Open-Label Extension Study of the Phase 3 VRX-RET-E22-302 Double-Blind Trial. 115097: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Open-Label Extension Study of the Phase 3 VRX-RET-E22-302 Double-Blind Trial. 115097 (NCT00310388), a non-randomized phase 3 study. The primary outcome is Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAEs).

2. Clinical Question

3. Trial Design

This was a Phase 3, open-label extension study of the double-blind VRX-RET-E22-302 trial. Its single-group, non-randomized structure means participants in the extension received retigabine; the registry does not identify a concurrent placebo or active-treatment arm. As an extension, the study focused on people who had completed the parent trial and met the extension’s eligibility criteria, rather than on a newly randomized comparison.

The registry describes retigabine as adjunctive treatment alongside participants’ current antiepileptic drugs or vagal nerve stimulation. The planned dose range was 600-1200 mg/day. Treatment was to continue until withdrawal or discontinuation of the program. Recruitment was planned across 55-60 sites in Europe, Israel, Australia, and South Africa.

The study’s primary objective concerned long-term safety and tolerability. Secondary objectives covered efficacy and quality of life, and whether retinal pigmentation, unexplained vision loss, pigmentation of non-retinal ocular tissue, or discoloration of nails, lips, skin or mucosa changed over time after retigabine was stopped. The registry lists 37 outcome measures.

Enrollment is listed as 376. The study status is terminated; the reason for termination is not reported in the registry record. The listed start date is 2006-07-05 and the primary completion date is 2017-04-18. These design details establish the setting for interpreting the results: they describe observations during an extension, not a randomized estimate of retigabine’s effect against a concurrent control.

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 376 adult epilepsy participants with partial-onset seizures who completed the parent study (VRX-RET-E22-302 \[NCT00235755\]) entered this open label extension (OLE) study.

Primary Reporting Phase

Reasons for not completing this period:

Safety Follow-up Continuation Phase

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Population

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 Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAEs), measured over Up to 122 months.

The primary outcome is the number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs), over a timeframe of up to 122 months. An adverse event is defined as an untoward medical occurrence temporally associated with use of a medicinal product, whether or not it is considered related to that product. A serious adverse event is defined by outcomes such as death, a life-threatening event, hospitalization or its prolongation, disability or incapacity, a congenital anomaly or birth defect, and specified other situations associated with impaired liver function.

For this study, a TEAE is an adverse event whose onset was on or after a retigabine dose in the extension and on or before 30 days after the last retigabine dose. An adverse event that began in the parent study and worsened during the extension also counted as a TEAE. The analysis population was the safety population, consisting of participants who took at least one dose after enrollment.

Counting participants with events is useful for describing how many people experienced an event during the defined observation period. It does not, on its own, show when events occurred, how long participants were exposed, or whether retigabine caused an event. Those questions require additional analyses and context; they are not answered by a participant count alone.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count represent?

The primary outcome is expressed as a number of participants with events. In general, this kind of count answers how many people in the analysis population met an event definition during the stated observation period. It is different from a count of all event episodes: one participant may have experienced more than one event, but the participant-level outcome counts that person as a participant with an event. The registry does not report episode counts alongside the primary outcome.

For this study, the safety population includes participants who took at least one dose of study medication after enrollment. That definition helps specify who could contribute to the safety outcome. It does not imply equal follow-up or equal time receiving treatment. A participant count also does not describe event timing, duration, severity beyond the stated classification, or the amount of exposure behind each observation.

How should the event definitions be understood?

The event window is tied to retigabine dosing: onset on or after a dose in the extension and no later than 30 days after the last dose. Worsening of an event that began in the parent study also qualified. These rules determine which events are categorized as treatment-emergent for this endpoint; they are not, by themselves, evidence that treatment caused an event. The serious adverse event definition is based on specified clinical consequences and other stated criteria.

As a general statistical point, clear event definitions matter because a change in the definition or observation window can change which observations are counted. In a long-term extension, differences in time under observation can also affect the opportunity to record an event. Participant counts can be informative descriptively, but event rates that account for time at risk require exposure information and a stated rate analysis. Such an analysis is not reported in the registry record.

What can a single-group design estimate?

The study is non-randomized, open-label and single-group. In general, a single-group study can describe events observed among participants receiving the study treatment in the specified setting. Without a concurrent control group, it cannot use random allocation to balance other causes of outcomes between treatment groups. Changes over time or events during treatment therefore cannot be attributed to retigabine by a randomized comparison within this extension.

Randomization is useful in comparative studies because it supports a fairer estimate of treatment differences by reducing systematic differences between groups on average. That design feature is absent. The parent study was double-blind and placebo-controlled, but this extension is not itself a randomized comparison of those parent-study groups. The registry record does not report a comparative analysis using parent-study assignment.

What do uncertainty measures add?

In general, a confidence interval describes the range of values reasonably compatible with an estimate under a specified statistical model and sampling assumptions. It helps readers assess precision rather than treating a single estimate as exact. The registry record does not report confidence intervals for the primary adverse event counts. It also does not report a hypothesis test for those counts. As a result, the registered figures do not quantify statistical uncertainty in the way an interval or model-based estimate would.

General statistical methods for counts may need to account for unequal observation time, repeated events, or greater variation than a simple model assumes. Over-dispersion, for example, means that observed variability is greater than a model’s expected variability; ignoring it can make uncertainty estimates too narrow. These are general considerations, not methods documented for this study. The registry record does not report a model for recurrent events, exposure adjustment, covariate adjustment, or a method for estimating uncertainty.

What does the sample-size illustration mean?

General planning calculations can show how many participants per arm might be needed to detect a chosen fraction of an observed effect under stated assumptions. The registry’s planning description refers to a two-sided significance level of 0.05, equal allocation, and a normal approximation. It says that the effect to detect is a stated fraction of the observed effect. Such calculations are planning illustrations, not observed power and not evidence that the trial was designed with those assumptions.

The same description distinguishes calculations for time-to-event outcomes, which use a total event count, from other outcomes, which use participants per arm. These are general planning conventions. The extension itself is a single-group study, and the registry identifies it as not being a like-for-like control comparison. A planning calculation based on an observed effect should not be mistaken for a randomized treatment effect from this extension. The registry record does not report the trial’s own sample-size justification.

Overall, the statistical information registered for this study is primarily descriptive: the outcome definitions, the safety population, and event counts. The registry does not report a detailed statistical analysis plan, model specification, treatment-effect estimate, or uncertainty interval. Those absences limit what can be inferred beyond the recorded observations.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 37 outcome measures, including the primary adverse event outcome and secondary outcomes concerning ocular pigmentation, skin and other tissue discoloration, visual acuity, visual fields, resolution of abnormalities after discontinuation, and time to resolution of abnormal eye pigmentation. With multiple outcomes, readers need to know which analyses were planned as primary or secondary and whether any adjustment or hierarchy was used to manage the possibility of chance findings across several tests. A multiplicity plan is not reported in the registry record.

The registry lists zero analyses. It therefore does not provide a registered set of statistical comparisons, test results, or confidence intervals for these outcomes. The record does not report whether outcome analyses were adjusted for covariates, how missing observations were handled, or whether any sensitivity analyses were conducted. It also does not describe imputation, censoring rules for the secondary outcomes, or procedures for participants who withdrew before the planned observation period ended. These details are not reported in the registry record.

The primary outcome identifies the safety population as participants who took at least one dose after enrollment. That gives a defined population for the safety assessment, but the record does not provide further information about exclusions from outcome-specific analyses or the handling of incomplete follow-up. The enrollment figure is 376; it should not be assumed that every participant contributed complete data to every listed outcome. Missing-data methods and outcome-specific denominators are not reported in the registry record.

These omissions matter because conclusions about safety, visual findings, or changes after discontinuation can depend on how incomplete observations and multiple outcomes are handled. The registered event counts remain descriptive; they do not substitute for a prespecified multiplicity strategy or a transparent account of missing data.

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 (4.3%), epilepsy (1.6%), generalised tonic-clonic seizure (1.3%), status epilepticus (1.3%), psychotic disorder (1.1%).

The registry reports 78 participants in the serious adverse event category, 239 in the other adverse event category, and 7 deaths. The at-risk count is 376 for each of the two adverse event categories. The primary outcome timeframe is up to 122 months, and the safety population includes participants who took at least one dose after enrollment.

These counts describe events recorded in the retigabine group. The record does not establish that an event was caused by retigabine, and it does not provide a concurrent control group for comparison. The listed serious event terms include seizure (4.3%), epilepsy (1.6%), generalised tonic-clonic seizure (1.3%), status epilepticus (1.3%), psychotic disorder (1.1%), and dizziness (0.8%). The percentages should be read as reported for those terms, not as a complete account of all possible events.

Participants could have different lengths of follow-up, and the registry does not report exposure-adjusted rates or the distribution of follow-up time. The counts therefore do not express risk per unit of treatment exposure. The record also does not report whether event categories or listed terms overlap at the participant level. They are descriptive safety results, not a causal comparison.

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

The posted results describe safety observations during an open-label retigabine extension among adults with partial-onset seizures who had completed the parent study. The registry reports counts for serious and other adverse events and deaths, with a specified safety population and event window. This information provides a record of events observed under the study’s definitions and follow-up structure.

The results do not establish that retigabine caused the reported events. There was no concurrent randomized control group in the extension, and the participants continued existing antiepileptic treatment or vagal nerve stimulation. The results also do not quantify how outcomes would have differed without retigabine. A parent study’s placebo-controlled design does not make the extension itself a controlled comparison.

The registry record does not report results for the secondary efficacy or quality-of-life objectives. It also does not provide outcome results for the listed retinal, non-retinal ocular, skin, visual acuity, visual field, or post-discontinuation assessments. The stated objectives should therefore not be mistaken for findings. No registered statistical analyses are listed, and confidence intervals, comparative estimates, and missing-data methods are not reported.

The study status is terminated, but the reason is not reported in the registry record. The outcome counts and the long maximum timeframe do not show that every participant was followed for the same duration. Interpretation is further limited by the absence of exposure-adjusted rates and by the lack of detail about outcome-specific denominators. In short, the registry record supports a descriptive account of recorded safety events, while leaving important questions about comparison, precision, causation, and the secondary objectives unanswered.

13. Why This Trial Matters Statistically

This study is statistically important as an example of the distinct role of an open-label extension. It follows participants who completed a double-blind parent study and records longer-term observations during continued treatment. Such follow-up can describe events and outcomes in a treatment setting that differs from a controlled comparison. It does not preserve the causal advantages of randomization within the extension itself.

The distinction between event counts and comparative estimates is central. The registry records counts for adverse event categories and identifies the safety population, but does not report uncertainty intervals or an exposure-adjusted analysis. A count can communicate what was recorded without establishing the rate over time or the treatment’s causal contribution. When follow-up duration varies, time at risk is a relevant part of interpretation, and it is not described in sufficient detail for an exposure-based estimate.

The study also illustrates why the presence of many planned outcomes does not itself provide evidence for each objective. The registry lists 37 outcome measures, spanning safety, vision and pigmentation, and other domains, but lists zero analyses. Without registered outcome results and information about multiplicity, missing data, and analysis methods, the secondary questions cannot be resolved from the record.

Finally, the record distinguishes a study’s objectives from its reported results. Long-term safety, efficacy, quality of life, and changes after discontinuation are objectives described for the study; the available registered results are safety counts. Keeping that distinction clear prevents planned assessments from being read as demonstrated 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 design limits causal interpretation: this was a non-randomized, open-label, single-group extension with no concurrent control. Participants had completed the parent study and met extension eligibility criteria, so the observations apply to that selected study population and should not automatically be generalized to people outside it. The registry does not report a comparison by parent-study assignment.

The safety population includes participants who took at least one dose, but the record does not describe outcome-specific denominators, the distribution of follow-up, or exposure time. Although the primary timeframe is up to 122 months, that maximum does not establish that each participant was observed for the full period. Counts without exposure-adjusted rates cannot account for differences in time at risk.

The record lists 37 outcomes but no registered analyses. Statistical methods for estimating uncertainty, handling missing data, addressing multiplicity, or analyzing repeated events are not reported. Nor does the record give confidence intervals or comparative estimates. These omissions constrain assessment of precision and of the secondary objectives.

The study is marked terminated, but its reason for termination is not reported in the registry record. The record also does not clarify overlap among adverse event terms or categories. Finally, it reports safety counts but not results for the stated efficacy, quality-of-life, or post-discontinuation pigmentation and vision objectives. These are limits of the registry information and should be kept distinct from conclusions about outcomes that are not reported.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Open-Label Extension Study of the Phase 3 VRX-RET-E22-302 Double-Blind Trial. 115097 — NCT00310388.
• Registry record last updated 2018-11-15; status last verified 2018-10.
• Results first posted 2018-06-06.
• 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

NCT00310388 is a Phase 3, open-label extension of the double-blind VRX-RET-E22-302 study. It enrolled 376 adults with epilepsy and partial-onset seizures to receive adjunctive retigabine, also called ezogabine, alongside existing antiepileptic drugs or vagal nerve stimulation. The study was non-randomized and single-group, with no concurrent comparator. Its primary objective concerned long-term safety and tolerability.

The registry reports 78 participants in the serious adverse event category, 239 in the other adverse event category, and 7 deaths. The listed timeframe was up to 122 months. It lists 37 outcome measures and zero analyses. Efficacy, quality-of-life, and detailed ocular or pigmentation outcome results are not reported in the registry record. The study status is terminated; the reason is not reported.