Study in Pediatric Subjects With Epilepsy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study in Pediatric Subjects With Epilepsy (NCT01494584), a na phase 2 study. The primary outcome is The Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC[0-tau]) Following Oral Administration of Ezogabine/Retigabine.

2. Clinical Question

The primary question is pharmacokinetic rather than a comparison of seizure outcomes between treatments. AUC[0-tau] characterizes drug exposure across a dosing interval. The record also names safety and tolerability as study objectives, with secondary outcomes covering adverse events and laboratory measurements. It does not report a primary endpoint estimate or a treatment-effect comparison. The clinical question therefore concerns how exposure was to be characterized during dose escalation and what safety observations were recorded, rather than whether ezogabine/retigabine performed better than another treatment.

3. Trial Design

This was a Phase 2, open-label, single-group study of ezogabine/retigabine as adjunctive treatment in pediatric subjects with epilepsy. The official title describes participants aged 12 years to less than 18 years with partial onset seizures or Lennox-Gastaut syndrome; the brief summary specifies uncontrolled partial onset seizures or Lennox-Gastaut syndrome. The allocation is listed as not applicable, and masking as none. No concurrent comparator is described, so the record does not support a like-for-like treatment comparison.

The listed intervention is ezogabine/retigabine, with an arm description of dose escalation. The adverse-event categories identify successive Regimen A dose stages: 300 mg; 300 mg followed by 450 mg; 300/450 mg followed by 600 mg; 300/450/600 mg followed by 750 mg; and 300/450/600/750 mg followed by 900 mg. The numbers at risk differ across these categories. The registry record does not provide further details explaining participant movement among stages or the reasons for changes in the numbers at risk.

The study enrolled 5 participants and its status is terminated. The recorded start date is 2012-07-25, and the primary completion date is 2013-04-29. These dates and status describe the record; the registry does not report a reason for termination in the information available. The sponsor is GlaxoSmithKline.

The primary outcome is AUC[0-tau], with blood sampling scheduled before dosing and at 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35. Although the registry lists 26 outcome measures, it lists no analysis entries. The primary endpoint results and a fuller statistical analysis plan 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: A total of 5 par. who met the eligibility criteria were assigned to Regimen A (\>50 kilograms \[kg\]) or B (30 to \<=50 kg) based on body weight and entered a 2-week Screening phase, followed by a dosing phase (up to 5 weeks). Upon completion of the dosing phase, par. either entered a follow-up phase or a separate extension study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic Population: all participants in the All Subjects Population (defined as all participants who received at least one dose of study medication) for whom a pharmacokinetic sample was obtained and analyzed

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.

6. Primary Endpoint

The registry lists the primary outcome as The Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC[0-tau]) Following Oral Administration of Ezogabine/Retigabine, measured over Pre-dose and 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35.

The primary endpoint is the area under the plasma concentration-time curve over the dosing interval, AUC[0-tau], following oral administration of ezogabine/retigabine. It is reported in Hour*Nanograms/Milliliter (h.ng/mL), and the specified summary is a geometric mean with a 95% confidence interval. The endpoint is intended to characterize the steady-state pharmacokinetic profile: how plasma drug concentration varies over the dosing interval and the resulting measure of exposure across that interval.

Blood samples were scheduled before dosing and at 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35. The registry says the AUC was calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. These rules use the sampled concentrations over time to estimate the area between measurements.

As a general statistical explanation, AUC is useful in pharmacokinetic studies because it condenses a concentration-time profile into a measure of overall exposure during a defined interval. A geometric mean describes a central value on a multiplicative scale, while its confidence interval conveys uncertainty about that estimate. Neither the endpoint definition nor the sampling schedule gives the observed result. The AUC estimates and confidence intervals are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint uses a concentration-time profile to estimate exposure over a dosing interval. The registry specifies AUC[0-tau] and identifies the geometric mean and 95% confidence interval as the planned summary. It also specifies the sampling times and the numerical integration approach: the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. These details explain how the endpoint was intended to be constructed, but the actual estimated values are not reported in the registry record.

What does AUC represent?

As a general statistical explanation, the area under a concentration-time curve combines information about concentration and time. The value is based on measurements taken at specified times and an integration rule that estimates the portions of the curve between those measurements. AUC over a dosing interval is therefore a summary of exposure during that interval, not a direct measure of a clinical outcome such as seizure frequency. The record’s use of AUC is aligned with its stated pharmacokinetic objective.

Why specify the integration rule?

Measured concentrations are available only at the stated sample times, so the curve between observations must be approximated. The registry says increasing concentrations were handled with the linear trapezoidal rule and decreasing concentrations with the logarithmic trapezoidal rule. In general, these methods use the measurements at neighboring times to estimate the area between them, with different assumptions about the shape of the curve. Reporting the approach supports interpretation of how the summary was obtained. It does not substitute for reporting the resulting AUC values or their uncertainty.

What does the geometric mean and confidence interval communicate?

As a general explanation, a geometric mean is a central summary suited to quantities interpreted on a multiplicative scale. A confidence interval communicates uncertainty around an estimate under the method’s assumptions. A narrower interval indicates greater precision than a wider interval, but precision and clinical importance are distinct questions. The registry identifies a 95% confidence interval for the primary endpoint but does not include the estimate or interval. No conclusion about the observed exposure or its precision can be drawn without those results.

What population contributes to the endpoint?

The stated pharmacokinetic population includes participants in the All Subjects Population, defined as participants who received at least one dose of study medication, for whom a pharmacokinetic sample was obtained and analyzed. This definition makes analysis membership depend on both treatment exposure and an available analyzed pharmacokinetic sample. The registry record does not report the number included in the primary endpoint analysis, the number with missing samples, or how any missing measurements were handled.

What can be learned from the adverse-event counts?

The record separates serious adverse events from other adverse events and provides numbers at risk and affected for each listed dose-regimen category. In general, these counts describe how many participants were recorded in each category, not event rates adjusted for follow-up time or a comparative treatment effect. The denominators vary across the categories, and the registry does not explain the changes. The counts should therefore be interpreted descriptively. The record does not provide a formal statistical comparison of these categories or list serious-event terms.

What is not specified about the analysis?

The registry lists 26 outcome measures and 0 analysis entries. It does not report a full statistical analysis plan, sample-size justification, interim analyses, or procedures for handling missing data. These details should not be inferred from the endpoint definition. General statistical practice may include prespecified decisions about analysis populations, transformations, uncertainty estimation, and multiplicity, but the specific choices for this trial are not reported in the registry record.

The posted sample-size assumptions describe 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 stated setup is not a description of this single-group study’s design, and no planning results are included in the record details. Any planning illustration is not observed power and does not establish what the study was designed to detect. The registry’s allocation is listed as not applicable, so an equal-allocation, two-arm illustration should not be mistaken for the trial’s actual allocation or a valid controlled comparison.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 26 outcome measures, including the primary pharmacokinetic endpoint, an adverse-event outcome, and multiple laboratory measures. It lists 0 analysis entries. This means the record identifies numerous outcomes but does not provide corresponding analysis details or results for them. The registry record does not report a multiplicity adjustment or explain how conclusions across outcomes were intended to be interpreted.

As a general statistical explanation, when many outcomes or comparisons are examined, the chance of finding an apparently unusual result somewhere among them can increase. Methods for addressing this issue depend on the study objectives and the prespecified analysis plan. The listed number of outcomes alone does not establish which outcomes were analyzed, whether any adjustment was used, or whether multiplicity was considered. Those details are not reported in the registry record.

The stated pharmacokinetic analysis population includes participants who received at least one dose and had a pharmacokinetic sample obtained and analyzed. The record does not give the number contributing to the primary endpoint, identify missing sample counts, or describe imputation, exclusions, or sensitivity analyses. The analysis population and missing-data approach for the secondary outcomes are also not reported in the registry record. Because enrollment was 5, incomplete measurements could materially affect the available descriptive information, but the extent of any missingness is unknown.

The record’s absence of analysis entries should not be read as proof that no analysis was performed. It means that analysis results and procedures are not reported in the registry record. The listed endpoint methods clarify how AUC was intended to be calculated, but they do not fill in the missing details about multiplicity, analysis populations across outcomes, or incomplete data.

11. 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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry lists serious adverse events and other adverse events separately for each dose-regimen category. For serious events, the numbers at risk are 5, 5, 4, 4, and 3, and 0 participants are listed as affected in every category. For other adverse events, the numbers at risk are 5, 5, 4, 4, and 3; the affected counts are 1, 1, 1, 0, and 0. These are the counts reported in the record and should be read as descriptive observations.

The categories describe successive Regimen A dose stages, not randomized comparison groups. The number at risk changes across them, and the record does not explain the changes or provide event-level details for the other adverse events. The serious-event terms list is empty. Death counts are not reported in the registry record.

As a general statistical explanation, a zero count in a small study does not establish that an event cannot occur or provide a precise estimate of its frequency. These counts also do not account for duration of exposure or establish whether an event was caused by treatment. The registry record does not provide enough detail to interpret the counts beyond their descriptive meaning.

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

This study addresses a pharmacokinetic and safety question in adolescents with epilepsy who received ezogabine/retigabine in an open-label dose-escalation study. The record specifies AUC[0-tau] as the primary endpoint and describes when samples were planned, how the endpoint was calculated, and which population was intended for its analysis. It also records selected adverse-event counts across listed regimen stages.

However, the primary endpoint results are not reported in the registry record. There is no AUC estimate or 95% confidence interval to show the observed exposure or its precision. The listed adverse-event counts do not provide a controlled estimate of risk, and the study is not a randomized comparison. The information therefore does not establish whether the treatment is more or less effective or safe than another option, nor does it quantify a comparative treatment effect.

As a general statistical explanation, study results depend on both the observed data and the design that produced them. A single-group study can describe measurements and events among enrolled participants, but without a comparator it cannot separate changes associated with treatment from other explanations. Small counts are also imprecise, and absence of a recorded event in a small group is not evidence that the event is impossible.

The record’s status is terminated, and enrollment was 5. It does not state why the study was terminated or provide a reason for the small enrollment. Those omissions do not establish why the study ended or whether the planned objectives were achieved. The record lists 26 outcome measures but no analysis entries, leaving the results and analysis details unavailable for most listed outcomes.

The appropriate interpretation is therefore limited: the registry documents a planned pharmacokinetic assessment and reports small descriptive adverse-event counts, but it does not report the primary pharmacokinetic findings or a controlled clinical comparison. Any broader conclusion would go beyond what the registry record reports.

13. Why This Trial Matters Statistically

Statistically, this trial illustrates the difference between a well-defined endpoint and an available result. The registry specifies AUC[0-tau], the geometric-mean summary, a 95% confidence interval, sample times, an integration method, and the population intended for analysis. Those elements make the planned measurement understandable. Yet without the endpoint estimate and its interval, readers cannot assess either the observed exposure or the precision of that estimate.

The study also illustrates why design determines the questions that results can answer. It is open-label and single-group, with no comparator described. Its adverse-event counts are organized by dose-regimen stages and have changing numbers at risk. These counts can describe observations recorded in the study, but they do not create a randomized contrast or identify a causal effect. Reporting counts without the analysis population, exposure duration, and event details limits interpretation further.

The enrollment of 5 makes the distinction between descriptive reporting and statistical inference especially important. Small counts can be useful for understanding what was recorded in this study, but they give limited information about the range of outcomes that might occur in a broader population. The registry does not provide the primary endpoint results, analysis entries, or a sample-size justification, so it is not possible to assess the planned precision or completeness of the intended analyses.

More broadly, this record shows why outcome definitions, population definitions, and reported results need to be read together. A specified endpoint method explains how a measurement should be summarized, while the actual estimate and uncertainty are needed to interpret the findings. When those results are absent, the study’s design and recorded counts remain informative about what was planned and documented, but not about the magnitude of the primary pharmacokinetic findings.

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.

The registry record gives limited information for evaluating this trial’s results. Although the primary endpoint is defined and its calculation method is described, the AUC[0-tau] estimate and 95% confidence interval are not reported in the registry record. The record lists 26 outcome measures but 0 analysis entries, so detailed results and analysis procedures are unavailable for the listed outcomes.

The study enrolled 5 participants and was open-label, single-group, and without a comparator. These features restrict interpretation to the participants and observations described; the record cannot support a controlled treatment comparison. The adverse-event counts are small, and the numbers at risk change across the successive regimen categories. The reasons for these changes, the detailed nonserious event terms, and the deaths information are not reported in the registry record.

The registry identifies the pharmacokinetic population but does not report the number included in the endpoint analysis or the handling of missing samples. Missing-data procedures, the statistical analysis plan, interim analyses, and sample-size justification are not reported in the registry record. The study status is terminated, but a reason for termination is not reported in the registry record. These omissions limit assessment of how closely the reported observations reflect the planned analyses and why the study ended.

The described dose-escalation categories should not be treated as randomized dose groups. With no comparator and no reported analysis entries, the adverse-event counts do not establish differences across doses or treatment effects. The study’s results should therefore be interpreted as limited descriptive information rather than a comparative estimate.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study in Pediatric Subjects With Epilepsy — NCT01494584.
• Registry record last updated 2020-11-30; status last verified 2020-11.
• Results first posted 2014-09-04.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

NCT01494584 is a Phase 2, open-label, single-group study of ezogabine/retigabine as adjunctive treatment in participants aged 12 years to less than 18 years with partial onset seizures or Lennox-Gastaut syndrome. The registry lists 5 participants, a status of terminated, and a primary endpoint of AUC[0-tau] measured at specified post-dose times on Day 7, Day 21, and Day 35.

The record describes a geometric-mean endpoint with a 95% confidence interval and gives the calculation method, but the primary endpoint results are not reported in the registry record. It lists 26 outcome measures and 0 analysis entries. Serious adverse-event counts are 0 in each listed regimen category; other adverse-event counts are 1, 1, 1, 0, and 0, with changing numbers at risk. The record does not describe a comparator or report a reason for termination.