Study for Verification of Efficacy and Safety for Perampanel Monotherapy in Untreated Participants With Partial Onset Seizures (Including Secondarily Generalized Seizures (FREEDOM Study): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study for Verification of Efficacy and Safety for Perampanel Monotherapy in Untreated Participants With Partial Onset Seizures (Including Secondarily Generalized Seizures (FREEDOM Study) (NCT03201900), a na phase 3 study. The primary outcome is Percentage of Participants With Partial-onset Seizures (POS) Who Achieved Seizure-free Status During the 26-week Maintenance Period of 4 mg Perampanel.

2. Clinical Question

The clinical question is about seizure freedom over a defined maintenance period among participants meeting the primary analysis population criteria. It is not a randomized comparison, and it does not estimate a treatment difference against an untreated or active-control group. The study also lists outcomes covering seizure-free status during longer treatment periods, time to first seizure, time to withdrawal, and adverse events. Those outcomes address other aspects of treatment experience, but the registry record does not report their numerical results in the posted results summarized for this analysis.

3. Trial Design

The FREEDOM study is described as a Phase 3, multicenter, uncontrolled, open-label study with an extension study. Its model is single group, and allocation is listed as not applicable. The record therefore does not describe randomized assignment or a masked comparison. The sponsor is Eisai Co., Ltd. Enrollment was 91. The study started on 2017-06-28, reached primary completion on 2019-02-28, and is listed as completed.

Participants were untreated and had partial-onset seizures, including secondarily generalized seizures. The primary endpoint concerns the 4-mg perampanel Maintenance Period. The treatment description states that the 4-mg Treatment Phase comprised a 6-week Titration Period and a 26-week Maintenance Period. It also describes an 8-mg Treatment Phase, with a 4-week Titration Period and a 26-week Maintenance Period, for participants requiring a higher dose. The description of the 4-mg phase is incomplete in the registry record, so additional details should not be inferred.

The primary efficacy population was a modified intent-to-treat set, defined by consent, receipt of at least one dose, entry into the 4-mg Maintenance Period, and at least one postdose primary efficacy measurement during that period. That definition is narrower than enrollment and is specific to the primary endpoint. The record does not report the number of participants included in this population or explain how participants outside it were handled in the analysis.

The registry lists nine outcome measures, including the primary endpoint, additional seizure-free outcomes, time-to-event outcomes, and adverse-event outcomes. It lists zero analyses. The completed study status and enrollment describe the trial’s conduct, but they do not supply an estimate of the primary outcome. The primary result and its confidence interval 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: Study consisted of 2 main phases: Treatment Phase (consisted of a 4 milligram \[mg\] Treatment Phase \[Titration Period {6 weeks} and Maintenance Period {26 weeks}\], and for those participants who need a higher dose, the 8 mg Treatment Phase \[Titration Period {4 weeks} and Maintenance Period {26 weeks}\]) and Extension Phase.

Treatment Phase (Up to 62 Weeks)

Reasons for not completing this period:

Extension Phase (From Week 63 to 156)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Modified intent to treat (mITT) set: group of participants who signed informed consent, received at least 1 dose of study drug, who entered the 4-mg Maintenance Period and had at least 1 postdose primary efficacy measurement in the 26-week Maintenance Period.

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: The safety analysis set was the group of participants who signed informed consent, received at least 1 dose of study drug and had at least one post dose safety assessment.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Partial-onset Seizures (POS) Who Achieved Seizure-free Status During the 26-week Maintenance Period of 4 mg Perampanel, measured over 26 weeks in Maintenance Period of 4 mg perampanel.

The primary endpoint is the percentage of participants with partial-onset seizures who achieved seizure-free status during the 26-week Maintenance Period of 4-mg perampanel. The record defines a seizure as a brief episode of signs or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. It defines POS as a seizure starting in one area of the brain, which may or may not be associated with loss of awareness and consciousness. For this endpoint, seizure-free status means no seizure during the specified Maintenance Period.

A percentage expresses the number of participants meeting the endpoint relative to the relevant analysis population. The specified population is the modified intent-to-treat set, not simply everyone enrolled. The registry record also identifies a 95% confidence interval as the endpoint’s dispersion measure. In general, a confidence interval conveys uncertainty around an estimated quantity; it does not guarantee that the true value lies within the interval.

In general, a seizure-free endpoint can describe whether participants experienced any seizure during a defined observation window. It differs from an endpoint based on change in seizure frequency because it classifies participants according to whether any seizure occurred. The result would need to be interpreted in light of the observation period, analysis population, and absence of a concurrent control group. The registry record does not report the observed percentage or confidence interval, so the endpoint’s numerical result cannot be interpreted from this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a binary participant-level outcome: each participant either met the stated definition of seizure-free status during the 26-week Maintenance Period or did not. The registry expresses the endpoint as a percentage of participants and specifies a 95% confidence interval. The reported record does not include the percentage, interval limits, or analysis count, so the statistical interpretation can address the planned measure but not its observed value.

What does a confidence interval communicate?

In general, a confidence interval describes uncertainty around an estimate under the assumptions of the method used to calculate it. A narrower interval indicates greater precision than a wider interval for the same type of estimate. Its interpretation depends on the analysis population, observed data, and calculation method. The registry names a 95% confidence interval but does not report its bounds or state the method used to calculate it. The interval’s width and the estimate’s precision therefore cannot be assessed.

What does a single-group result describe?

In general, a single-group estimate describes the observed outcome in the participants included in that analysis. Without a concurrent control group, it does not estimate a between-group treatment difference. The FREEDOM study is listed as uncontrolled and single group, with allocation not applicable and no masking. Those design features mean that a numerical seizure-free estimate, if reported, would need to be interpreted as a result among the analyzed participants rather than as a randomized contrast. The record does not report a control-group outcome or an adjusted comparative estimate.

Why does the analysis population matter?

The primary endpoint population is defined by several eligibility conditions for analysis: participants had to consent, receive at least one dose, enter the 4-mg Maintenance Period, and have at least one postdose primary efficacy measurement during that period. The size of this modified intent-to-treat set is not reported in the registry record. In general, an endpoint estimate depends on which participants are included and on how incomplete observations are treated. Because the record does not report the population count or missing-data procedures, readers cannot determine how those choices may have influenced the estimate.

How should the treatment periods be understood?

The primary endpoint focuses on the 4-mg Maintenance Period, not the entire treatment experience. The treatment description specifies a 6-week Titration Period followed by a 26-week Maintenance Period for the 4-mg Treatment Phase. It also describes a possible 8-mg Treatment Phase for participants requiring a higher dose, with a 4-week Titration Period and 26-week Maintenance Period. Other listed outcomes refer to seizure-free status during longer treatment periods and to the last evaluated dose of 4 or 8 mg. These are distinct endpoint definitions; one should not treat them as interchangeable measures. Numerical results for them are not reported in the registry record.

Why can’t the endpoint be interpreted as a treatment comparison?

In general, randomization and a concurrent comparator help distinguish outcome differences between assigned groups from other influences. This study is described as uncontrolled and single group, so the registry record does not support a randomized comparison. Open-label conduct also means the study is not described as masked. The record does not provide information about any blinded outcome assessment. These design features do not invalidate the description of observed outcomes, but they limit the interpretation of those outcomes as evidence of a comparative treatment effect.

What can the sample-size assumptions tell us?

The record describes a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. For time-to-event outcomes, the described planning quantity is the total number of events; for other outcomes, it is participants per arm. These are planning assumptions, not the actual design of this single-group study. The registry record does not report the planning outputs or the effect value on which an illustration would depend. In general, a sample-size illustration is not observed power and does not show the probability that the completed study detected an effect.

Over-dispersion is a general concern when observed variability is greater than a model assumes; it can make model-based uncertainty too small if not addressed. The registry record does not report a model for the primary binary endpoint, an over-dispersion assessment, or a correction for it. No claim about whether over-dispersion was relevant or handled can be made from the record.

The registry lists nine outcome measures and zero analyses. It does not report the statistical analysis plan, the inferential procedures for secondary outcomes, or whether any interim analyses were conducted. Any further account of those methods would be speculation. The primary endpoint’s numerical result and uncertainty remain unavailable in 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("Perampanel")
n      <- c(73)
events <- c(46)
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  Perampanel  73  46  63.0  50.9  74.0  51.5  73.2  51.5  73.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists nine outcome measures, including seizure-free outcomes across different treatment periods and doses, time-to-event outcomes, and adverse-event outcomes. It lists zero analyses. The statistical plan for handling multiple outcomes or comparisons is not reported in the registry record. In general, testing multiple hypotheses can increase the chance of observing at least one apparently notable result by chance; methods for addressing multiplicity depend on the planned analyses and inferential goals. No particular adjustment or testing hierarchy can be attributed to this study from the record.

The primary population is defined as participants who consented, received at least one dose, entered the 4-mg Maintenance Period, and had at least one postdose primary efficacy measurement during that period. The number meeting these criteria is not reported in the registry record. The record also does not describe whether participants with missing seizure assessments were counted as not seizure-free, excluded, handled through an imputation method, or treated in another way. The missing-data approach is not reported in the registry record.

In general, missing outcome data can affect both the estimated percentage and its uncertainty, particularly when the chance of missingness is related to a participant’s outcome or treatment experience. Without the missingness counts and analysis rules, the direction or size of any potential effect cannot be established. The registry record also does not report protocol deviations, analysis-population sensitivity checks, interim analyses, or a statistical analysis plan. These details should be regarded as unavailable, not inferred from the endpoint definition or study status.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: humerus fracture (2.2%), epilepsy (2.2%), malaise (1.1%), influenza (1.1%), otitis media chronic (1.1%).

The registry lists 89 participants at risk for the reported adverse-event figures. Among them, 13 are listed with serious adverse events, and 73 are listed with other treatment-emergent adverse events. The record lists zero deaths. It also gives serious adverse event terms and percentages: Humerus fracture and Epilepsy are each listed at 2.2%; Malaise, Influenza, Otitis media chronic, and Osteoarthritis are each listed at 1.1%.

These figures are descriptive counts and event-term percentages, not estimates of comparative risk. The trial has no concurrent control group, so the registry record cannot show whether the listed events occurred more or less often than they would in another group. A listed event during a study does not, by itself, establish that the study drug caused it. The record does not provide further detail about event timing, duration, outcome, or attribution for the listed terms.

In general, serious adverse events and other treatment-emergent adverse events are distinct reporting categories; the categories should not be treated as equivalent measures of severity or as mutually exclusive participant groups unless the record says so. The registry data do not explain overlap among event categories. The listed figures describe the safety information reported for the study, but they do not by themselves establish a complete comparative safety profile.

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

The registry record establishes that FREEDOM was a completed, Phase 3, single-group study of perampanel monotherapy in untreated participants with partial-onset seizures. It defines the primary question as the percentage achieving seizure-free status during the 26-week Maintenance Period of 4-mg perampanel and specifies a modified intent-to-treat population. It also reports safety counts for participants at risk and lists several serious adverse event terms.

The central limitation for interpreting efficacy is that the registry record does not report the primary endpoint percentage or its 95% confidence interval. Without the estimate, there is no basis in this record for describing the observed seizure-free proportion or its precision. The listed secondary efficacy outcomes also lack numerical results in the record. A statement about the magnitude, consistency, or duration of any efficacy finding would therefore go beyond the registry information.

Even if an observed percentage were available, this uncontrolled, open-label, single-group design would not establish a comparative treatment effect. In general, an outcome observed during treatment is not the same as an outcome contrast from a concurrent randomized comparison. The study design can describe what happened among analyzed participants, but it cannot by itself determine how those outcomes compare with another treatment or with no treatment.

The safety counts likewise do not establish causation or comparative risk. The record lists adverse events during the study but does not provide a control group. It also does not report details sufficient to assess event timing or attribution beyond the listed categories and terms. The figures should be read as descriptive registry reporting rather than as proof that treatment caused or prevented an event.

Accordingly, the record supports an understanding of the research question, treatment-period structure, endpoint definition, and selected safety reporting. It does not support a conclusion about the numerical primary efficacy result, its precision, or comparative benefit and risk. Missing analysis details—including the handling of missing outcomes and multiplicity—further limit what can be concluded from the registry entry.

14. Why This Trial Matters Statistically

This study is statistically notable because its primary question is precise while its design is not comparative. The endpoint specifies seizure-free status over the 26-week Maintenance Period of 4-mg perampanel, and the record defines the population in which that outcome was intended to be assessed. Those details help distinguish the primary measure from other listed outcomes that use different treatment periods or doses.

The single-group, open-label design is central to interpreting any result. In general, a single-group proportion describes outcomes among the participants analyzed; it does not estimate a randomized difference between treatment groups. This distinction matters when readers encounter a treatment outcome and need to understand what the design can support. Here, the registry record does not report the primary estimate, so even the descriptive efficacy result cannot be assessed from the entry.

The study also illustrates why outcome definitions and analysis populations need to be read together. Participants had to enter the 4-mg Maintenance Period and have at least one postdose primary efficacy measurement to be included in the defined modified intent-to-treat set. Enrollment was 91, but the number meeting the primary population definition is not reported in the registry record. Without that denominator and a missing-data description, a percentage would be difficult to evaluate fully even if an estimate were present.

Finally, the safety information is reported as event counts and terms without a concurrent comparator. Such information can describe what was recorded during the study, but it does not provide a comparative safety estimate. The statistical lesson is that study design, denominator, endpoint, and reporting completeness all shape what a registry result can mean; none should be replaced by assumptions about unavailable analyses.

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 most direct limitation is the absence of the primary efficacy estimate and its confidence interval from the registry record. The record defines the endpoint and names its dispersion measure, but does not report the numerical result. It also lists zero analyses, and numerical results for the listed secondary efficacy outcomes are not reported in the registry record.

The design is uncontrolled, open-label, and single group. There is no concurrent comparison group in the record, and allocation is listed as not applicable. Therefore, the record cannot provide a randomized comparison. The description does not report whether outcome assessment was blinded, so no such procedure should be assumed.

The enrollment was 91, while the primary endpoint population requires entry into the 4-mg Maintenance Period and at least one postdose primary efficacy measurement. The size of that population is not reported in the registry record. The record also does not describe missing outcome handling, participant flow through the treatment periods, or sensitivity analyses. These omissions prevent assessment of how incomplete observations or exclusions might affect the endpoint.

The treatment description indicates that some participants could enter an 8-mg Treatment Phase if a higher dose was required, but the primary endpoint is specific to the 4-mg Maintenance Period. The numerical results for outcomes involving the last evaluated dose or longer treatment periods are not reported in the registry record. The record does not provide enough information to interpret differences across dose or period definitions.

Finally, the registry record does not report the statistical analysis plan, multiplicity procedures, interim analyses, or the methods used to calculate the confidence interval. Safety figures are descriptive and have no concurrent control group. These limitations restrict both efficacy and safety interpretation without implying any particular unreported result.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study for Verification of Efficacy and Safety for Perampanel Monotherapy in Untreated Participants With Partial Onset Seizures (Including Secondarily Generalized Seizures (FREEDOM Study) — NCT03201900.
• Registry record last updated 2021-08-05; status last verified 2020-02.
• Results first posted 2020-02-25.
• 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

FREEDOM is a completed Phase 3, multicenter, uncontrolled, open-label, single-group study of perampanel monotherapy in untreated participants with partial-onset seizures. Enrollment was 91. The study started on 2017-06-28, with primary completion on 2019-02-28.

The primary endpoint is the percentage of participants with POS who achieved seizure-free status during the 26-week Maintenance Period of 4-mg perampanel. The defined modified intent-to-treat population required entry into that period and at least one postdose primary efficacy measurement. The primary estimate, confidence interval, and population size are not reported in the registry record.

The registry lists nine outcome measures and zero analyses. Safety reporting lists 89 participants at risk, 13 with serious adverse events, 73 with other treatment-emergent adverse events, and zero deaths. Because the trial has no concurrent control group, the safety figures are descriptive rather than comparative.