A Clinical Study Examining the Safety and Effectiveness of a New Medication (Keppra®) for the Prevention of Migraine Headaches: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Clinical Study Examining the Safety and Effectiveness of a New Medication (Keppra®) for the Prevention of Migraine Headaches (NCT00203216), a non-randomized na study. The primary outcome is The Primary Outcome is Defined as Average Change in Frequency of Migraine Attacks Over Each 4-week Interval of the Treatment Period as Compared to the 4-week Baseline Period..

2. Clinical Question

In practical terms, the study was intended to describe how migraine-attack frequency changed during treatment with levetiracetam, while also collecting information about safety. Because everyone received active study drug and there was no control group, the design cannot directly contrast the medication with placebo or another treatment. A before-and-after change can describe what happened in the enrolled group, but it does not by itself isolate the cause of that change.

The study also included Transcranial Magnetic Stimulation. The registry summary says the procedure measured brain activity in relation to the idea that migraine may involve periods of cortical hyperexcitability. That rationale is distinct from the primary clinical question about the frequency of migraine attacks. The record does not report a primary outcome analysis linking TMS measurements to clinical outcomes.

3. Trial Design

This was a single-center, open-label trial of levetiracetam for prophylactic treatment of migraine, with or without aura. The registry lists the allocation as non-randomized, the model as single group, and masking as none. Enrollment was 31. The phase is listed as NA, and the study status is completed.

Participants received active study drug rather than being assigned to a control arm. The arm description states that levetiracetam was titrated to a maximally tolerated dose, with a maximum of 3000 mg. per date and a minimum daily dose of 1000 to remain in the study. Transcranial Magnetic Stimulation was also part of the study. The registry summary describes it as a procedure intended to measure brain activity; it was not a comparator intervention.

The primary outcome compared migraine-attack frequency during a 28-day baseline period with changes over successive treatment-period intervals. The description identifies four follow-up intervals, starting with days 0 to 28 and continuing through days 84 to 126. The registry also lists secondary outcomes for migraine days, attack severity, and use of acute agents across consecutive 4-week intervals.

The registry record does not report a separate control group, random assignment, masking, or a comparative treatment estimate. It also does not report detailed eligibility criteria, the number completing each follow-up interval, or the analysis population. Although the primary outcome description mentions a multiple regression model considering visit number, age, gender, and BMI, the record does not report an outcome analysis using that model.

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 The Primary Outcome is Defined as Average Change in Frequency of Migraine Attacks Over Each 4-week Interval of the Treatment Period as Compared to the 4-week Baseline Period., measured over Compare frequency of migraine attacks in baseline period to the average of the change following these 28 day periods prior to: Visit 4 (day 0-28), visit 5 (day 28-56), visit 6 (day 576-84), visit 7 (day 84-126)..

The primary endpoint was the average change in the frequency of migraine attacks over each 4-week treatment interval compared with the 4-week baseline period. The measure is expressed as migraine attacks per month, and the endpoint is described as a mean. Baseline attacks were to be counted during the 28 days before study medication began. Subsequent counts were to be assessed across the treatment-period intervals.

Attack frequency is a direct measure of how often the episodes targeted by a preventive-treatment study occur. Repeated interval measurements can describe whether the frequency changed over the course of follow-up, rather than relying on a single post-treatment observation. The registry description says changes would be averaged in a multiple regression model considering visit number, age, gender, and BMI. That description specifies an intended analytical approach; it does not establish that the model was fitted or that an adjusted result is available.

The endpoint is a within-group change, not a comparison between levetiracetam and an untreated or alternative-treatment group. Without a reported estimate, variability measure, or uncertainty interval, the size and precision of any change cannot be assessed from the registry record. The primary outcome result is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The methods can be understood by separating the study design, the outcome definition, and the analysis description. The trial is listed as single group, non-randomized, and open-label. These labels mean that the registry describes one group receiving active medication, without random assignment to a comparator or masking of treatment. The primary contrast was between a baseline period and later observations in that group.

What does a within-group change estimate?

A within-group change compares an outcome measured at one time with the same outcome measured at another time among the study participants. Here, the planned outcome was migraine-attack frequency during a 28-day baseline period compared with treatment-period intervals. Such a contrast describes change over time. General statistical interpretation requires care: without a concurrent control group, time-related changes cannot be separated from treatment effects using the contrast alone. Natural variation, expectations, changes in behavior, or other events could also contribute to an observed difference. These are general limitations of the design, not claims about events in this trial.

Why measure multiple intervals?

The endpoint description calls for follow-up across successive 4-week intervals. Repeated measurements can describe how an outcome varies during follow-up and can make time itself relevant to the analysis. The record specifies the first interval as days 0 to 28, the second as days 28 to 56, the third as days 56 to 84, and the fourth as days 84 to 126. The timing description therefore includes intervals with different stated durations. The registry does not explain how that feature was handled analytically, and it does not report interval-specific estimates.

The primary outcome is a continuous measure summarized as a mean, with standard deviation identified as the dispersion measure. In general, a mean represents the average value in the observations being analyzed. A standard deviation describes how spread out those observations are around the mean. A standard deviation is not the same as the uncertainty of the mean: uncertainty depends on the analysis and the amount and structure of available data. No primary-outcome mean or standard deviation is reported in the registry record.

What is regression used for?

The endpoint description says that change would be averaged in a multiple regression model considering visit number, age, gender, and BMI. In general, regression models relate an outcome to one or more variables. Including visit number can account for the fact that observations occur at different follow-up times, while including participant characteristics can describe adjusted associations. The record does not report coefficients, model specifications beyond the listed variables, assumptions, or model diagnostics. It also lists zero analyses, so the registry does not establish that this regression was carried out or show any estimates from it.

Repeated observations from the same participant are generally related rather than independent. General methods for repeated-measures data account for this within-participant structure so that uncertainty is not treated as if every observation came from a different person. The record does not explain what covariance structure, if any, was used, nor does it identify a method for handling incomplete repeated observations. Those details cannot be inferred from the brief model description.

How should uncertainty be read?

A confidence interval is a range of values compatible with an estimate under the assumptions of the analysis. It communicates precision in a way that a point estimate alone cannot. A p-value, when reported, addresses compatibility between data and a specified null model; it does not measure clinical importance or establish causation. Neither a confidence interval nor a p-value for the primary outcome appears in the registry record. Because no primary estimate is posted, there is no numerical result whose uncertainty can be interpreted.

The registry identifies standard deviation as the primary measure of dispersion, but it does not give the number of observations available at each visit or the amount of missing outcome data. Without those details and a completed analysis, the precision of the repeated-measures estimate cannot be reconstructed from the record.

What does over-dispersion mean generally?

Over-dispersion is a general concern when observed variability exceeds what a statistical model assumes. It can make model-based uncertainty too small if the extra variability is ignored. The primary outcome is described as a mean of a continuous measure, and the registry does not report an analysis diagnosing over-dispersion or a model requiring a particular dispersion assumption. It would therefore be inappropriate to claim that over-dispersion occurred in this study.

The registry also lists planning assumptions for a sample-size illustration based on an observed effect, including a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The actual trial, however, is listed as single group and non-randomized, and no numerical planning estimates are reported in the record. Such planning illustrations are not observed results or observed power. The registry does not report the trial’s own sample-size justification, so its design rationale cannot be inferred from those assumptions.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Levetiracetam/Transcranial Magnetic Stimulation")
n   <- c(31)
m   <- c(-0.058)
sp  <- c(5.1)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Levetiracetam/Transcranial Magnetic Stimulation  31  -0.058  5.100  -1.929  1.813

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome and three secondary outcomes: change in migraine days, average severity of migraine attacks, and use of acute agents across treatment intervals compared with baseline. It does not report a multiplicity strategy. In general, testing multiple outcomes or time intervals can increase the chance of at least one apparently notable result when all are examined. Methods such as prespecifying a hierarchy or adjusting the interpretation of multiple tests can address that issue, but the registry record does not say whether any such approach was planned or used.

The primary outcome description refers to successive treatment intervals and an average change. It does not report how comparisons across visits were prioritized, whether interval-specific tests were planned, or how results across the listed secondary outcomes would be interpreted. The record lists zero analyses and does not post outcome estimates or p-values, so the practical impact of multiplicity cannot be assessed.

Missing-data methods and analysis populations are not reported in the registry record. The record does not state how many participants contributed outcome data at each interval, how incomplete diaries or missed visits were handled, or whether any imputation or sensitivity analysis was performed. In general, missing outcome data can affect both the estimate and its precision, particularly when the reasons for missingness relate to symptoms or treatment experience. That is a general methodological concern; the registry does not describe the extent or pattern of missing data in this study.

The registry also does not identify an intention-to-treat, per-protocol, or other analysis population for the primary endpoint. Enrollment of 31 is reported, but enrollment alone does not establish how many participants were included in an outcome analysis. With no analysis results or population definitions, the record does not permit assessment of whether the intended analysis population was followed.

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 non-serious adverse event terms

The listed safety group combines levetiracetam and Transcranial Magnetic Stimulation. The registry reports 31 at risk for serious adverse events and zero affected. It reports 31 at risk for other adverse events and 21 affected. These are the posted counts for the group; they should not be treated as a comparison between treatments because the study had no separate control arm.

The record does not list any top serious adverse-event terms. That means no such terms are posted in the registry record; it does not describe the nature, timing, or severity of other events. Deaths are not reported in the registry record. The record also does not provide detail on how adverse events were defined, collected, or attributed to medication or the procedure.

Safety counts are descriptive and do not by themselves establish causation. In an open-label, single-group study, these counts cannot show whether events occurred more or less often than they would have in a comparator group. The other-event count should be read separately from the serious-event count, and neither substitutes for the missing primary-outcome estimate.

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

The record establishes that a completed, open-label, single-center study enrolled 31 participants and planned to assess change in migraine-attack frequency during treatment with levetiracetam. It also records the use of Transcranial Magnetic Stimulation and lists secondary measures relating to migraine days, attack severity, and use of acute agents. The primary endpoint is described, but its result is not reported in the registry record.

That absence matters. Without a reported estimate, there is no basis in this record for describing the direction or size of change in attack frequency. Without a measure of variability or an uncertainty interval, the precision of such a change cannot be evaluated either. The record lists zero outcome analyses. A study’s status as completed does not itself supply an analyzed result.

Even if a within-group change had been reported, this design would not provide a randomized comparison with a control group. General statistical reasoning therefore cautions against attributing an observed before-and-after difference solely to the study medication. The open-label design also means participants and investigators were not masked, but the record does not quantify how that might have affected measurement or reporting.

The safety counts give a limited descriptive view: zero participants are listed with serious adverse events among 31 at risk, and 21 are listed with other adverse events among 31 at risk. These figures do not establish comparative safety, and the registry provides little event-level detail. They should not be read as a complete account of all possible harms.

Accordingly, the registry record documents what the trial intended to investigate and the counts it posted for safety, but it does not permit an efficacy conclusion or a precise estimate of the primary outcome. The absence of a posted analysis is not evidence that there was no change; it means the record does not report a result that can be interpreted.

14. Why This Trial Matters Statistically

This study is statistically instructive because it pairs a clinically direct outcome with a design that limits causal interpretation. Counting migraine attacks over baseline and follow-up intervals gives a concrete description of symptom frequency. Repeated measurements can capture change over time. But the absence of a separate randomized comparison means that any observed temporal change would remain difficult to attribute to the medication alone.

The registry also illustrates the difference between a planned endpoint and a reported analysis. It names the primary measure, its baseline comparison, a dispersion measure, and variables to be considered in a regression model. Yet the record lists zero analyses and does not report an outcome estimate. A detailed outcome definition is useful for understanding intent, but it cannot replace the results needed to assess magnitude and precision.

Another statistical lesson is that design labels matter. Open-label treatment and a single-group structure define what comparisons are available. Without a concurrent control group, changes in symptoms over time can reflect influences beyond treatment. General concerns include natural variation, expectations, and other changes during follow-up; none can be quantified from this record.

The record also separates clinical outcomes from a mechanistic measurement. Transcranial Magnetic Stimulation was described as a procedure to measure brain activity, while the primary endpoint concerned attack frequency. Connecting such measures would require reported analyses, which are not present in the registry record.

Finally, the safety counts show why outcome categories and reporting detail matter. The record distinguishes serious from other adverse events, but provides no serious-event terms and does not report deaths. A small set of counts can summarize what was posted without resolving comparative safety or explaining the events. Statistical interpretation depends not only on the planned methods, but also on complete, analyzable results and their uncertainty.

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 principal limitation for interpreting the clinical outcome is that no primary-outcome result is reported in the registry record. The record does not provide a mean change, standard deviation, confidence interval, p-value, or interval-specific estimate. It lists zero analyses, so the planned endpoint description cannot be treated as an observed finding.

The single-group, non-randomized, open-label design has no concurrent control for separating treatment-period changes from other influences over time. A baseline comparison can describe change within the enrolled group, but it cannot on its own establish that the study drug caused that change. The registry does not report masking, because masking is listed as none, or a comparator group, because the model is listed as single group.

The record does not report detailed eligibility criteria, participant characteristics, follow-up completion, or the number contributing data to each outcome interval. Missing-data handling and analysis populations are also not reported in the registry record. Those omissions limit assessment of representativeness, attrition, and the population underlying any estimate.

The primary description mentions a multiple regression model considering visit number, age, gender, and BMI, but no fitted model or diagnostic information is reported. The record does not explain how repeated measurements were handled, how the stated intervals were incorporated, or whether the model description reflects the analysis actually performed.

Safety reporting is also limited: the record gives counts for serious and other adverse events, but does not list serious-event terms, describe event collection or attribution, or report deaths. Multiplicity procedures and the trial’s own sample-size justification are not reported in the registry record. These limitations restrict both statistical interpretation and the detail of conclusions that can be drawn from the posted information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Clinical Study Examining the Safety and Effectiveness of a New Medication (Keppra®) for the Prevention of Migraine Headaches — NCT00203216.
• Registry record last updated 2011-08-11; status last verified 2011-07.
• Results first posted 2011-08-11.
• 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

The registry describes a completed, single-center, open-label, non-randomized, single-group study of levetiracetam for migraine prevention, with or without aura. Enrollment was 31. Participants received levetiracetam, and Transcranial Magnetic Stimulation was also performed.

The primary outcome was the average change in migraine-attack frequency across treatment-period intervals compared with a 4-week baseline period. Secondary outcomes concerned migraine days, attack severity, and use of acute agents. The registry lists zero analyses and does not report a primary-outcome estimate or its precision.

For safety, zero of 31 participants at risk are listed with serious adverse events, and 21 of 31 are listed with other adverse events. Serious-event terms are not listed, and deaths are not reported in the registry record. The design and posted counts permit description, but not a controlled estimate of treatment effect.