Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients (NCT00522418), a randomized phase 4 study. The primary outcome is Overall Quality of Life in Epilepsy-89 (QOLIE-89) Score in Patients With Baseline & at Least One Post-baseline QOLIE Assessment.

2. Clinical Question

The trial addressed a post-market comparison of adjunctive VNS Therapy with best medical practice against best medical practice alone. Its primary outcome was change from baseline in the QOLIE-89 overall score at 12 months. The measure is intended to capture quality of life across several domains, including emotional well-being, social functioning, energy, seizure-related worry, medication effects, attention, memory, physical function, pain, and health perceptions. Scores range from 0 to 100, with higher scores indicating better quality of life.

The registry reports mean changes of 5.5 units in the VNS Therapy group and 1.2 units in the best-medical-practice group among the participants included in the primary analysis. The estimated between-group difference, expressed as best medical practice minus VNS Therapy, is -4.3 units. These are results at the 12-month assessment, not a complete account of all follow-up: the record states that 24-month data were unavailable after early termination and that only a few patients achieved 2-year follow-up.

The clinical question is about the observed group contrast in this trial, not whether either approach is effective in other settings. The registry record does not report enough information to establish how participants who lacked an eligible assessment differed from those included in the analysis.

3. Trial Design

This was a phase 4, randomized, parallel-group study with no masking. It was sponsored by Cyberonics, Inc. and registered as NCT00522418. The study began in 2006-02, had a primary completion date of 2008-07, and its status is listed as terminated. Enrollment was 122. The registry describes the study as a post-market medical device study comparing best medical practice with or without adjunctive VNS Therapy in patients aged 16 years and older with pharmacoresistant partial epilepsy.

Participants were assigned to VNS Therapy plus best medical practice or to best medical practice alone. Because masking was listed as none, the study was open-label: participants and study personnel were not masked to assignment according to the registry entry. The record identifies random allocation and a parallel model. Further details of the randomization procedure, allocation concealment, or the timing and reasons for termination are not reported in the registry record.

The primary outcome was the mean change from baseline in QOLIE-89 overall score at 12 months. The registry describes the outcome population as those with a baseline and at least one post-baseline QOLIE assessment, and notes that data were available for analysis at 12 months. The posted group summaries include 31 participants in the VNS Therapy group and 29 in the best-medical-practice group. The registry says 24-month data were unavailable because of early study termination and only a few patients (n=7) reached 2-year follow-up.

The registry lists 22 outcome measures and 6 analyses. It does not report the trial's original sample-size justification, detailed statistical analysis plan, or the full set of procedures used to handle missing measurements. The displayed outcome counts should therefore be read as analysis-specific, not as a replacement for a complete participant flow account.

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: Patients were randomized in a 1:1 ratio to the Best Medical Practice With Adjunctive VNS Therapy study group or to the Best Medical Practice Without VNS Therapy study group. VNS Therapy is delivered by an implantable device similar to a pacemaker that sends mild stimulation to the left vagus nerve to help improve seizure control.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Due to early study termination \& only a few patients (n=7) achieving 2 year follow-up, study data for the 24 month time point is not available. However, at the 12 month time point there was an adequate amount of patient study data for analysis. This outcome measure evaluates the data for sixty (60) patients.

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.

Population: All participants who completed the baseline assessment and at least one postbaseline follow-up QOLIE-89 assessment, and met local IRB consent requirements

6. Primary Endpoint

The registry lists the primary outcome as Overall Quality of Life in Epilepsy-89 (QOLIE-89) Score in Patients With Baseline & at Least One Post-baseline QOLIE Assessment, measured over Mean change from baseline QOLIE-89 Overall Score at 12 months.

The primary endpoint is mean change from baseline in the QOLIE-89 overall score at 12 months. The QOLIE-89 contains 17 multi-item measures covering aspects of quality of life such as emotional well-being, social support, energy and fatigue, seizure-related worry, medication effects, cognitive function, physical function, and health perceptions. Its score ranges from 0 to 100, with higher scores reflecting better quality of life.

Using change from baseline focuses the comparison on how the recorded score shifted from each participant's starting assessment. The between-group contrast then asks whether the average change differed between randomized groups. This is a continuous outcome: each participant's score can take a range of values rather than falling into only two categories. Reporting a mean and standard deviation describes the average change and the spread of observed changes within each group.

Quality of life is a patient-reported dimension that complements outcomes such as seizure frequency. It is relevant to the study's stated comparison because an intervention's overall experience may involve more than the frequency of seizures alone. That general rationale does not establish that the endpoint captures every outcome important to patients, or that a given score change is clinically meaningful. A threshold for clinically important change is not reported in the registry record.

The primary result pertains to patients with baseline and at least one post-baseline QOLIE assessment, as described in the record. The registry notes that 12-month data were available for analysis but gives no further detail about missing-item rules, the analysis population definition, or methods used for missing follow-up assessments.

7. Results Posted in the Registry

• Best Medical Practice: mean 1.20 versus 5.50 on control; difference -4.30 (95% CI -7.87 to -0.73), standardized effect d = -0.61; z-test p = 0.018.

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.

Response Rate

• 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:
  • Best Medical Practice: 24.1% (7/29) versus 32.3% (10/31) on control; risk difference -8.1 percentage points (95% CI -30.8 to 14.5), risk ratio 0.75 (0.33–1.70); unadjusted two-proportion z-test p = 0.485.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Best Medical Practice and the control. The interval gives the range of effects that remain compatible with the data.

Mean Percent Change in Seizure Frequency

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Best Medical Practice: mean -1.00 versus -19.10 on control; difference 18.10 (95% CI -7.67 to 43.87), standardized effect d = 0.36; z-test p = 0.169.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Best Medical Practice and the control. The interval gives the range of effects that remain compatible with the data.

Change From Baseline in Center for Epidemiologic Studies Depression Scale (CES-D) Score

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Best Medical Practice: mean 0.50 versus -2.20 on control; difference 2.70 (95% CI -1.14 to 6.54), standardized effect d = 0.36; z-test p = 0.168.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Best Medical Practice and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists a broad set of secondary outcomes spanning responder status, seizure frequency and seizure-free measures, depression scales, and a clinical global impression measure. Numerical results are posted for some of these outcomes. Across the secondary comparisons with recalculated estimates, the intervals include the no-difference value, so the data do not provide precise evidence of a between-group contrast for those measures on their own.

The secondary outcomes add context to the primary quality-of-life comparison by addressing other aspects of seizure experience and reported well-being. They are not substitutes for the primary endpoint, and a different result on a secondary measure would not automatically confirm or overturn the primary comparison. The posted secondary findings should be considered alongside the primary result and the study's limited follow-up.

The registry record lists 21 secondary outcomes as posted, but it does not report a complete multiplicity strategy or identify which outcomes, if any, were designated for confirmatory testing. When many outcomes are examined, unadjusted tests create more opportunities for apparently notable findings arising by chance. For that reason, unadjusted secondary results carry less weight than a prespecified primary comparison and should generally be treated as exploratory unless the record documents otherwise.

The registry's posted analyses for some continuous secondary measures use F tests, while the simple recalculations use the posted group summaries. The record does not provide enough detail to equate every reported analysis with its recalculation. The overall interpretation is therefore cautious: the secondary results do not form a uniformly precise pattern, and their role is supportive or descriptive rather than definitive.

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

• Response Rate
• Percent of Patients That Are Seizure Free
• Mean Percent Change in Seizure Frequency
• Seizure Free Days
• Seizure Free Days Over the Last 6 Months
• Change From Baseline in Center for Epidemiologic Studies Depression Scale (CES-D) Score
• Change From Baseline in Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) Score
• Mean Change From Beginning of Intervention Clinical Global Impression-Improvement Scale (CGI-I) Score at 12 Months

9. Statistical Interpretation

10. Statistical Methods Explained

What does a mean difference describe?

The primary endpoint is continuous, so the registry reports a mean change for each group and a standard deviation describing the spread of participant changes around that mean. A difference between group means expresses the contrast on the original QOLIE-89 score scale. The comparison is stated as best medical practice minus VNS Therapy: the estimate is -4.3 units. Because higher scores indicate better quality of life, the negative sign means the observed mean change was lower in the comparator group than in the VNS Therapy group. This is a description of the contrast's direction, not a stand-alone judgment about clinical importance.

A mean is useful for summarizing a group, but it does not show every participant's experience. The standard deviations, 7.2 units for VNS Therapy and 6.9 units for best medical practice, indicate that participant-level changes varied around their respective group averages. A group mean cannot be assumed to describe the change for every participant.

What does the confidence interval add?

A confidence interval gives a range of estimates compatible with the observed data under the calculation's assumptions. The primary interval runs from -7.868 to -0.732 units for the stated comparator-minus-VNS contrast. Its width conveys uncertainty about the magnitude of the difference: the data are more informative than a single point estimate alone, but they do not pinpoint one exact value. A confidence interval is not a range containing a specified proportion of individual patient outcomes, and it does not account for every possible source of bias or uncertainty in the study.

How should the p-values be read?

The registry reports an F Test p-value of .01 for the primary analysis. The unadjusted recalculation from the posted summary statistics gives p=0.018. In general, a p-value describes how incompatible the observed data are with a specified no-difference model, assuming the model and its assumptions are appropriate. It is not the probability that the null hypothesis is true, nor does it measure the size or importance of a difference. The registry's reported test and the summary-statistic recalculation need not match because the registry does not give enough detail about the sponsor's analysis to confirm that they use identical methods.

The recalculation is an unadjusted comparison based on the posted group summaries. It does not recreate unreported participant-level adjustments, data handling, or analysis choices. The registry record does not report a full statistical analysis plan or the test's detailed specification.

Why can over-dispersion matter?

General: for counts or rates, over-dispersion means that observed variability is greater than the variability assumed by a simple model. If a method fails to allow for that extra variation, its standard errors and uncertainty intervals may be too small. The primary endpoint is a continuous score, and the posted summaries do not establish whether over-dispersion is relevant to its analysis. This concept is included as general statistical context, not as a claim about a model used in the trial.

How do secondary outcome tests fit in?

The registry lists secondary outcomes that include responder count, seizure-related measures, and depression-scale measures. A binary outcome such as responder status is summarized as a count, while a continuous outcome such as a scale change is summarized by a mean and standard deviation. Risk differences express contrasts in proportions; mean differences express contrasts on the measured scale. Confidence intervals help show how much uncertainty accompanies those contrasts.

When many endpoints or tests are examined, some may appear notable by chance even when there is no underlying difference. General: multiplicity procedures can control or describe the increased chance of false-positive findings across a family of tests. Whether the trial used such procedures is not reported in the registry record. Consequently, unadjusted secondary p-values should not be treated as if each were the sole prespecified test.

What are the limits of summary-statistic recalculation?

The recalculated comparisons use posted group-level summaries rather than individual participant data. They are useful for describing a simple, unadjusted contrast and its approximate precision under the calculation's assumptions. They cannot verify the sponsor's data set, reproduce covariate-adjusted analyses, assess the handling of missing observations, or establish whether all analysis decisions followed a prespecified plan. The sponsor's posted analysis and the independent recalculation should therefore be interpreted as distinct statistical descriptions.

11. Confidence Intervals and Precision

The primary mean difference is -4.3 units for best medical practice minus VNS Therapy, with a 95% confidence interval from -7.868 to -0.732. The interval lies on the negative side of zero, so its values are consistent with a lower mean change in the comparator group than in the VNS Therapy group under the calculation used. The interval does not identify one exact difference; its endpoints indicate the range of estimates compatible with the data and assumptions at the stated confidence level.

The interval's scale is QOLIE-89 units, which makes it possible to compare the estimated contrast with the outcome's measurement scale. The registry describes the scale as ranging from 0 to 100, with higher scores reflecting better quality of life. However, a clinically important difference threshold is not reported in the registry record. Statistical precision alone therefore cannot establish whether the estimated difference is important to patients.

The analysis counts are 31 and 29, and the standard deviations are 7.2 and 6.9. These summarize the analyzed groups but do not remove uncertainty caused by the smaller analysis set, missing outcomes, early termination, or unreported analysis choices. The registry's primary analysis eligibility description and the 12-month availability note provide some context, but the details of missing-data handling are not reported in the registry record.

The sponsor's F Test p-value is .01, while the unadjusted recalculation gives p=0.018. The difference between those reported quantities is another reason to distinguish methods rather than infer precision from one statistic alone. The registry does not report sufficient detail to establish whether the sponsor's test and the recalculation address exactly the same estimand under the same assumptions.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size figures are planning illustrations based on the observed effect, not the trial's original design calculations. The registry record does not report the original sample-size justification or design assumptions. For the primary continuous outcome, the displayed planning quantities are participants per arm. The calculations use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the effect to detect is the stated fraction of the observed effect.

The 80% power column describes the number of participants per arm that the planning calculation estimates would be needed to have an 80% chance of detecting the specified effect under those assumptions, if that effect were present. The 90% power column uses a higher target chance of detection and therefore calls for more participants per arm. For example, planning for 100% of the observed primary effect gives 43 participants per arm for 80% power and 57 participants per arm for 90% power. Planning for 75% of the observed effect gives 76 and 101 participants per arm, respectively; planning for 50% gives 170 and 227.

Smaller target effects require more participants because they are harder to distinguish from the variability in the outcome. The curve is another way to read this relationship across assumed effect sizes. These estimates are not observed power: they are forward-looking illustrations under stated assumptions, not a measure of the probability that the completed trial detected an effect.

The planning assumptions apply to the calculation, not necessarily to the trial. The registry record does not say that the original investigators used equal allocation, a two-sided significance level of 0.05, or the normal approximation when designing the study. The sample-size figures should not be used to infer the study's original rationale or to substitute for its unreported design documentation.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -4.300; pooled standard deviation σ = 7.057.
2. n = 2 × (1.96 + 0.842)² × 7.057² / -4.300² = 42.3, rounded up to 43 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -4.3                      # observed difference in means
sigma <- 7.05676491279699                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(522418)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 43 (80% power), 57 (90% power)
 75% of observed effect: n per arm = 76 (80% power), 101 (90% power)
 50% of observed effect: n per arm = 170 (80% power), 227 (90% power)
power.t.test: 43.3 
Simulated power at n = 43 per arm: 0.795 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Analyses Reported by the Sponsor

The registry reports a sponsor analysis for the primary comparison using an F Test, with p=.01. The unadjusted recalculation from the posted group summaries gives a mean difference of -4.3 units and p=0.018, with a 95% confidence interval from -7.868 to -0.732. Both descriptions point to a contrast in the direction of a higher mean change in the VNS Therapy group, but the p-values are not identical.

The recalculation is a simple comparison of the posted summary statistics. It does not reproduce an analysis that may have used additional data handling, adjustments, or a different specification. The registry record does not provide enough methodological detail to determine precisely why the sponsor's test differs from the recalculation or whether the tests target precisely the same quantity.

The sponsor's reported analysis is the trial's own analysis and should be kept distinct from the recalculated result. The two values are not evidence of a data discrepancy by themselves; the registry's discrepancy indicator is false. Neither p-value communicates clinical importance, and neither replaces the estimate and its interval when assessing the size and precision of the observed comparison.

15. Multiplicity, Missing Data and Analysis Populations

The registry lists 22 outcome measures and 6 analyses, including a primary outcome and numerous secondary outcomes. Testing several outcomes can increase the chance that at least one result appears statistically notable by chance. General: a multiplicity plan may define which comparisons are confirmatory and may adjust inference to account for multiple tests. Such a plan can include an ordering of hypotheses or an adjustment to significance thresholds. The registry record does not report whether any multiplicity procedure was used, which outcomes were included in a testing family, or how the primary and secondary tests were ordered.

Missing data are also important to interpretation. The primary endpoint population is described as patients with a baseline and at least one post-baseline QOLIE assessment. The record says 12-month data were available for analysis, while the primary group summaries include 31 and 29 participants. Overall enrollment was 122. The registry does not provide a full accounting of participant flow into each analysis or explain all reasons for absent outcome data, so the relationship between enrollment and the primary analysis counts cannot be fully reconstructed from the record.

The registry notes that the study ended early and that only a few patients (n=7) achieved 2-year follow-up; 24-month data were unavailable. Early termination limits the follow-up information available beyond the reported 12-month assessment. The reasons for termination and whether the timing was related to outcome information are not reported in the registry record.

The record does not report the detailed statistical analysis plan, the original sample-size justification, the missing-data method, or a complete definition of the analysis population for each outcome. It also does not report whether sensitivity analyses were used to examine alternative assumptions about missing outcomes. Without these details, the posted estimates can be described, but the robustness of the results to unobserved outcomes and analysis choices cannot be determined from the registry entry alone.

16. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: laryngospasm (1.9%), fall (1.9%), suicide attempt (1.9%), convulsion (1.9%), head injury (1.9%).

The registry reports serious adverse events affecting 5 of 54 participants at risk in the VNS Therapy group and 3 of 58 at risk in the best-medical-practice group. Other adverse events affected 21 of 54 and 10 of 58 participants, respectively. These are participant counts in the registry's adverse-event reporting, not estimates of a causal difference between groups.

The listed serious adverse-event terms include laryngospasm, fall, suicide attempt, convulsion, head injury, and epilepsy, each reported as 1.9%. These entries should be read as the registry's listed terms, not as a complete characterization of event severity, timing, recurrence, or relatedness to treatment. The record does not report whether the events were judged related to either intervention, nor does it provide enough detail to compare exposure time or event ascertainment between groups.

Deaths are not reported in the registry record. Adverse-event counts alone do not establish that an event was caused by a treatment, and the counts should not be interpreted as a complete safety assessment without the definitions and follow-up procedures used to collect them.

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

The posted primary results describe a difference in mean 12-month QOLIE-89 change between the two randomized groups. The VNS Therapy group had a mean change of 5.5 units and the best-medical-practice group had a mean change of 1.2 units. The estimated contrast, expressed as best medical practice minus VNS Therapy, is -4.3 units, with a 95% confidence interval from -7.868 to -0.732. The score's direction means that higher values reflect better quality of life.

This is a group-level estimate among participants included in the primary outcome analysis. It does not mean every participant experienced the average change, and it does not establish the result for people who were not represented in that analysis. The registry does not report a threshold for clinically important change, so the statistical estimate alone cannot determine the importance of the difference to patients.

The findings are limited to the reported study, outcome definition, and follow-up. The study was open-label, ended early, and did not have available 24-month outcome data. The registry record does not report enough detail about missing-data handling, the full analysis plan, or the reasons for termination to resolve all questions about how those features affect interpretation.

The posted statistics do not establish that one treatment should be selected for an individual, nor do they establish what would happen in other populations or care settings. They describe the observed comparison in this randomized study and the uncertainty around that comparison. Secondary results and adverse-event counts offer additional context, but they do not remove the limitations of the primary analysis or provide a complete account of long-term outcomes.

18. Why This Trial Matters Statistically

This study illustrates why a trial's analyzed population and follow-up matter alongside its overall enrollment. The record reports enrollment of 122, while the primary outcome summaries include 31 and 29 participants. The registry describes eligibility for the primary analysis as having a baseline and at least one post-baseline QOLIE assessment, but does not provide a complete participant flow explanation. Readers therefore need to distinguish the number enrolled from the number contributing to a specific outcome estimate.

It also shows why estimates and confidence intervals should be read together with p-values. The primary difference is expressed on the QOLIE-89 scale and has a reported interval, while the registry's F Test and the unadjusted summary-statistic recalculation yield different p-values. Each statistic answers a related but not necessarily identical question under its own method. Reporting the estimate and interval helps keep attention on the magnitude and precision of the observed contrast.

The study's early termination and lack of 24-month data highlight the importance of outcome availability over time. The sample-size illustrations likewise require careful interpretation: they describe hypothetical planning under stated assumptions, not the study's original design rationale or observed power. Finally, the number of secondary outcomes makes multiplicity relevant. Without a reported strategy for interpreting multiple tests, secondary findings warrant less confirmatory weight than a clearly prespecified primary result.

19. 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 limitations are specific to this registry record. The trial was open-label, so participants and study personnel were not masked to group assignment. The record does not describe whether outcome assessment procedures addressed the possibility that awareness of assignment could influence reporting or other study processes.

The study status is terminated, and the registry states that 24-month data were unavailable because of early termination; only a few patients (n=7) achieved 2-year follow-up. The reason for termination and its relationship, if any, to study results are not reported in the registry record. Consequently, the posted 12-month comparison does not answer questions about outcomes at 24 months or later.

Overall enrollment was 122, while the primary outcome analysis summaries include 31 participants in the VNS Therapy group and 29 in the comparator group. The record identifies a baseline and post-baseline assessment requirement but does not provide enough information to reconstruct participant flow, explain every missing measurement, or assess whether those with available outcome data differed from those without them. The missing-data method and sensitivity analyses are not reported.

The original sample-size justification, detailed statistical analysis plan, and multiplicity procedures are not reported in the registry record. These omissions limit assessment of whether analyses were prespecified and how multiple outcomes were handled. The record also does not report a clinically important difference threshold for QOLIE-89, so the clinical importance of the mean contrast cannot be determined from the score difference alone.

Finally, the adverse-event entries do not include enough information about event relatedness, timing, exposure, or ascertainment to support a full comparative safety assessment. The reported counts are descriptive registry data and should not be interpreted as causal effects.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients — NCT00522418.
• Registry record last updated 2015-01-26; status last verified 2012-10.
• Results first posted 2010-05-17.
• 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.

23. Record Summary

NCT00522418 was a phase 4 randomized, open-label, parallel-group study of VNS Therapy plus best medical practice versus best medical practice alone in patients aged 16 years and older with pharmacoresistant partial epilepsy. Enrollment was 122, and the study status is listed as terminated.

The primary endpoint was mean change from baseline in QOLIE-89 overall score at 12 months. The posted means were 5.5 units for VNS Therapy and 1.2 units for best medical practice; the recalculated comparator-minus-VNS difference was -4.3 units, with a 95% confidence interval from -7.868 to -0.732. The registry reports an F Test p-value of .01; the unadjusted recalculation gives p=0.018.

The registry reports early termination and unavailable 24-month outcome data. It does not report the original sample-size rationale, detailed missing-data procedures, or a multiplicity strategy. Secondary outcomes and adverse-event counts add context but do not resolve those limitations.