Study of Intranasal Clonazepam in Adult Subjects With Epileptic Seizures: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Intranasal Clonazepam in Adult Subjects With Epileptic Seizures (NCT00594945), a non-randomized phase 2 study. The primary outcome is Number of Spikes and Sharp Waves, Relative Change From Baseline to Treatment Day (%)..

2. Clinical Question

3. Trial Design

The study is identified as a Phase 2a, open-label, proof-of-concept study of intranasal clonazepam in adult subjects with epileptic seizures. Its phase is also recorded as Phase 2. The listed condition is epilepsy, and the sponsor is Jazz Pharmaceuticals. The registry record gives a start of 2007-12, a primary completion date of 2008-12, and a status of completed.

The design fields describe the study as non-randomized, unmasked, and crossover. These features matter when interpreting comparisons. In a randomized study, allocation by chance is intended to make comparison groups similar on average. Here, allocation is explicitly non-randomized, so the record does not support interpreting the dose groups as randomized counterparts. Open-label means masking is listed as none; expectations and knowledge of treatment can potentially influence study conduct or assessments. That is a general design consideration, not evidence that bias occurred in this study.

A crossover design generally involves participants receiving more than one treatment condition, which can permit within-participant comparisons. Such comparisons can be affected by the order of conditions, changes over time, and carryover from an earlier condition. The registry record does not report the treatment sequence, period structure, washout arrangements, or how any such issues were handled. The arm descriptions list intranasal clonazepam 2 mg, intranasal clonazepam 3 mg, and a combined 2 mg and 3 mg group, but the details behind these labels are not reported in the registry record.

The enrollment entry is 45; it should not be mistaken for the number contributing to a particular endpoint analysis. Endpoint-specific participant counts and analysis-population definitions are not reported in the registry record. There is one registered outcome measure and no analysis listed.

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: Based on preliminary PK data, the study was terminated early prior to achieving planned enrollment numbers. Cohort 1 was dosed at 2mg. Cohort 2 was dosed at 3mg. Two subjects participated in both Cohorts.

Cohort 1 / Treatment Period 1

Cohort 2 / Treatment Period 2

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: There were 9 subjects total and 2 subjects were enrolled in both Cohorts.

6. Primary Endpoint

The registry lists the primary outcome as Number of Spikes and Sharp Waves, Relative Change From Baseline to Treatment Day (%)., measured over Change from baseline to treatment day.

The primary endpoint is the relative change from baseline to treatment day in the number of spikes and sharp waves. The record describes the measure as a mean, with standard deviation as the dispersion measure, and expresses the unit as percentage of baseline. The underlying measure is a video EEG count assessed over a 24-hour period.

Video EEG records electrical activity in the brain. Spikes and sharp waves are features of that electrical signal, so counting them provides a way to describe EEG activity during the stated observation period. A baseline-to-treatment comparison can characterize how the measured activity changes across those assessment points. Expressing change relative to baseline places the change in relation to each participant’s starting measurement; the registry record does not state the formula used to derive the relative change.

This endpoint is not itself a count of clinical seizures, and it should not be described as one. It is a physiological measurement selected as the primary outcome in a proof-of-concept study. As a general statistical point, a continuous endpoint can retain information about the magnitude of measured values rather than reducing observations to a yes-or-no category. Its usefulness for interpretation still depends on complete outcome definitions, participant data, and an analysis that accounts appropriately for the design. Numerical endpoint results and the analysis method are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies a continuous primary outcome and a mean as its summary measure. It does not report the analysis used to estimate that mean, any inferential procedure, or a numerical result. The explanations below describe general statistical concepts relevant to this kind of outcome and design; they do not assert that a particular method was used in this study.

What does a mean describe?

A mean summarizes the central level of a continuous measurement by averaging observed values. For this study, the registered quantity is the relative change from baseline to treatment day in the video EEG count of spikes and sharp waves. A mean can provide a concise description, but it does not show how much participants differ from one another. A small number of unusually large or small changes can also influence it. The registry record specifies standard deviation as the dispersion measure, but no standard deviation value is reported.

Standard deviation describes how spread out individual measurements are around their mean. It is not the same as the uncertainty in the estimated mean. The latter depends on the amount of information available and on the analysis design. Because the endpoint-specific sample size and summary values are not reported, the precision of the mean cannot be assessed from this record.

Why does the crossover design matter?

In general, crossover data contain repeated observations on the same participant. Those observations are usually correlated: a participant’s measurements under different conditions may resemble one another more than measurements from different participants do. An analysis that treats repeated measurements as independent may represent uncertainty incorrectly. Within-participant comparisons can account for stable differences between participants, but interpretation also depends on the treatment sequence, period effects, and possible carryover.

The registry record identifies a crossover model, but does not report the sequence of treatments, period definitions, washout arrangements, or statistical handling of repeated measurements. It also does not report whether the primary analysis used within-participant changes or another approach. Therefore, the analysis cannot be reconstructed or judged for alignment with the design based on the registry record.

What does non-randomized allocation imply?

Randomization is a method intended to make treatment groups comparable on average with respect to measured and unmeasured characteristics. Non-randomized allocation does not provide that same protection. In general, observed group differences may reflect baseline differences, treatment selection, timing, or other factors in addition to the intervention. Statistical adjustment can sometimes address measured differences, but it cannot guarantee removal of unmeasured confounding. The registry record does not report an adjustment method or covariates used in analysis.

Because the record also labels the model crossover, it is not possible to assume that the dose groups represent independent parallel arms. The dose-group labels alone do not explain which participants received each condition or how the groups were formed. Those details are not reported in the registry record.

How should uncertainty be understood?

A confidence interval is a statistical range that communicates the uncertainty around an estimated quantity under stated assumptions. Narrower intervals indicate greater precision, while wider intervals indicate greater uncertainty. A p-value, when used, measures how compatible observed data are with a specified null model; it is not the probability that a treatment works or that the null hypothesis is true. Neither a confidence interval nor a p-value for the primary outcome is reported in the registry record. There is no basis for describing statistical significance.

Variability in an endpoint can also affect precision. For continuous measurements, standard deviation is one way to describe observed spread. In count outcomes, over-dispersion can arise when variability exceeds what a simple Poisson model would expect; general statistical approaches may then need to accommodate that extra variability. This registered outcome is described as a relative change and summarized by a mean, but its distribution and the model used are not reported. It would therefore be speculative to claim that over-dispersion was present or that a particular count model was appropriate.

What does the planning illustration represent?

The planning assumptions describe an illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The stated effect to detect is a fraction of the observed effect. Such calculations are planning illustrations, not observed power and not evidence that the study was designed with those assumptions. The registry record does not report its own sample-size justification or identify these assumptions as the original design plan. Because no observed primary outcome effect is reported in the registry record, the effect underlying the illustration cannot be assessed from the posted record.

General power calculations estimate how often a specified analysis would detect a specified effect under assumptions. They do not measure whether an observed result is reliable, and they do not replace the observed estimate and its uncertainty. The analysis count is zero, so no primary outcome estimate is available for a reader to evaluate alongside the planning 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("Intranasal Clonazepam 2 mg", "Intranasal Clonazepam 3 mg")
n   <- c(6, 5)
m   <- c(-7.4, -26.1)
sp  <- c(35.12, 33.94)
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  Intranasal Clonazepam 2 mg  6  -7.400  35.120  -44.256  29.456
CARM  Intranasal Clonazepam 3 mg  5  -26.100  33.940  -68.242  16.042

11. Multiplicity, Missing Data and Analysis Populations

The record lists one outcome measure, identified as the primary outcome, and no analyses. A single listed endpoint does not establish that the study assessed only one outcome or performed only one statistical test; the registry record does not report the full analysis plan. It also does not report whether any multiplicity adjustment was planned or used. Multiplicity is a general concern when many outcomes, time points, subgroups, or comparisons are tested: repeated testing can increase the chance of a false-positive finding unless the analysis plan addresses it. There is no result for which to assess that issue.

Missing-data handling is not reported in the registry record. The record does not provide the number of participants with primary outcome measurements, the reasons for any missing measurements, or the method used to handle missing data. This matters because analyses based only on participants with observed measurements can be biased when the likelihood of missingness is related to participant characteristics or outcomes. General approaches to missing data rely on assumptions, and the credibility of those assumptions depends on information about why data are missing.

The analysis population is also not reported in the registry record. The enrollment entry of 45 does not establish how many participants were included in an endpoint analysis, whether all enrolled participants were analyzed, or how crossover observations were handled. Definitions such as intention-to-treat or per-protocol should not be attributed to this study without a reported analysis population. The registry record also does not report an interim-analysis plan or whether any interim analyses occurred.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry record lists serious adverse events for the 2 mg group among 6 participants at risk, with 0 affected, and for the 3 mg group among 5 participants at risk, also with 0 affected. These are the serious-event counts recorded for those groups. The record does not list any serious-event terms. Deaths are not reported in the registry record; a null entry should not be read as a reported count of zero.

For other adverse events, the record lists 6 participants at risk and 6 affected in the 2 mg group, and 5 at risk and 2 affected in the 3 mg group. These entries describe counts, not a randomized comparison of the groups. Allocation was non-randomized, and the registry record does not explain the relationship between these safety groups, the crossover periods, or the overall enrollment entry of 45.

Adverse-event counts should be interpreted in light of how events were defined, collected, and attributed. Those details are not reported in the registry record. The counts alone do not establish causation, comparative risk, or the frequency of events in a broader population.

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

The record establishes that the study was registered as a Phase 2a, open-label, non-randomized crossover evaluation of intranasal clonazepam in adults with epilepsy. It identifies a primary video EEG endpoint: relative change from baseline to treatment day in the number of spikes and sharp waves over a 24-hour period. It also gives selected adverse-event counts for the listed dose groups.

It does not report a numerical result or analysis for the primary outcome. As a result, the record cannot show the direction or magnitude of the measured change, how variable participant measurements were, or how precise an estimated effect might be. The registry status of completed does not fill that gap. Nor can the listed safety counts alone establish comparative safety, especially given the non-randomized allocation and the lack of further information about event collection and group structure.

The outcome is a video EEG measure rather than a direct count of clinical seizures. An observed change in this measure, if reported, would need to be interpreted as a change in the registered physiological endpoint. It should not automatically be equated with a change in seizure frequency or with a clinical benefit. The registry record does not report clinical seizure results or an analysis linking this EEG endpoint to clinical outcomes.

These limitations do not establish that the study found no effect. They mean that the registry record does not provide the results needed to quantify or judge the primary outcome. Conclusions beyond the registered design and the specific reported counts would require information that is not reported in the registry record.

14. Why This Trial Matters Statistically

This study is statistically notable because its registered design combines a crossover model with non-randomized allocation and no masking. Each feature shapes what a comparison can establish. In general, crossover designs can make use of within-participant data, but the sequence, period structure, and possible carryover need to be understood. Non-randomized allocation can leave group comparisons vulnerable to differences between participants or treatment conditions. The registry record does not report the details needed to assess how these issues were addressed.

The primary endpoint also illustrates the distinction between an outcome definition and an outcome result. The record carefully identifies a continuous video EEG measure, its summary as a mean, and standard deviation as the dispersion measure. Yet it lists no analysis and gives no numerical primary outcome estimate. Without those results, readers cannot evaluate effect magnitude or statistical precision, regardless of the study’s completed status.

The safety entries likewise demonstrate why counts need context. The registry lists at-risk and affected participants for serious and other adverse events, but the record does not fully explain group membership, follow-up, or event collection. Those counts are descriptive entries rather than a randomized comparison.

More broadly, a registry record can identify study intent and design while still leaving central statistical questions unanswered. For this study, analysis populations, missing-data handling, multiplicity procedures, and sample-size justification are not reported in the registry record. These omissions limit independent assessment of how the planned question was analyzed. Recognizing those limits is part of interpreting the evidence accurately, rather than treating design labels or enrollment as substitutes for results.

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 primary limitation for interpreting the registered efficacy question is that no numerical primary outcome result or analysis is reported in the registry record. The measure is defined, but the mean relative change, standard deviation, endpoint-specific sample size, and uncertainty estimates are not available. Therefore, neither the magnitude nor precision of the primary outcome can be assessed from this record.

The design details are also limited. Allocation is non-randomized, masking is listed as none, and the study model is crossover. The record does not report treatment sequence, period structure, washout arrangements, or how repeated measurements were analyzed. It also does not explain the membership or role of the listed 2 mg, 3 mg, and combined-dose groups. These omissions prevent a detailed assessment of dose comparisons and potential crossover effects.

The entry of 45 for enrollment does not identify the number with outcome data or the analysis population. Missing-data methods, participant flow, and endpoint-specific denominators are not reported in the registry record. The record also does not report a statistical analysis plan, multiplicity handling, an interim-analysis plan, or the study’s own sample-size justification.

For safety, at-risk and affected counts are listed for the two dose groups, but the record does not report detailed event definitions, collection methods, follow-up, or the relationship of the safety groups to the crossover periods. Deaths are not reported, rather than recorded as zero. These limitations constrain interpretation of both efficacy and safety information in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of Intranasal Clonazepam in Adult Subjects With Epileptic Seizures — NCT00594945.
• Registry record last updated 2014-07-01; status last verified 2014-05.
• Results first posted 2014-07-01.
• 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

The registry record describes a completed Phase 2a, open-label, non-randomized crossover study of intranasal clonazepam in adults with epilepsy. Enrollment is listed as 45. The primary outcome is mean relative change from baseline to treatment day in the number of spikes and sharp waves on video EEG over a 24-hour period, with standard deviation identified as the dispersion measure.

No analysis is listed, and no numerical primary outcome result is reported in the registry record. Serious adverse events affected 0 participants among 6 at risk in the 2 mg group and 0 among 5 at risk in the 3 mg group. Other adverse events affected 6 participants in the 2 mg group and 2 in the 3 mg group. Deaths are not reported. The available record supports description of the study design and listed counts, but does not provide a quantitative estimate of the primary outcome.