The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy (NCT00807989), a randomized phase 4 study. The primary outcome is Retention Rate After 52 Weeks Maintenance Period.

2. Clinical Question

3. Trial Design

This was a randomized, multicenter, parallel-group Phase 4 clinical trial sponsored by Yonsei University. The official title describes an open-label comparison of lamotrigine/valproate coadministration and carbamazepine as initial pharmacotherapy in epilepsies. The registry lists epilepsy as the condition and enrollment of 207 participants. The recorded start was 2008-03, primary completion was 2012-05, and the status is completed.

Participants were assigned to carbamazepine or lamotrigine/valproate. Masking was listed as none. That matters when interpreting outcomes: participants and trial personnel could know which treatment was assigned, and expectations or decisions during follow-up could potentially be influenced by that knowledge. The registry record does not describe whether any outcome assessment was independently masked.

The primary outcome is described as a retention rate after a 52-week maintenance period, while its definition says that retention means completion of the 60-week study as planned. These descriptions do not use the same follow-up duration. The registry does not clarify the relationship between the 52-week label and the 60-week completion definition, so interpretation should stay close to the endpoint wording and posted counts.

The arm counts recorded for the primary outcome are 104 for carbamazepine and 98 for lamotrigine/valproate. Each count is also the reported outcome value in its arm. These counts should not be treated as a description of every participant enrolled or as proof that no participants were missing from other outcomes. The registry record does not report detailed analysis populations, participant flow, or a statistical analysis plan.

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.

Overall 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 Retention Rate After 52 Weeks Maintenance Period, measured over 52 weeks.

The primary outcome is titled “Retention Rate After 52 Weeks Maintenance Period.” Its definition says that retention rate means completion rate: the proportion of patients who completed the 60-week study as planned. Retention is a measure of remaining in a study through its planned course, rather than a direct measurement of seizure control. It can therefore reflect the ability or willingness to continue the assigned treatment and study procedures, alongside other influences on completion.

The registry records 104 participants for carbamazepine and 98 for lamotrigine/valproate, with those same numbers entered as the outcome values. The comparison reports a risk difference of 0.0 and a confidence interval from 0.0 to 0.0. On the posted record, the primary endpoint counts are identical to the corresponding arm counts, and the reported comparison indicates no difference in this measure.

The endpoint definition and title leave an important timing ambiguity: the title refers to a 52-week maintenance period, whereas the definition refers to completing a 60-week study. The registry record does not explain this distinction. That uncertainty limits how specifically the endpoint can be described beyond the recorded completion definition and its stated timing.

7. Results Posted in the Registry

• Lamotrigine/Valproate: 100.0% (98/98) versus 100.0% (104/104) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0), risk ratio 1.00 (1.00–1.00); unadjusted two-proportion z-test p = n/a.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Seizure Free Rate for 24 Weeks at Initial Target Dose

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Lamotrigine/Valproate: 75.6% (59/78) versus 56.7% (51/90) on control; risk difference 19.0 percentage points (95% CI 5.0 to 33.0), risk ratio 1.33 (1.07–1.66); unadjusted two-proportion z-test p = 0.010.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Lamotrigine/Valproate than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Seizure Free Rate for 52 Weeks at Initial Target Dose

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Lamotrigine/Valproate: 64.1% (50/78) versus 47.8% (43/90) on control; risk difference 16.3 percentage points (95% CI 1.5 to 31.2), risk ratio 1.34 (1.02–1.76); unadjusted two-proportion z-test p = 0.034.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Lamotrigine/Valproate than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Across the two posted secondary outcomes, the direction of the unadjusted comparison is consistent: the recorded seizure-free count is higher in the lamotrigine/valproate group at each stated follow-up. The confidence intervals for the risk differences exclude zero, and the registry lists unadjusted p-values for both comparisons. Taken together, the outcomes suggest a similar directional pattern across the two follow-up measures, rather than opposing patterns.

That pattern is distinct from the primary endpoint, which measures retention or completion rather than seizure freedom. A completion outcome and a seizure-free outcome are not interchangeable, so a difference in one does not imply a difference in the other. The primary result describes the recorded completion counts; the secondary outcomes describe seizure-free counts among the denominators recorded for those specific outcomes. The registry does not provide enough detail to explain why those denominators differ from the primary counts.

Secondary results generally carry less weight when several outcomes are examined, especially when the analysis plan and any multiplicity procedure are not reported. Testing multiple outcomes increases the chance that at least one result will appear notable by chance. The registry record does not say whether these outcomes were prespecified, how many outcomes were considered during analysis, or whether adjustments were made. Their unadjusted comparisons are therefore useful descriptive evidence, but they do not by themselves establish a definitive treatment effect.

The secondary outcomes also do not resolve the uncertainty in the primary endpoint’s wording. The registry title refers to a 52-week maintenance period, while the completion definition refers to the 60-week study. The seizure-free outcomes have their own stated timeframes at the initial target dose. Keeping these outcome definitions separate avoids treating the results as measurements of a single common endpoint.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Seizure Free Rate for 24 Weeks at Initial Target Dose
• Seizure Free Rate for 52 Weeks at Initial Target Dose

9. Statistical Interpretation

10. Statistical Methods Explained

The outcomes are binary counts: the record reports how many participants had the outcome in each group. For a binary outcome, a risk is the proportion of participants in a group who experienced the event. A risk difference compares those proportions by subtracting one group’s risk from the other’s. A positive risk difference in the posted secondary comparisons means the recorded event proportion is higher in the lamotrigine/valproate group; for seizure freedom, that describes a higher observed seizure-free proportion in that group. This is a statistical description, not a clinical recommendation.

What the risk difference expresses

The primary risk difference is reported as 0.0, with limits also reported as 0.0 and 0.0. The secondary risk differences are positive, and their confidence intervals exclude zero. A confidence interval expresses a range of values compatible with the observed data under the method used to construct it. It does not show the probability that the true effect lies in the interval, and it does not account for sources of bias that the analysis method does not address.

Risk ratios and odds ratios are other ways to compare binary outcomes. A risk ratio compares the outcome risks in the groups, while an odds ratio compares their odds. These measures use different scales and should not be read as interchangeable with a risk difference. The secondary outcomes have posted risk-ratio and odds-ratio estimates, but interpretation should take account of the event definition, group denominators, and uncertainty intervals. The record does not report adjusted estimates from a model.

What a p-value can and cannot say

A p-value describes how unusual data at least as discrepant as those observed would be under a specified null model and its assumptions. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. The registry lists unadjusted p-values of 0.01 for the 24-week seizure-free outcome and 0.034 for the 52-week seizure-free outcome. No p-value is needed to describe the primary risk difference, which is reported as zero with a zero-width interval. The registry record does not report a multiplicity adjustment or the complete analysis plan behind these comparisons.

Random allocation is intended to make the assigned groups comparable on average, including for characteristics that were not measured. It does not guarantee balance in a particular trial, and it does not prevent bias after allocation. This trial was open label, so knowledge of assignment may have affected participant behavior, follow-up, or outcome assessment. The registry does not state whether outcome assessors were masked or describe methods to limit such influences.

Planning illustrations are not observed power

The planning illustrations use the observed secondary-outcome effects as a starting point and consider detecting the full observed effect, 75% of it, or 50% of it. They assume a two-sided significance level of 0.05, equal allocation, and a normal approximation. The listed values are participants per arm for 80% power and participants per arm for 90% power under those assumptions. They are illustrations of sample sizes under hypothetical planning choices, not evidence that the completed trial had a particular power and not estimates of power observed after the results were known.

The sample sizes change across those illustrations because a smaller effect is harder to distinguish from random variation, all else being equal. This is a general statistical principle. The registry record does not report that these assumptions were used to design the trial, nor does it report the trial’s own sample-size justification. The illustrations therefore cannot be used to infer the original design target.

Limits of the reported analysis detail

The registry lists no reported analyses for the secondary outcomes. The record does not specify the statistical tests, model adjustments, handling of missing data, analysis population, or whether the outcome comparisons were prespecified. Without that information, the posted counts and unadjusted comparisons can be described, but the analysis cannot be fully reproduced or checked against a complete protocol. The meaning of over-dispersion is not central to these binary-count outcomes; in general, over-dispersion describes variability beyond what a chosen statistical model expects and can make standard uncertainty estimates too narrow if not addressed.

11. Confidence Intervals and Precision

The primary comparison is reported with a risk difference of 0.0 and a confidence interval from 0.0 to 0.0. As recorded, this interval indicates no estimated difference in the primary completion measure and no interval width. The arm counts and outcome values are identical within each arm. The registry record does not explain why the interval has zero width, and it does not provide additional detail about the calculation. That absence makes it important to report the number as recorded rather than infer a different precision estimate.

For the two secondary seizure-free outcomes, the posted confidence intervals for the risk differences exclude zero. This indicates that the unadjusted intervals do not include no difference under their calculation method. The interval for each outcome nevertheless spans a range of possible effect sizes, and the point estimate alone does not capture that uncertainty. The registry does not describe a multiplicity adjustment, so the intervals should not be treated as if they jointly preserve a stated overall confidence level across all outcomes.

Confidence intervals address sampling variability under a statistical method. They do not automatically account for open-label assessment, outcome selection, missing data, or ambiguity in the endpoint definition. The reported secondary denominators are smaller than the primary arm counts, but the record does not explain the reasons for that difference. Precision therefore needs to be considered alongside the incomplete information about analysis populations and follow-up.

The planning illustrations also show how required sample size depends on the assumed effect and target power. Those values are hypothetical planning quantities, not precision estimates for the completed trial and not observed power. They do not remove uncertainty about whether the trial was originally designed around these assumptions.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists two secondary seizure-free outcomes and reports unadjusted comparisons for each. It does not report a multiplicity adjustment, a hierarchy for testing outcomes, or a statistical analysis plan explaining how the primary and secondary questions were intended to be interpreted together. When multiple outcomes are tested, the chance of at least one apparently unusual result can increase. Adjustment procedures can address that issue, but the record does not say whether one was planned or used.

The record lists no reported analyses for the secondary outcomes. This does not establish that no analysis was conducted; it means the registry entry does not describe reported analyses beyond the posted summary comparisons. The record does not identify the analysis population, whether the comparisons followed the randomized assignment regardless of treatment received, or whether any other population was used.

Information about missing outcome data is also limited. The registry gives arm counts for the primary and secondary outcomes, but does not explain why the denominators differ across outcomes, whether participants withdrew, or how missing outcomes were handled. It does not report imputation, sensitivity analyses, or reasons for non-completion. These omissions matter because missingness can affect both the estimated outcome proportions and the groups to which those estimates apply.

The primary endpoint has an additional reporting ambiguity: it is titled as retention after a 52-week maintenance period but defined as completion of the 60-week study. The record does not clarify the intended endpoint timing or how that wording maps to the posted counts. These limitations do not invalidate the recorded numbers, but they constrain the interpretation and prevent a full assessment of the analysis choices.

13. 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: meningoencephalitis herpetic (1.0%), pneumonia (1.0%), alcoholic seizure (1.0%), atonic seizures (1.0%), ventricular tachycardia (1.0%).

The registry records serious adverse events for 9 participants in the carbamazepine group and 0 in the lamotrigine/valproate group. It records other adverse events for 60 participants and 59 participants, respectively. These are participant counts in the registry’s safety summary; they are not by themselves adjusted comparisons or estimates of causal effects.

The listed serious-event terms are Meningoencephalitis herpetic, Pneumonia, Alcoholic seizure, Atonic seizures, Ventricular tachycardia, and Joint dislocation, each reported as 1.0%. The record does not establish from this listing which group each term belongs to, nor does the listing necessarily describe every serious event. Death counts are not reported in the registry record.

A zero count in one group means no serious adverse event was recorded for that group in this summary. It does not show that the underlying risk is zero. The registry does not report exposure-adjusted rates, event timing, severity details, or a statistical comparison for safety. The counts should therefore be read descriptively, with attention to the limited safety detail.

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

The posted primary result describes equal retention/completion counts relative to the arm counts: 104 for carbamazepine and 98 for lamotrigine/valproate. The risk difference is reported as 0.0, with a confidence interval from 0.0 to 0.0. This supports a narrow statement about the recorded primary outcome. It does not establish that the groups were identical on every outcome or that there were no differences in other aspects of treatment or follow-up.

The secondary seizure-free outcomes show a different pattern in their recorded counts, with higher counts in the lamotrigine/valproate group at both stated timeframes. Those results are unadjusted, and the registry does not report a multiplicity procedure or full analysis plan. They should not be treated as conclusive evidence about all relevant outcomes. Nor does the registry entry by itself establish a causal explanation for the observed differences.

The record does not provide enough detail to resolve missing-data handling, analysis populations, or the timing ambiguity in the primary endpoint definition. The trial was open label, which is relevant to interpretation of outcomes that may be influenced by behavior, reporting, or assessment. The posted results also do not describe the doses in detail or provide a complete account of treatment exposure.

These findings are statistical descriptions of the registry record, not medical advice. They do not determine which treatment is appropriate for an individual, and they do not settle the balance of benefits and harms. The interpretation is bounded by the outcomes and analysis details recorded in the registry.

15. Why This Trial Matters Statistically

This trial is statistically informative because it juxtaposes a completion endpoint with seizure-free outcomes. Retention and seizure freedom measure different things. Reading them as separate questions prevents a completion result from being mistaken for a clinical outcome, or a secondary seizure-free pattern from being treated as a replacement for the primary endpoint.

The record also illustrates why endpoint definitions need to be read closely. The primary outcome title refers to a 52-week maintenance period, while the definition describes completion of the 60-week study. That difference in wording affects what the endpoint can be said to measure and when it is assessed. The registry does not resolve the distinction, so readers should avoid assuming a more precise definition than the record gives.

Another statistical issue is the distinction between unadjusted secondary comparisons and a complete confirmatory analysis. The secondary outcomes share a directional pattern, but the record does not state how multiple testing was handled, whether the outcomes were prespecified, or how missing data were addressed. This is a useful reminder that numerical estimates need to be interpreted alongside design and analysis transparency.

Finally, the sample-size illustrations are explicitly based on observed effects and hypothetical planning assumptions. They can show how different effect assumptions relate to planning sample sizes, but they cannot tell readers what power the trial actually had or what assumptions informed the original design. The registry does not report the original sample-size justification.

16. 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.

Several trial-specific limitations constrain interpretation. The study was open label, with masking listed as none. The record does not state whether outcome assessors were masked, so the extent to which assessment could have been influenced by knowledge of treatment assignment is unclear.

The primary endpoint wording is not fully aligned: the title refers to a 52-week maintenance period, while the definition describes completion of a 60-week study. The registry record does not explain this difference. The primary result is reported with a risk difference and confidence limits all equal to 0.0, but the record does not provide calculation details to explain the zero-width interval.

For secondary outcomes, the record lists no reported analyses and does not describe a statistical analysis plan, multiplicity adjustment, or analysis population. It also does not explain the differing denominators across the primary and secondary outcomes or report missing-data handling. These details limit reproducibility and make it difficult to assess potential bias from exclusions or incomplete follow-up.

The safety summary gives participant counts and selected serious-event terms, but does not provide event timing, exposure-adjusted rates, or a formal comparison. Death counts are not reported in the registry record. The trial’s sample-size justification is also not reported in the registry record; the planning illustrations based on observed effects cannot fill that gap.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy — NCT00807989.
• Registry record last updated 2015-07-27; status last verified 2015-06.
• Results first posted 2015-05-29.
• 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.

20. Record Summary

The registry record describes a completed, randomized, open-label, parallel-group Phase 4 trial sponsored by Yonsei University. It enrolled 207 participants with epilepsy and compared carbamazepine with lamotrigine/valproate combination therapy. The recorded start was 2008-03, and primary completion was 2012-05.

The primary outcome was retention/completion, with a stated 52-week title and a definition referring to completion of the 60-week study. The posted comparison reports a risk difference of 0.0 and a confidence interval from 0.0 to 0.0. Two secondary seizure-free outcomes have positive unadjusted comparisons favoring higher recorded counts in the combination group, but no reported analyses are listed and the record does not describe multiplicity or missing-data methods.

Serious adverse events were recorded for 9 participants in the carbamazepine group and 0 in the combination group; other adverse events were recorded for 60 and 59 participants. The registry does not report death counts. Key details, including the analysis plan, sample-size justification, and explanation of endpoint timing, are not reported in the registry record.