Study of Midazolam Hydrochloride Oromucosal Solution (MHOS/SHP615) in Pediatric Patients With Status Epilepticus (Convulsive) in the Community Setting: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Midazolam Hydrochloride Oromucosal Solution (MHOS/SHP615) in Pediatric Patients With Status Epilepticus (Convulsive) in the Community Setting (NCT03336450), a non-randomized phase 3 study. The primary outcome is Efficacy: Number of Participants With Therapeutic Success.

2. Clinical Question

3. Trial Design

This was a Phase 3, multicenter, open-label extension study of buccally administered MHOS/SHP615 in pediatric patients with convulsive status epilepticus in community settings. The registry record describes the study as completed, with a start date of 2018-04-23 and primary completion date of 2020-10-13. Enrollment was 3. The study's stated purpose was to assess safety and efficacy in children in the community setting.

The design was non-randomized and single group, with no masking. The registry lists SHP615 and MHOS/SHP615 as drug interventions, and its arm description states that participants would receive a single age-specific dose of SHP615 oromucosal solution through the buccal route upon seizure onset. No concurrent control arm is described. The registry record therefore does not provide a randomized estimate of a treatment contrast, nor does it describe an allocation process that would balance measured or unmeasured characteristics between groups.

This extension enrolled patients who had completed SHP615-301 and who tolerated and responded to MHOS/SHP615 treatment in the hospital setting. That prior-treatment history is central to the study's scope. The experience recorded in this extension concerns a selected group with prior exposure and reported response and tolerability, rather than all children who might present with convulsive status epilepticus. The record does not report the protocol's detailed eligibility criteria, the number screened or excluded, or the reasons for any exclusions.

The primary endpoint was a participant count based on a prespecified clinical definition of therapeutic success within the post-dose observation period. Secondary outcomes included sustained absence of seizure activity, time to resolution of convulsions, time to recovery of consciousness, additional anticonvulsant medication, failure to respond, and safety measures. Although the registry lists 15 outcome measures, it lists zero analyses. The endpoint-specific results and analysis procedures are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: A total of 12 participants were screened, of which 9 participants were screen failures and withdrawn prior to randomization. Only 3 participants were enrolled to receive treatment and completed the study.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Full analysis set (FAS) consisted of all participants in the safety set who had at least 1 assessment for determination of therapeutic success (cessation of seizure within 10 minutes with sustained absence of seizure for 30 minutes) performed after the administration of IP.

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: Safety set consisted of all participants who had received a single dose of Investigational product (IP), regardless of whether the study drug administration was documented to be complete or not on the study drug administration electronic case report form (eCRF).

6. Primary Endpoint

The registry lists the primary outcome as Efficacy: Number of Participants With Therapeutic Success, measured over From start of study drug administration up to 30 minutes post-dose.

The primary endpoint counted participants classified as having therapeutic success from the start of study drug administration up to 30 minutes post-dose. The registry definition required visible seizure activity to cease within 10 minutes and remain absent for 30 minutes after a single dose, with no additional rescue medication. A binary endpoint of this kind distinguishes participants who meet the full response definition from those who do not. It combines the timing of seizure cessation, its subsequent persistence, and the absence of rescue medication into one outcome.

This type of endpoint can provide a direct description of how many participants met a clinically defined response criterion during the specified observation period. It is important, however, to keep the endpoint definition separate from broader claims about efficacy. A participant count does not show the duration of benefit beyond the period specified, and the registry record does not report the primary endpoint count or a confidence interval for it. It also does not report whether there were protocol-defined approaches for classifying participants with incomplete assessments or missing observations.

The endpoint population was the full analysis set, defined in the record as participants in the safety set who had at least one assessment for determining therapeutic success after administration of investigational product. This definition identifies who could contribute to the endpoint, but the registry record does not give the number in that set or the number with an endpoint assessment. Without those results, the primary endpoint's observed response proportion and its precision are not available from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study design determines what kinds of statistical conclusions are possible. This trial is classified as non-randomized and single group, with no masking. In a randomized comparison, allocation can help make treatment groups comparable on average, including for factors not measured by investigators. Here there is no concurrent randomized control group in the registry record, so the study can describe outcomes among participants who received treatment but cannot estimate a randomized between-group treatment effect. Open-label status also means participants and study personnel were not masked to treatment assignment; the record does not report additional procedures intended to reduce assessment bias.

What does a participant count measure?

The primary outcome is a count of participants with therapeutic success. It applies a binary classification: a participant meets the endpoint only if visible seizure activity ceases within 10 minutes and remains absent for 30 minutes after one dose without additional rescue medication. Counts can be useful because they state the number meeting a defined criterion. To understand how precisely a count estimates a broader response rate, readers would also need the relevant analysis population and an uncertainty measure, such as a confidence interval. The primary endpoint count, analysis population size, and interval are not reported in the registry record.

A confidence interval, as a general statistical concept, describes a range of values compatible with the observed data under a specified method. It expresses uncertainty in an estimate; it is not a guarantee that the true value lies within the interval. In a small study, estimates based on few participants are generally imprecise, and an interval would help show that uncertainty. No confidence interval for the primary result is reported in the registry record.

Why does the absence of a comparator matter?

In a single-group study, outcomes after treatment can be counted, but there is no concurrent group to indicate what would have happened under a different treatment or without the study treatment. Comparisons with earlier experience or with external populations are vulnerable to differences in eligibility, setting, care, and outcome measurement. The registry record does not report an external comparator or a comparative analysis. Therefore, descriptive outcomes, if reported, would not by themselves establish that treatment caused the observed outcome.

Selection into an extension study is another consideration. Eligibility was tied to completing SHP615-301 and having tolerated and responded to MHOS/SHP615 in the hospital setting. This selected history can affect how representative the participants are of a broader population. Statistical adjustment cannot necessarily remove this limitation, especially when there is no comparison group and the registry record does not report detailed participant characteristics or an adjustment plan.

What can sample-size planning illustrations tell readers?

The planning assumptions describe illustrations based on an observed effect, not the trial's own design. They specify a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is described as a stated fraction of the observed effect. For time-to-event outcomes, the assumptions describe total event counts, while other illustrations concern participants per arm. These are planning conventions, not evidence that this study randomized participants between two arms. They must not be interpreted as observed power or as the actual enrollment rationale for this extension.

In general, a sample-size calculation asks how much information a future study might need under chosen assumptions. Its answer depends on the assumed effect, variability, error rate, allocation, and analysis method. A planning illustration is conditional on those assumptions; it does not predict the result of a future study and does not demonstrate that a completed study had adequate precision. The registry record does not report the protocol's sample-size justification, nor does it report numerical planning outputs in the information.

How should sparse event data be understood?

Counts of participants with events are descriptive. When the group is small, each participant's experience represents a substantial part of the total observed experience, and estimates of event frequency can be unstable. A reported percentage should be read alongside the count and the number at risk, not as a precise estimate of the risk in a wider population. The serious adverse event figures list 1 affected participant among 3 at risk; the registry also lists febrile convulsion at 33.3% among serious adverse event terms. Those figures do not provide a comparative risk estimate.

Over-dispersion is a general statistical issue in count data. It occurs when variation in counts is greater than a model assumes, which can make standard errors too small if the model is not adapted. The posted primary outcome is a participant count for a binary endpoint, and the registry record does not report a fitted model or an over-dispersion analysis. This concept therefore provides general context rather than a description of a method documented for this trial.

What is known about the analyses?

The registry lists zero analyses. It does not report the statistical tests, estimation procedures, confidence intervals, adjustment methods, or handling of repeated outcomes. The record also does not report interim analyses. These absences prevent evaluation of the detailed analysis plan or whether it was followed. They should not be filled by assuming standard practice: different methods can yield different uncertainty estimates, and the registry record does not identify which approach was used.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("SHP615")
n      <- c(3)
events <- c(3)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  SHP615  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 15 outcome measures, covering efficacy and safety, but lists zero analyses. It does not report whether any outcomes were designated for formal hypothesis testing beyond identifying the primary endpoint, whether secondary outcomes were exploratory, or whether an adjustment for multiple comparisons was planned or performed. When many outcomes are tested, the chance of at least one apparently unusual result can increase; multiplicity procedures are methods intended to address that issue. This is general statistical context, not a description of a method reported for this study. The record does not report a multiplicity strategy.

Missing-data handling is also not reported in the registry record. The primary endpoint population is defined as participants in the safety set with at least one post-administration assessment for determining therapeutic success. That definition indicates an assessment requirement for inclusion in the full analysis set, but the record does not report the number of participants in the safety set or full analysis set, the amount of missing endpoint data, or how incomplete observations were classified. It also does not report sensitivity analyses for missing outcomes.

These omissions matter because the population included in an analysis and the treatment of missing observations can affect an endpoint estimate. Without participant flow, analysis-set counts, and missing-data procedures, readers cannot determine whether endpoint results would represent all enrolled participants or a subset with evaluable observations. No imputation, exclusion, or other missing-data procedure should be presumed. The registry record does not report those details, so the impact of missingness cannot be assessed from the posted information.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

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: febrile convulsion (33.3%).

The registry safety figures identify the SHP615 group with 3 participants at risk. The serious adverse event count is 1 participant affected, and the separate other adverse event count is 2 participants affected. The listed number of deaths is 0. Febrile convulsion appears among the serious adverse event terms at 33.3%. These are descriptive counts and a reported percentage, not a comparison of treatment groups.

Because only 3 participants were enrolled, the observed counts provide limited information about how frequently events might occur in a wider population. The figures do not establish whether an event was caused by study treatment. Nor do they indicate comparative risk, since there is no randomized control group described. The registry record does not report additional details about event timing, duration, severity beyond the serious-event classification, or participant-level overlap between event categories in the information summarized by these figures.

Counts, percentages, and denominators should be interpreted together: the count states how many participants were affected, while the denominator indicates the group size used for the figure. The 33.3% term should not be mistaken for a precise population risk estimate. The absence of deaths in this enrolled group is a description of the recorded study experience, not evidence that the risk of death is absent.

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

The registry record establishes that a completed Phase 3, open-label extension study enrolled 3 pediatric patients and evaluated buccally administered MHOS/SHP615 in community settings. It defines therapeutic success using seizure cessation within 10 minutes, sustained absence of visible seizure activity for 30 minutes, and no need for additional rescue medication after a single dose. These design and endpoint details clarify what the study set out to observe.

The record does not report the number of participants who met the primary endpoint. It therefore cannot show the observed rate of therapeutic success or the precision of that rate. It also lists 15 outcome measures but zero analyses, so the posted record does not provide efficacy estimates or statistical comparisons for the listed secondary outcomes. The absence of those results is not evidence that participants did or did not experience the outcomes.

The study was non-randomized, single group, and unmasked. It offers no concurrent control for estimating how outcomes might differ under another condition. The extension population was selected from patients who completed SHP615-301 and had tolerated and responded to treatment in the hospital setting. These design features constrain both causal interpretation and generalizability beyond the selected study population.

The safety figures report 1 participant with a serious adverse event, 2 participants with other adverse events, and 0 deaths among 3 participants at risk in the SHP615 group. Febrile convulsion is listed at 33.3% among serious adverse event terms. These numbers describe the recorded events in this study; they do not establish treatment causation or quantify comparative risk. With so few participants, the record offers limited information about uncommon or variable outcomes.

Overall, the registry record documents the study question, design, endpoint definitions, and limited safety counts, but it does not provide the primary efficacy result or its uncertainty. The findings that can be stated are descriptive and specific to the enrolled group. Broader or causal conclusions are not supported by the information reported in the registry record.

14. Why This Trial Matters Statistically

This study is statistically notable because its question concerns treatment in community settings, while its population was an extension group with prior hospital treatment experience. That distinction illustrates why the target population and eligibility history matter when interpreting clinical outcomes. A result in people who previously tolerated and responded to treatment may not describe outcomes in a broader group with different treatment histories.

The endpoint also combines several conditions into a single success classification: prompt cessation of visible seizure activity, continued absence of visible activity, and no additional rescue medication. Defining the endpoint in this way makes clear what counts as success, but the composite nature of the rule means readers need to understand each component and the observation window. The record does define those components, while not reporting how many participants met the overall criterion.

The design underscores the difference between description and comparison. A single-group extension can record outcomes and adverse events, but without randomization and a concurrent control it does not isolate the effect of treatment from other influences. Open-label conduct adds another interpretive consideration for outcomes involving assessment. These features are not defects that can be resolved by calculation; they describe the limits of what the design can establish.

Finally, the record highlights the importance of complete results reporting. Enrollment was 3, yet the primary endpoint count and analyses are not reported. Without the endpoint estimate and a measure of uncertainty, readers cannot assess the observed efficacy result or its precision. The safety counts remain useful as a record of events in the enrolled group, while their small denominator limits broader interpretation. These are practical examples of how design, population, endpoint definition, and result availability jointly shape statistical conclusions.

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 enrolled group was small, with 3 participants, which limits the information available about outcome variability and event frequency. The registry record does not report the primary endpoint count, the size of the full analysis set, or an uncertainty interval. As a result, the primary efficacy result and its precision cannot be assessed from the posted record.

The study was non-randomized, single group, and open-label, with no concurrent control described. Outcomes therefore cannot be interpreted as a randomized comparison, and the record does not establish that any observed outcome was caused by treatment. The extension population was also restricted to patients who completed SHP615-301 and tolerated and responded to treatment in the hospital setting. This selection limits how far results, if available, could be generalized to patients with different prior treatment experiences.

The registry lists 15 outcome measures but zero analyses. It does not report statistical methods for endpoint estimation, confidence intervals, multiplicity adjustment, interim analyses, or missing-data handling. Although the primary full analysis set is defined in general terms, participant counts for that set are not given. The protocol's sample-size justification and detailed eligibility criteria are also not reported in the registry record.

Safety interpretation is limited by the small group and the descriptive nature of the reported figures. The record lists 1 participant with a serious adverse event, 2 with other adverse events, and 0 deaths, but these figures do not provide a control comparison or establish causality. Further event-level details are not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of Midazolam Hydrochloride Oromucosal Solution (MHOS/SHP615) in Pediatric Patients With Status Epilepticus (Convulsive) in the Community Setting — NCT03336450.
• Registry record last updated 2021-09-14; status last verified 2021-08.
• Results first posted 2021-09-14.
• 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 NCT03336450 as a completed Phase 3, multicenter, open-label extension study of buccally administered MHOS/SHP615 in pediatric patients with convulsive status epilepticus in community settings. It lists non-randomized allocation, a single-group model, no masking, and enrollment of 3. The study was intended for patients who completed SHP615-301 and tolerated and responded to MHOS/SHP615 treatment in the hospital setting.

The primary endpoint counted participants with therapeutic success, defined by cessation of visible seizure activity within 10 minutes and sustained absence for 30 minutes after a single dose without additional rescue medication. The registry lists 15 outcome measures and zero analyses, but does not report the primary endpoint result. Safety figures list 1 participant with a serious adverse event, 2 with other adverse events, and 0 deaths among 3 participants at risk; febrile convulsion is listed at 33.3% among serious adverse event terms. The record does not provide a randomized comparison or the detailed statistical and missing-data methods.