Long-term, Open-label Safety Extension Study of Retigabine/Ezogabine in Pediatric Subjects (>= 12 Years Old) With POS or LGS: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Long-term, Open-label Safety Extension Study of Retigabine/Ezogabine in Pediatric Subjects (>= 12 Years Old) With POS or LGS (NCT01668654), a na phase 3 study. The primary outcome is Number of Participants (Par.) With Any Adverse Event (AE) or Serious Adverse Event (SAE) During the Treatment Period.

2. Clinical Question

3. Trial Design

This was a Phase 3, long-term, open-label safety extension study of retigabine/ezogabine. Its registry title identifies participants with partial onset seizures or Lennox-Gastaut syndrome, and the brief summary says participants had taken part in a previous parent study. The study was intended to evaluate long-term safety and tolerability when the medicine was used as adjunctive treatment.

The design is recorded as single group, with no masking and allocation listed as not applicable. The only arm is Retigabine/Ezogabine TID; the arm description specifies add-on therapy administered three times a day based on weight. Enrollment is recorded as 4. Because there is no reported concurrent comparison arm, the outcome data do not support a randomized, like-for-like comparison between treatments.

The study start date is 2012-09-04, and the primary completion date is 2013-06-18. Its status is terminated. The registry record does not report why the study was terminated, how long each participant was followed, or whether the planned follow-up period was completed by every participant. The primary outcome timeframe allows follow-up up to 178 days, but that maximum does not establish the actual follow-up duration for each participant.

The registry lists 37 outcome measures. Secondary outcomes include seizure-frequency change, responder counts, clinician global-impression assessments, child health status for participants younger than 18 years, and pharmacokinetic measures. The registry record does not report analyses for these outcomes. The primary outcome is a count of participants with adverse events, not a comparison of seizure outcomes or a measure of efficacy.

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: Eligible par. began the Treatment Period at the eligibility assessment Visit followed by a 3-week Taper Phase, and a Follow-Up Visit within 3 days from the end of the Taper Phase. The study was prematurely discontinued after enrolling only 4 of the planned 500 par.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All Subjects Population: all participants who enrolled in the study.

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 (Par.) With Any Adverse Event (AE) or Serious Adverse Event (SAE) During the Treatment Period, measured over From the start of study medication until the end of Follow-Up (up to 178 days).

The primary endpoint counts participants with any adverse event or serious adverse event during the treatment period. The registry defines an adverse event as an untoward medical occurrence temporally associated with study medication, whether or not considered related to that medication. A serious adverse event is defined by specified consequences, including death, a life-threatening event, hospitalization or prolonged hospitalization, disability or incapacity, or a congenital anomaly or birth defect. Medical or scientific judgment could also inform reporting in other situations.

The endpoint is useful for describing the safety experience during exposure and follow-up. Counting participants with an event gives a direct summary of how many people in the study group were recorded as affected, rather than a measure of event severity, duration, or frequency per person. The primary timeframe begins with study medication and extends through the end of follow-up, up to 178 days.

In the posted results, the group has four participants at risk for any adverse event and four affected. For serious adverse events, four are listed at risk and zero affected. The registry record does not report event-level detail for serious events, and the serious-event terms list is empty. These participant counts do not establish whether an event was caused by treatment. Nor do they describe the safety experience beyond the reported follow-up period or establish a comparison with another treatment.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary participant-level outcome: a participant either appears in the count of people with an event during the specified period or does not. The registry expresses the result as a number of participants, with separate counts for any adverse event and serious adverse event. This is different from counting every individual event. One participant could experience multiple events, but the endpoint as described counts participants with an event rather than giving a total event count.

What does a participant count tell us?

A count is a direct description of the observed group. Its interpretation depends on knowing who was eligible for the outcome and the observation period. The registry identifies the primary population as all participants who enrolled and gives the timeframe as the period from the start of study medication to the end of follow-up, up to 178 days. The posted safety information lists four at risk for each adverse-event category. The record does not provide further details about exposure or follow-up for each participant.

In general, a count by itself does not describe uncertainty or allow comparison with a different group. Statistical estimates such as a confidence interval can express uncertainty around an estimated event frequency, but no interval is reported in the registry record. A p-value or model-based estimate is also not reported for the primary outcome. The record lists zero analyses, so the reported result should be read as descriptive rather than as an inferential analysis.

Why does the design affect interpretation?

A randomized comparison can help distinguish treatment-related differences from differences that arise because the groups have different characteristics or experiences. This study is recorded as a single-group study with no masking and no applicable allocation. There is no reported concurrent control group against which to estimate a treatment contrast. Therefore, methods that compare outcomes between randomized groups are not applicable to interpreting the reported count as a treatment effect.

In general, open-label studies can be useful for observing outcomes during treatment, but knowledge of treatment assignment may affect reporting or assessment. That general possibility does not establish that it affected the results in this study. The registry record does not report whether outcome assessment was blinded, how events were elicited, or what steps were used to standardize event recording.

What does over-dispersion mean for count data?

In general, over-dispersion describes count data that vary more than a statistical model expects. It matters when investigators model event counts, because uncertainty can be understated if the model assumes less variability than the data exhibit. The primary outcome is reported as the number of participants with an event, not as a modeled count of repeated events per participant. The registry record does not report a model, a dispersion estimate, or an analysis that addresses over-dispersion. It would therefore be inappropriate to infer that such a method was used.

Other listed outcomes involve different kinds of measurements. Seizure frequency, responder status, global-impression assessments, child health status, and pharmacokinetic measures would not all be interpreted with the same statistical approach. The registry record names these outcome areas but reports no analyses for them. It does not report the analysis populations, model specifications, missing-data procedures, or outcome-specific estimates.

How should planning illustrations be understood?

Sample-size calculations are planning exercises, not evidence about the observed treatment effect or the certainty of a study's findings. The stated assumptions for planning illustrations include a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is described as a stated fraction of the observed effect. For time-to-event outcomes, the stated convention is a total event count, while other illustrations refer to participants per arm for a power target.

Those are generic planning assumptions, not a report of this study's design. The actual study is single group, with allocation recorded as not applicable, and the registry does not report its own sample-size justification or a statistical plan. An illustration based on an effect cannot be treated as observed power, nor does it replace the uncertainty assessment that would come from an appropriate analysis. The record does not provide such an analysis for the primary safety endpoint.

In general, interpretation also depends on whether the study population and follow-up align with the question of interest. Participants came from a parent study, and the stated purpose was long-term safety and tolerability. The registry information describes that context but does not establish how representative the enrolled participants were, whether all eligible participants entered the extension, or how outcomes among those who did not enroll might differ. These unknowns constrain extrapolation beyond the participants described by the record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 37 outcome measures, including the primary adverse-event count and secondary outcomes covering seizure frequency, responder status, clinician global impressions, child health status, and pharmacokinetic measures. When many outcomes are considered, multiplicity can matter: in general, the more statistical tests conducted, the greater the chance of finding an apparently notable result by chance. The registry record does not report a multiplicity adjustment, a hierarchy of secondary outcomes, or an analysis plan specifying how multiple outcomes were to be interpreted.

The record lists zero analyses. It therefore does not provide analysis estimates or tests for the primary outcome or the listed secondary outcomes. No procedures for missing outcome data, participant withdrawal, or incomplete follow-up are reported. The primary population is described as all participants who enrolled, but the registry record does not explain how that population was handled in each outcome analysis.

Missingness is important because participants with incomplete follow-up may have less opportunity for an event to be recorded, and missing measurements can affect interpretation in different ways depending on why they are absent. In general, statistical approaches to missing data require assumptions about the reasons information is unavailable. No such assumptions or methods are reported. The registry record also does not report whether any outcome data were missing or how incomplete observations, if any, were treated.

These reporting gaps mean that the posted counts can be described, but the record does not support a fuller assessment of multiplicity, missing-data sensitivity, or the consistency of analysis populations across outcomes.

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

For any adverse event, the registry lists four participants at risk and four affected. For serious adverse events, it lists four at risk and zero affected. These are participant counts during the stated period, from the start of study medication through the end of follow-up, up to 178 days. They are not counts of every separate event or estimates of events per unit of time.

The registry's definition of an adverse event includes a medical occurrence temporally associated with study medication whether or not it was considered related to the medication. A serious adverse event is categorized by specified consequences, with medical or scientific judgment also relevant in other situations. Thus, the any-event count should not be interpreted as a count of confirmed medication-caused events.

The serious-event terms list is empty, and the posted serious-event count is zero. This describes the recorded result in the enrolled group; it does not establish that serious events cannot occur or that the risk is zero in other populations. The death count is not reported in the registry record. Event details, timing, duration, and assessments of relatedness are not reported in the primary safety summary.

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

The result establishes what the registry reports for this study group: four participants were recorded with any adverse event, and zero were recorded with a serious adverse event during the defined treatment and follow-up period. The counts provide a compact description of safety reporting among the enrolled participants. They do not give a detailed account of event types, recurrence, timing, severity outside the serious-event classification, or the judgments made about relationship to study medication.

The result does not show whether the medicine caused any particular event. The adverse-event definition explicitly includes events whether or not considered related to the study medication. Without a concurrent comparison group, the study cannot estimate how the observed counts differ from counts under another treatment or without the study medication. The open-label, single-group design also means the registry results should not be interpreted as a randomized comparison.

Zero serious adverse events in the posted count is not proof that the chance of a serious event is zero. General statistical reasoning recognizes uncertainty around observations, especially when the group is small; the registry does not report a confidence interval or other uncertainty estimate. Nor does a zero count establish that other populations or longer observation periods would have the same experience.

The study's aim was long-term safety and tolerability in participants coming from a parent study, but the registry record does not report why the study was terminated or whether every participant completed the intended follow-up. The maximum stated follow-up is up to 178 days, and the record does not give each participant's actual observation time. These details limit conclusions about duration and completeness of safety surveillance.

Accordingly, the defensible interpretation is descriptive: the registry records adverse-event counts for this treatment group. It does not establish comparative effectiveness, comparative safety, causation, or generalizability beyond the study participants and observed period. The absence of recorded analyses means that no adjusted or inferential result should be attributed to the registry data.

13. Why This Trial Matters Statistically

This study illustrates an important distinction between a safety observation and a comparative treatment effect. A single-group extension can record adverse events among participants who continue from a parent study. Such information contributes to the description of experience during treatment, but without a concurrent comparator it cannot isolate how much of that experience is attributable to treatment rather than to underlying illness, other circumstances, or chance.

It also shows why denominators and outcome definitions matter. The registry separately reports participants at risk and participants affected for any adverse event and serious adverse event. The any-event definition is broad and does not require that an event be judged related to medication. The serious-event definition reflects specified consequences. Interpreting these as distinct classifications, rather than treating them as interchangeable measures, is essential to accurate reading.

The small enrollment and the absence of reported inferential analyses further limit precision. A count can communicate the observed experience clearly while leaving substantial uncertainty about what might be seen in a larger or different group. General statistical methods can quantify uncertainty when the design and data support them, but the registry record does not report such an estimate for the primary endpoint.

Finally, the extension-study context matters. Participants had taken part in a parent study, so the enrolled group represents that pathway into follow-up rather than a general sample of all people with the conditions named. The record's counts are useful as a narrowly bounded description, while the design and reporting details define what can and cannot be inferred from them.

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 reports enrollment of 4, and the observed safety counts come from one treatment group. This limits the scope for estimating how often events might occur beyond the enrolled participants. A single-group design also provides no concurrent reference for distinguishing outcomes during treatment from outcomes that might occur under another condition or treatment.

The study was open label and unmasked. The record does not describe event ascertainment procedures or whether any outcome assessment was conducted independently of knowledge of treatment. That absence does not show that reporting was biased, but it leaves the potential influence of unmasked assessment uncharacterized.

The primary outcome timeframe extends from the start of study medication to the end of follow-up, up to 178 days. Actual participant-level observation time and the handling of incomplete follow-up are not reported. The registry also does not explain why the study was terminated, whether the intended follow-up was completed, or whether any participants discontinued before follow-up ended.

Safety reporting is limited to the posted participant counts for any adverse event and serious adverse event. The serious-event terms list is empty, and the death count is not reported in the registry record. The primary outcome information does not provide event narratives, event timing, severity detail beyond the serious classification, or relatedness judgments for individual events.

The registry lists 37 outcome measures but records zero analyses. It does not report estimates, uncertainty intervals, tests, missing-data methods, multiplicity procedures, or a statistical analysis plan. Participant characteristics beyond the eligibility context are not reported. These limitations mean the posted counts should be treated as descriptive observations from this extension study, not as a complete analysis of safety or evidence of comparative effects.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Long-term, Open-label Safety Extension Study of Retigabine/Ezogabine in Pediatric Subjects (>= 12 Years Old) With POS or LGS — NCT01668654.
• Registry record last updated 2020-10-30; status last verified 2020-10.
• Results first posted 2014-08-04.
• 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

NCT01668654 is a Phase 3, open-label, single-group safety extension study of retigabine/ezogabine in participants with partial onset seizures or Lennox-Gastaut syndrome who had participated in a parent study. The treatment was described as add-on therapy administered three times a day based on weight. Enrollment is recorded as 4; the study status is terminated.

The primary outcome counts participants with any adverse event or serious adverse event from the start of study medication through follow-up, up to 178 days. The registry reports four affected participants for any adverse event and zero for serious adverse events. It records zero analyses and does not report comparative estimates, uncertainty intervals, or missing-data procedures.

The study design supports a descriptive account of the treatment group's recorded safety outcomes, but not a randomized comparison or a causal estimate. The registry record does not report the reason for termination.