented by the posted results. The record does not report a prespecified threshold for a clinically important difference, so the intervals cannot be used to declare that any possible difference is clinically negligible.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size table gives planning illustrations based on the observed effect, rather than the original trial’s design assumptions. The listed figures are participants per arm for the 80% and 90% power columns; they are not total events. The assumptions stated for these illustrations are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set at the stated fraction of the observed effect. The trial’s own sample-size justification and original planning assumptions are not reported in the registry record.

The 80% power column describes a planning scenario in which a study designed under the stated assumptions would have an 80% chance of detecting the specified effect if that effect were the true one. The 90% power column represents a higher planned chance of detecting that same specified effect, and therefore generally requires more participants per arm. These are design calculations, not a measure of what the completed trial achieved.

The rows distinguish planning for 100%, 75%, and 50% of the observed effect. Planning for a smaller effect requires more participants, because smaller differences are harder to distinguish from sampling variation. The displayed calculations use observed effects from this small trial, so they are illustrations of how assumptions affect planning, not a recommended enrollment target or a reconstruction of the trial’s protocol. For a comparison whose observed effect is close to zero, the planning implications can be especially sensitive to that estimate.

The sample-size curve should be read as a visual counterpart to those calculations: it represents how the required number of participants changes with the effect size under the stated planning assumptions. The sample-size values are not observed power, and they do not show that the completed trial had a particular probability of finding a difference. The original protocol’s power target, effect-size assumption, and sample-size justification are not reported in the registry record.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.769; treatment proportion p₁ = 0.731; average p̄ = 0.750.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6124 = 1.2002.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6118 = 0.5149.
4. n = (1.2002 + 0.5149)² / (-0.0385)² = 1,988.5, rounded up to 1,989 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.769230769230769                          # control proportion
p1 <- 0.730769230769231                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(1405508)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 1,989 (80% power), 2,662 (90% power)
 75% of observed effect: n per arm = 3,491 (80% power), 4,672 (90% power)
 50% of observed effect: n per arm = 7,750 (80% power), 10,375 (90% power)
power.prop.test: 1988.5 
Simulated power at n = 1,989 per arm: 0.806 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary endpoint and two secondary outcomes. The secondary outcomes concern withdrawal due to a treatment-emergent adverse event and participants with at least one injection-related treatment-emergent adverse event during the evaluation period. Their results are not reported in the registry record. The primary endpoint has comparisons of three other groups with the placebo-tablets-then-bolus group.

When several comparisons or outcomes are examined, the chance of at least one apparently notable result can increase. Statistical approaches can address that issue, but the registry record does not report a multiplicity strategy, such as an adjustment, a hierarchy of tests, or a designated confirmatory comparison. The comparison p-values are unadjusted. They should not be interpreted as multiplicity-controlled evidence across the set of comparisons and outcomes.

The record defines the primary analysis population as the safety population, consisting of participants who took at least one dose of study drug. It does not report the number randomized to each arm separately from the endpoint group counts, the number excluded from the safety population, or how participants with incomplete endpoint information were handled. Missing-data methods and rules for withdrawals are not reported in the registry record. The secondary outcome concerning withdrawal does not, by itself, explain how missing primary endpoint data were treated.

The registry record also does not report an intention-to-treat analysis, a per-protocol analysis, covariate adjustment, interim analyses, or a detailed statistical analysis plan. These absences limit what can be concluded about prespecification and robustness. They do not change the descriptive event counts, but they constrain interpretation of inferential results, especially when several group contrasts are considered. No unreported analysis should be assumed to have been performed.

14. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry lists zero participants with a serious adverse event in each of the four treatment groups. It also lists other adverse-event counts of 17 in the placebo-tablets-then-bolus group, 15 in the placebo-tablets-then-infusion group, 15 in the brivaracetam-tablets-then-bolus group, and 14 in the brivaracetam-tablets-then-infusion group. These are group-level counts, and the primary endpoint counts should not be confused with the separate adverse-event summary.

No serious adverse-event terms are listed in the registry record. Deaths are not reported in the registry record. The adverse-event counts describe what was recorded during the study, but they do not establish that treatment caused an event. The primary endpoint definition explicitly includes events whether or not they are judged related to treatment. The record does not provide further detail on event severity beyond the serious-event classification or on individual event duration.

Zero serious adverse events recorded in these small groups does not establish that serious events cannot occur. It describes the registry’s reported counts for this study. The record also does not report the secondary results for injection-related events or withdrawals due to treatment-emergent adverse events.

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

The results describe the number of participants with at least one treatment-emergent adverse event during a study of four treatment sequences. The primary endpoint counts were similar in size across groups: 20, 19, 21, and 20 participants, with group sizes of 26, 26, 27, and 26, respectively. The estimated risk differences were close to zero, but their confidence intervals were broad and included values in both directions.

These results do not establish that the treatment sequences have identical safety profiles. The uncertainty intervals leave room for differences that the trial did not estimate precisely, and the registry provides no equivalence margin. The unadjusted p-values likewise do not prove equality. The small groups and the open-label design are important context for interpreting a broad endpoint that includes any adverse event temporally associated with treatment, without requiring a causal relationship.

The comparisons are also specific to these sequences. Two groups received placebo tablets for one week and then intravenous brivaracetam; they were not maintained on placebo throughout the study. The other groups received brivaracetam tablets before intravenous treatment. The results therefore should not be recast as a comparison of intravenous brivaracetam with a continuing placebo group.

The registry’s serious adverse-event counts were zero in all groups, but that observation does not rule out uncommon events or resolve risk outside the study’s size and follow-up. The registry does not report serious-event terms, deaths, or the results for the listed secondary outcomes. The posted data support a description of observed events and uncertain between-group contrasts; they do not answer broader questions about efficacy, long-term safety, or outcomes in populations not represented by the trial.

16. Why This Trial Matters Statistically

Statistically, this trial illustrates the distinction between similar observed counts and precise evidence of similarity. The primary event counts were close across the four groups, and the estimated risk differences were near zero. Yet each comparison involved only 26 or 27 participants per group, and the confidence intervals spanned both negative and positive values. The estimates therefore remain uncertain even though the observed counts look alike.

The endpoint also demonstrates why outcome definition matters. Counting participants with at least one event answers how many people experienced an event, not how many events occurred in total or how often events recurred. The primary endpoint includes events whether or not causally related to treatment, so it describes occurrence during the study rather than treatment-attributable harm. Separate safety outcomes may answer narrower questions, but the registry does not report results for the listed secondary outcomes.

The design adds interpretive context: four sequences varied both the initial tablet treatment and the later intravenous route, and the study was open-label. Comparisons should therefore be read as contrasts between the full assigned sequences, not as isolated tests of bolus versus infusion alone or of ongoing drug versus ongoing placebo. The registry record does not report multiplicity handling, missing-data methods, or a detailed analysis plan, so the limits of the inferential framework are relevant.

Finally, the sample-size illustrations make visible how assumed effect size and planned power affect enrollment needs. They are planning scenarios based on the observed effects, not evidence that the completed trial was adequately powered or that it had a particular probability of detecting an effect. Together, these features make the study useful for understanding the relationship between observed safety counts, uncertainty, and the limits of small randomized comparisons.

17. 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 four treatment groups were small, with 26 or 27 participants in the primary endpoint results. As a result, the observed event counts provide limited precision for between-group risk differences. The confidence intervals include zero and extend in both directions, so the data do not narrowly constrain the possible differences. The registry does not report an equivalence margin that would define what range of differences could be regarded as unimportant.

The study was open-label, with masking listed as none. The registry does not report details about outcome assessment procedures that might clarify how knowledge of treatment assignment was handled. The endpoint itself is broad: it includes any untoward medical occurrence temporally associated with product use, whether or not the event is related to treatment. The posted counts therefore do not establish causation.

The treatment sequences differed in the initial tablet phase as well as in the later intravenous route. The comparisons are comparisons of complete sequences, not isolated route effects. In two groups, placebo tablets preceded intravenous brivaracetam, rather than continuing throughout the study. The registry does not report a separate analysis that isolates the effect of bolus versus infusion.

The registry record does not report the original sample-size justification, missing-data handling, multiplicity approach, interim analyses, or a detailed statistical analysis plan. It lists the safety population but does not explain the disposition of randomized participants who may not have taken study drug or had endpoint data. Results for the listed secondary outcomes are not reported in the registry record. Serious-event terms and deaths are also not reported in the registry record. These gaps limit assessment of completeness and of the intended inferential framework.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Safety and Tolerability of Intravenous Brivaracetam (Infusion or Bolus) as Adjunctive Antiepileptic Therapy — NCT01405508.
• Registry record last updated 2018-07-11; status last verified 2016-07.
• Results first posted 2016-04-13.
• 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.

21. Record Summary

NCT01405508 is a completed, randomized, open-label, parallel-group phase 3 trial sponsored by UCB Pharma. It enrolled 105 participants with epilepsy and evaluated four treatment sequences involving placebo or brivaracetam tablets followed by intravenous brivaracetam by bolus or infusion. The primary endpoint was the number of participants with at least one treatment-emergent adverse event during a maximum of 40 days, among participants who took at least one dose of study drug.

Primary endpoint counts were 20 of 26, 19 of 26, 21 of 27, and 20 of 26 participants across the listed groups. The three risk-difference confidence intervals all included zero and extended in both directions. The registry lists zero participants with serious adverse events in every group, but does not report serious-event terms or deaths. Results for the two listed secondary outcomes are not reported in the registry record.