Valproate Dose Reduction and Its Clinical Evaluation by Introducing Lamotrigine in Japanese Women With Epilepsy - Single Arm, Multicenter, and Open-label Study: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Valproate Dose Reduction and Its Clinical Evaluation by Introducing Lamotrigine in Japanese Women With Epilepsy - Single Arm, Multicenter, and Open-label Study (NCT02100644), a na phase 4 study. The primary outcome is Percentage of Participants Who Achieved Reduction in Daily VPA Dose.

2. Clinical Question

The clinical question is about the proportion of participants who reached a lower valproate dose after lamotrigine was introduced, not a comparison of lamotrigine against a concurrent alternative. The registry defined dose reduction as the last valproate dose during the maintenance phase being lower than the baseline dose. The endpoint timeframe was 24-46 weeks, with variation attributed to the durations of the lamotrigine escalation and valproate reduction phases.

The study objective, as stated in the record, was to examine whether valproate dose could be reduced by adding lamotrigine in this population. The record does not report the percentage who achieved the endpoint or its confidence interval. Consequently, it does not establish from the posted primary result how often dose reduction occurred. Its single-group design also means that the endpoint is descriptive of participants’ outcomes under the study approach, rather than a direct estimate of the difference between that approach and a control treatment.

3. Trial Design

This was a Phase 4, open-label, multicenter, single-group study. The registry lists allocation as not applicable and masking as none. Enrollment was 33. The study status is completed; the recorded start date is 2014-04-12 and the primary completion date is 2015-05-11.

The population was described as Japanese pre-menopausal female epilepsy patients aged 15 years or older, with seizures well controlled by valproate monotherapy. Lamotrigine tablets 25/100 mg were the listed intervention. The study objective was to assess whether adding lamotrigine could allow reduction of the valproate dose. The arm description clarifies that valproate was the standard product, not the investigational product.

Without a separate control group, the study cannot estimate a between-group treatment contrast. Participants’ baseline valproate doses provide the reference for the primary endpoint, but a before-and-after assessment is not equivalent to a randomized comparison. Changes over the study period could reflect the study approach as well as other influences that the single-group design cannot separate.

The registry lists seven outcome measures. In addition to the primary dose-reduction percentage, the secondary outcomes include seizure days up to the maintenance phase, age-specific quality-of-life measures, study completion or discontinuation, and adverse events. The listed quality-of-life instruments are QOLIE-31-P for participants aged 18 years and older and QOLIE-AD-48 for participants aged 15-17 years. Detailed information about the study procedures beyond the listed objective, phases, interventions and outcomes is 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 33 participants were enrolled into the study and 20 participants completed the study.

LTG Escalation Phase

Reasons for not completing this period:

VPA Reduction Phase

LTG and VPA Maintenance Phase

Analysis population for the primary outcome, as defined in the registry: Full analysis set (FAS): comprised of all participants in the Safety Population who provided at least one efficacy data after the first dose of the investigational product during the LTG Escalation Phase.

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 Percentage of Participants Who Achieved Reduction in Daily VPA Dose, measured over Baseline and at the end of the LTG and VPA Maintenance Phase, 24-46 weeks that can be varied by durations of the LTG Escalation Phase and VPA Reduction Phase.

The primary endpoint is the percentage of participants who achieved a reduction in daily valproate dose. The registry defines a reduction as the post-baseline valproate dose minus the baseline dose being < 0. Baseline is the dose at the Week 0 visit; the post-treatment value is the last valproate dose during the lamotrigine and valproate maintenance phase. The assessment period is described as 24-46 weeks, varying with the durations of the lamotrigine escalation and valproate reduction phases.

A percentage expresses how common the specified endpoint was among the participants in the analysis population. Using the last maintenance-phase dose anchors the measure to the planned treatment period, rather than to an arbitrary dose observation during escalation. The endpoint therefore addresses whether participants reached a lower dose by the stated endpoint assessment. It does not, by itself, describe seizure control, quality of life, or the safety of reducing valproate; those are distinct outcomes in the registry.

The primary analysis population was the full analysis set: participants in the safety population who provided at least one efficacy datum after their first dose of the investigational product during the lamotrigine escalation phase. The endpoint definition and population are reported, but the observed percentage and its 95% confidence interval are not reported in the registry record. Without those results, the frequency and precision of the primary endpoint cannot be evaluated from the posted record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary outcome as a percentage and names a 95% confidence interval as its measure of dispersion. It does not report a numerical estimate or interval for that outcome. The interpretation below explains the statistical concepts relevant to the stated endpoint; it does not imply that a particular calculation or analysis was performed beyond what the registry record describes.

What does a percentage estimate?

For a binary endpoint such as achieving or not achieving dose reduction, each participant is classified according to whether the endpoint definition is met. The percentage describes the share of the analysis population classified as having achieved the outcome. In this study, the criterion was a last maintenance-phase valproate dose lower than the baseline dose. The percentage is a population summary, not a description of the amount by which each participant’s dose changed. It also does not convey other outcomes, such as seizure days or adverse events.

The result depends on which participants are included in the denominator. The registry defines the full analysis set as participants in the safety population who provided at least one efficacy datum after the first investigational-product dose during lamotrigine escalation. That definition makes the endpoint population more specific than the enrollment count alone. The number in the full analysis set is not reported in the registry record, so the denominator for the primary percentage cannot be confirmed from the posted information.

How should a confidence interval be understood?

A confidence interval expresses uncertainty around an estimate. For a percentage, it gives a range of values compatible with the observed data under the interval method’s assumptions. A narrower interval generally indicates greater precision, while a wider interval indicates more uncertainty. The interval does not resolve limitations in study design: it cannot create a control group, remove bias, or show that the observed proportion would be the same in another population.

The registry states that the primary endpoint is accompanied by a 95% confidence interval, but neither the percentage nor the interval is reported in the registry record. It is therefore not possible to assess the endpoint’s precision, determine whether the interval is wide or narrow, or compare the estimate with a benchmark. No interval method is specified in the record available for this analysis; the precise method used is not reported in the registry record.

Why does the single-group design matter?

A single-group study can describe what happened among participants following a study approach. Here, baseline dose is the reference value for determining dose reduction, and the last maintenance-phase dose is the post-baseline value. This within-participant definition supports a descriptive assessment of dose change. It does not supply the counterfactual outcome: what would have happened to similar participants over the same period without the added lamotrigine and dose-reduction approach.

Randomized concurrent comparisons are one way to estimate differences between treatment strategies while limiting some sources of confounding. This study has no such comparison: allocation is listed as not applicable, the model as single group, and masking as none. Thus, a percentage achieving a lower dose would not be evidence of a comparative treatment effect. Time-related changes, clinician decisions, participant expectations, or other influences cannot be disentangled using the primary percentage alone. These are general interpretive limitations of a single-group, open-label design, not additional outcomes reported by the registry.

What does the endpoint definition contribute?

The threshold is directional: the post-treatment dose must be lower than baseline, rather than equal to or higher. The definition does not require a particular magnitude of reduction. As a result, the primary binary endpoint treats any qualifying reduction alike, even though the actual dose changes might vary. The endpoint also focuses on dose status at the last maintenance-phase assessment. It does not summarize the full dose trajectory during escalation and reduction, nor does it alone establish whether a lower dose was sustained outside the stated assessment period.

The timeframe of 24-46 weeks is described as variable according to the durations of the lamotrigine escalation and valproate reduction phases. The record does not report participant-level time in each phase or how varying assessment duration was handled in the statistical analysis. Further details about the handling of observations taken at different times are not reported in the registry record.

What can be inferred from the safety summaries?

Adverse-event summaries use participants at risk and participants affected. The count of participants with an event is not the same as an event count: one participant may experience more than one event, and a participant count does not communicate how long each person was observed. The record lists 33 at risk for serious adverse events and 4 affected, and 33 at risk for other adverse events and 23 affected. These are descriptive summaries for the LTG plus VPA group.

The top serious terms are listed with percentages. The record does not provide the underlying term counts in the registry record for this analysis, nor does it describe how the terms were grouped or coded. The listed percentages should be read as registry-reported values rather than recalculated. Without a comparison group, exposure-time information, and fuller event detail, these summaries do not estimate relative risk or establish a causal relationship.

What statistical plan is documented?

The registry indicates the primary endpoint’s form and its stated confidence interval, but detailed analysis procedures are not reported in the registry record. The record does not specify the interval construction method, a hypothesis test for the primary endpoint, covariate adjustment, or a missing-data method. Sample-size justification, interim analyses, and a detailed statistical plan are not reported in the registry record. No additional analytic procedures should be presumed from the endpoint description alone.

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("LTG Plus VPA (Phase 1, 2 and 3)")
n      <- c(33)
events <- c(20)
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  LTG Plus VPA (Phase 1, 2 and 3)  33  20  60.6  42.1  77.1  43.7  75.3  43.6  75.4

11. Multiplicity, Missing Data and Analysis Populations

The registry lists seven outcome measures, including the primary percentage achieving valproate dose reduction and secondary outcomes concerning seizure days, quality of life, study disposition and adverse events. The record does not provide a multiplicity strategy describing whether or how inference across outcomes was controlled. It also does not report an outcome hierarchy beyond identifying the primary endpoint. Without a stated approach, separate findings across multiple outcomes should not automatically be treated as confirmatory evidence.

Quality of life was divided by age group: QOLIE-31-P for participants aged 18 years and older and QOLIE-AD-48 for participants aged 15-17 years. The record lists these outcomes but does not provide their estimates, analysis populations, or missing-data handling. Numerical results for the other listed secondary outcomes are also not reported in the registry record.

The primary endpoint population is defined by inclusion in the safety population and availability of at least one efficacy datum after the first investigational-product dose during lamotrigine escalation. This definition identifies an analysis population, but the record does not state how participants lacking later endpoint data were handled. The number contributing to the primary endpoint, the amount of missing endpoint data, and any imputation or other missing-data method are not reported in the registry record.

For the listed completion or discontinuation outcome, the record does not provide numerical results or detailed rules for classifying participants. The registry also does not describe whether participants who discontinued were included in endpoint summaries or how their last dose was treated. These omissions limit assessment of whether missingness or discontinuation could affect the observed percentage. The stated population definition should not be taken as evidence that all enrolled participants contributed to every outcome.

12. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: drug eruption (9.1%), histiocytic necrotising lymphadenitis (3.0%).

The registry’s safety summary lists the LTG plus VPA group, with 33 participants at risk for serious adverse events and 4 participants affected. For other adverse events, 33 participants were at risk and 23 were affected. These values are participant counts, not a count of all event episodes, and they describe only the group listed in the record. No separate control-group figures are available for comparison.

The top serious adverse-event terms are reported as drug eruption at 9.1% and histiocytic necrotising lymphadenitis at 3.0%. The registry entries do not give the corresponding term counts. These percentages are therefore best retained as registry-reported summaries rather than converted into counts. The number of deaths is not reported in the registry record.

Participant-level counts do not convey event timing, duration, recurrence, severity beyond the serious-event classification, or time at risk. The record’s adverse-event outcome also includes categories such as events leading to discontinuation, drug-related events and serious adverse events, but numerical details for those categories are not reported. Because the study is open-label and single-group, the summaries are descriptive and cannot establish whether the observed events were more or less common than under another treatment approach.

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

The study addresses whether valproate dose could be reduced after adding lamotrigine in Japanese pre-menopausal women with epilepsy whose seizures were well controlled on valproate monotherapy. The registry defines a clear primary outcome: the proportion with a last maintenance-phase valproate dose lower than baseline. That definition makes the intended endpoint interpretable, but the result itself is not reported in the registry record.

Without the primary percentage and its 95% confidence interval, readers cannot determine how many participants met the endpoint as a proportion of the analysis population or how precise that estimate was. Enrollment of 33 does not substitute for the endpoint denominator, which is defined by the full analysis set. The size of that set is not reported in the registry record.

Even a reported dose-reduction percentage would answer a descriptive question within this study, not establish a comparative effect. Participants were not assigned to a separate control arm, and the study was open-label. The findings therefore could not, on their own, determine how dose outcomes would differ under an alternative treatment strategy. Nor would the primary dose endpoint alone establish effects on seizure control, quality of life, or safety; these are separate outcomes listed in the registry.

The adverse-event counts and serious-event terms offer descriptive safety information for the LTG plus VPA group. They do not provide a controlled comparison, and the record does not report the death count. The registry’s outcome definitions, design features and safety summaries should be distinguished from results that are absent. In particular, the posted information does not support a conclusion about the frequency of primary endpoint achievement or the comparative balance of benefits and harms.

The most defensible interpretation is limited: this completed study was designed to assess dose reduction after lamotrigine was introduced, and the registry records certain safety counts. The primary outcome estimate and several secondary numerical results are not reported in the registry record. Any broader conclusion would require results and analysis details not present in the record.

14. Why This Trial Matters Statistically

This study is statistically notable for the distinction between a well-defined endpoint and an unavailable endpoint result. The primary question is expressed as a percentage, and the registry specifies how a participant qualifies: the last valproate dose during maintenance must be lower than baseline. It also names a 95% confidence interval. Yet the estimate and interval are not reported in the registry record. Clear outcome definitions help readers understand what was intended to be measured, but they cannot replace the numerical findings needed to assess frequency and precision.

The design also illustrates the difference between a within-participant reference and a controlled comparison. Baseline dose anchors the dose-reduction classification, but there is no concurrent group to show how outcomes compare under another approach. The percentage, if available, would describe observed dose changes in the single group; it would not independently isolate the effect of adding lamotrigine.

The analysis population definition matters as well. The full analysis set required at least one post-dose efficacy datum after the first investigational-product dose during escalation. Because its size and missing endpoint handling are not reported in the registry record, the relationship between enrollment and the primary analysis denominator remains unclear. This is a reminder that a stated enrollment count is not necessarily the denominator for every reported outcome.

Finally, the safety figures show why descriptive counts need careful framing. Participants affected are not the same as event episodes, and counts in a single group do not provide comparative risk estimates. The registry records useful design and outcome definitions, but missing primary results and analysis details limit the statistical conclusions that can be drawn from the available record.

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 main trial-specific limitation is that the primary endpoint’s numerical result is not reported in the registry record. The record gives the definition and states that a 95% confidence interval is used, but does not give the estimate or interval. This prevents assessment of the frequency and precision of the principal outcome.

The single-group, open-label design has no concurrent control group. It can describe participants’ outcomes under the study approach, but cannot distinguish the approach’s effect from other influences over time. The record also does not describe masking, which is listed as none, and does not report a randomized allocation process.

The enrolled count is 33, but the primary population is defined as the full analysis set and its size is not reported in the registry record. The record does not report how missing endpoint measurements, discontinuations, or incomplete follow-up were handled. This matters because the primary measure uses a last maintenance-phase dose, and the assessment period could vary from 24-46 weeks according to phase durations.

The registry lists secondary endpoints and safety categories, but their numerical results are not reported in the registry record for this analysis. The death count is also not reported in the registry record. For the adverse-event terms, percentages are available but term counts and further event details are not. Finally, sample-size justification, interim analyses, and detailed statistical methods are not reported in the registry record. These gaps limit evaluation of precision, missingness, and the full analysis strategy.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Valproate Dose Reduction and Its Clinical Evaluation by Introducing Lamotrigine in Japanese Women With Epilepsy - Single Arm, Multicenter, and Open-label Study — NCT02100644.
• Registry record last updated 2017-11-17; status last verified 2017-10.
• Results first posted 2016-02-01.
• 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

This completed Phase 4 study was a multicenter, open-label, single-group investigation in Japanese pre-menopausal women aged 15 years or older with epilepsy whose seizures were well controlled on valproate monotherapy. Enrollment was 33. The recorded start date was 2014-04-12, and the primary completion date was 2015-05-11. Lamotrigine tablets 25/100 mg were listed as the intervention, with valproate described as the standard product.

The primary outcome was the percentage achieving a lower daily valproate dose at the end of the lamotrigine and valproate maintenance phase, defined as 24-46 weeks depending on phase durations. The registry specifies a 95% confidence interval, but the primary estimate and interval are not reported in the registry record. Safety summaries list 4 participants with serious adverse events and 23 with other adverse events among 33 at risk. The record lists drug eruption at 9.1% and histiocytic necrotising lymphadenitis at 3.0% among the top serious terms. Numerical results for the primary endpoint and listed secondary outcomes are not reported in the registry record.