Study to Evaluate SAGE-547 Injection as Adjunctive Therapy for the Treatment of Super-Refractory Status Epilepticus: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Evaluate SAGE-547 Injection as Adjunctive Therapy for the Treatment of Super-Refractory Status Epilepticus (NCT02052739), a randomized phase 1, phase 2 study. The primary outcome is Number of Participants With Treatment-Emergent Adverse Events (TEAEs).

2. Clinical Question

3. Trial Design

The registry record describes an open-label, randomized, parallel-group Phase 1/Phase 2 study. Participants were assigned to a standard-dose or high-dose SAGE-547 regimen. No masking was used, so the study was not blinded. The record does not report the randomization procedure, allocation ratio, or whether any safeguards were used to conceal assignments before allocation.

Both groups received SAGE-547 by intravenous infusion. The listed regimens include loading, maintenance, and taper phases, with different maintenance dosing in the two groups. The arm descriptions in the registry record are incomplete, so the full taper schedules cannot be reconstructed from them. No separate placebo or usual-care comparison group is listed.

The planned enrollment was 25 participants. The posted primary outcome includes 19 participants in the standard-dose group and 6 in the high-dose group. The study began on 2014-03-21, had a primary completion date of 2015-05-03, and is recorded as completed. The registry lists the purpose as evaluating safety and tolerability in participants with super-refractory status epilepticus.

Although allocation is described as randomized, the study is open label and the reported results are principally counts of events in small groups. The registry record does not report a statistical analysis plan, a sample-size justification, or methods for estimating a dose-group contrast. Those details therefore cannot be used to interpret the allocation or to establish what comparative analyses were intended.

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 25 participants were enrolled into the study to receive either SAGE-547 standard dose or SAGE-547 high dose,19 participants of whom completed the study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety population included all participants who were initiated with an infusion of SAGE-547.

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 population included all participants who were initiated with an infusion of SAGE-547.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment-Emergent Adverse Events (TEAEs), measured over Up to Day 29.

The primary endpoint is the number of participants with treatment-emergent adverse events, or TEAEs, through Day 29. A TEAE is defined as an adverse event that begins on or after initiation of the SAGE-547 infusion. The record defines an adverse event broadly as an untoward medical occurrence during the investigation; it need not be judged related to treatment. The definition includes unfavorable signs, symptoms, diseases, or clinically significant laboratory findings temporally associated with drug use.

The endpoint is a participant count, rather than a count of every event episode. It summarizes how many participants experienced at least one qualifying event during the stated timeframe. The primary safety population consists of all participants who started a SAGE-547 infusion.

Counting participants with TEAEs is useful for describing the observed safety experience in each group. It does not establish causation: an event may occur after treatment begins without being caused by the drug. Nor does the count describe event severity, duration, or clinical consequences. Those questions require other outcome details. The endpoint also does not directly answer whether treatment affected seizure activity or other measures of efficacy.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count describe?

The primary outcome is binary at the participant level: each participant either had a recorded TEAE during the defined timeframe or did not. The reported values are counts of participants with an event, accompanied by the number of participants in each group. This format is straightforward to interpret descriptively, but the counts alone do not quantify uncertainty around a comparison.

In general, an estimate of a difference between two groups answers a comparative question, while a count in each group answers a descriptive one. A confidence interval can show the range of effect sizes compatible with the observed data under the chosen method. A p-value can summarize how compatible the data are with a specified statistical model and null hypothesis. Neither type of result is reported for the primary two-arm comparison in the registry record. The record states that values were missing or not estimable for a two-arm comparison.

Why is uncertainty important?

In general, estimates based on fewer participants tend to be less precise than estimates based on more participants, all else being equal. The high-dose group includes 6 participants, compared with 19 in the standard-dose group. That imbalance means the observed count in the smaller group represents fewer observations. It does not make the count invalid, but it is important when considering how much information the groups contribute to a comparison.

In general, a confidence interval is more informative than a point estimate alone because it communicates both the estimated effect and its uncertainty. No confidence interval for the primary comparison is reported, so the precision of a dose-group contrast cannot be assessed from the posted primary outcome. The counts should not be interpreted as proof of equivalence, a difference, or a causal effect.

How do the planning assumptions relate to the trial?

The registry record describes a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between groups, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. This is a planning exercise, not evidence about the trial's original design or a measure of the probability that the study detected an effect. The sample-size justification and the trial's own design assumptions are not reported in the registry record.

In general, a planning sample size depends on assumptions about the effect to be detected, variability or event frequency, the significance threshold, and the desired power. Changing those assumptions changes the resulting planning estimate. Such an estimate is not an observed outcome and should not be described as observed power. The registry record does not report a sample-size justification that can be attributed to the study team.

What does randomization contribute?

Random allocation can, in general, help balance known and unknown participant characteristics between groups, supporting a causal comparison when the design and analysis are suitable. The registry record identifies the study as randomized, but does not state the randomization method, allocation ratio, or concealment procedure. The study was open label, so participants and investigators were not masked to assigned group according to the listed masking status. Randomization alone does not resolve limitations from the small groups, the absent comparative estimate, or missing methodological details.

Why does the binary outcome matter?

For a binary endpoint, each participant contributes an event status rather than a measurement on a continuous scale. In general, methods for estimating a between-group effect can use different scales, such as a difference in event probabilities or a relative measure. The registry record does not report a comparative estimate on any scale for the primary endpoint. No new estimate can be inferred solely from the posted counts without performing a recalculation, and the posted analysis does not supply such an estimate.

For count outcomes, over-dispersion matters when observed variation exceeds what a chosen statistical model expects; in general, ignoring it can make uncertainty estimates too narrow. That concern is not directly assessable for this primary endpoint, which is reported as the number of participants with an event, and the registry record does not describe a model or an over-dispersion assessment. The study's statistical methods for the primary outcome are not reported in the registry record.

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("SAGE-547 Standard Dose", "SAGE-547 High Dose")
n      <- c(19, 6)
events <- c(17, 6)
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  SAGE-547 Standard Dose  19  17  89.5  66.9  98.7  68.6  97.1  68.3  96.8
ARM  SAGE-547 High Dose  6  6  100.0  54.1  100.0  61.0  100.0  59.0  99.6

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists secondary outcomes covering relapse, treatment response, duration of response, and several plasma concentration or exposure measures. It reports 61 outcome measures overall and 16 secondary outcomes posted. The presence of multiple outcomes raises a general interpretive issue: when many statistical hypotheses are tested, the chance of at least one apparently noteworthy result can increase. Whether and how that issue was addressed depends on the prespecified analysis plan.

A multiplicity adjustment or hierarchy for testing outcomes is not reported in the registry record. Nor is a statistical analysis plan describing confirmatory and exploratory analyses. The record lists no inferential analyses for the posted results. Consequently, it is not possible to assess any multiplicity strategy or determine whether secondary findings were intended as formal hypothesis tests.

Missing-data methods are also not reported in the registry record. The primary safety population is defined as participants who started an infusion of SAGE-547, but the record does not describe how incomplete follow-up, missing event assessments, or withdrawals were handled. The posted primary counts do not explain whether every participant had complete observation through Day 29.

The registry record does not report analysis populations for the secondary outcomes or specify whether analyses followed intention-to-treat, per-protocol, or other principles. Those labels should not be inferred from the randomized design. The safety-population definition is the only primary population detail stated for the TEAE outcome.

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: sepsis (16.7%), peritonitis (16.7%), hypotension (16.7%), multi-organ failure (16.7%), metabolic acidosis (16.7%).

The registry record reports serious adverse events for 14 of 19 participants in the standard-dose group and 2 of 6 in the high-dose group. It reports other adverse events for 15 of 19 and 6 of 6, respectively. Deaths are listed for 5 participants in the standard-dose group and 1 in the high-dose group. These are separate reported counts; the record does not establish that the categories are mutually exclusive, so they should not be added together.

The listed serious adverse event terms are sepsis, peritonitis, hypotension, multi-organ failure, metabolic acidosis, and acute renal failure, each reported as 16.7%. The registry record does not specify the denominator or further detail for those percentages in the information available for interpretation.

These figures are descriptive observations from the study groups. They do not establish that SAGE-547 caused the events or deaths, and they do not support a causal comparison between regimens. The groups are small, and the registry record does not report comparative estimates or uncertainty intervals for these safety categories. A listed event count also does not convey timing, duration, severity beyond its classification, or individual clinical circumstances.

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

The posted results establish that TEAEs were recorded in 17 participants in the standard-dose group and 6 in the high-dose group, through Day 29. The registry also records serious adverse events, other adverse events, and deaths in both dose groups. These observations describe the safety experience recorded during the study, using the endpoint definitions and populations stated in the registry record.

The results do not establish that SAGE-547 caused each event, because the TEAE definition does not require a causal relationship. They do not establish that one dose regimen has a higher or lower risk than the other: the record does not report a comparative estimate, confidence interval, or p-value for the primary endpoint. The observed counts alone cannot show how precise a dose-group contrast would be.

The study does not include a listed placebo or untreated group, so the reported results do not provide a direct comparison with no SAGE-547 treatment. The open-label design and the limited methodological details also constrain interpretation. Although the study is described as randomized, the allocation method and analysis plan are not reported in the registry record.

The primary endpoint is a safety measure, not a direct measure of seizure response. Secondary outcomes include response and relapse measures, but the information available does not support a claim about their results. The posted counts should therefore be read as descriptive safety data from a completed study, not as proof of benefit, harm, or equivalence between dose regimens.

14. Why This Trial Matters Statistically

This study illustrates why a trial's design label and its reported analysis need to be considered together. Randomization can support fair comparisons, but the registry record does not describe how allocation was carried out or provide a comparative estimate for the primary outcome. The study is also open label, and the safety results are reported as counts in two groups.

The group sizes are 19 participants in the standard-dose group and 6 in the high-dose group. Those counts show that the evidence for the high-dose group comes from a smaller set of participants. In general, small groups limit precision and make estimates more sensitive to the experience of individual participants. Without uncertainty intervals, readers cannot quantify that limitation for a particular contrast.

The primary endpoint is clinically relevant to safety monitoring because it records participants with events after infusion begins. Its broad definition is also important: an event need not be caused by the treatment to qualify. Distinguishing event occurrence from treatment causation is essential when interpreting safety counts.

Finally, the record demonstrates the value of transparent reporting. Information about analysis methods, missing data, multiplicity, and sample-size justification is not reported in the registry record. These omissions limit what can be concluded from the posted results, even though the registry supplies outcome counts and a defined safety population. Clear descriptions of design and uncertainty help readers distinguish observed data from comparative evidence.

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 main limitation for interpreting the primary outcome is that no comparative estimate or uncertainty interval is reported. The registry record states that values were missing or not estimable for a two-arm comparison. Thus, the group counts cannot be translated into a reported estimate of the contrast's size or precision.

The high-dose group includes 6 participants, while the standard-dose group includes 19. Both groups are small, and the difference in group size means that the counts are based on unequal amounts of information. The record does not report the reason for this allocation pattern or whether it was planned.

The study is open label, and no separate placebo or untreated group is listed. The primary outcome is a broad adverse-event measure that does not require investigators to judge an event as treatment-related. The record does not report how event attribution was assessed or whether assessments were independently reviewed.

Additional methodological details are absent: the randomization procedure, allocation concealment, sample-size justification, statistical analysis plan, multiplicity approach, and missing-data methods are not reported in the registry record. The arm descriptions are incomplete, so the full infusion taper schedules cannot be established from the record. The listed serious-event percentages also lack a specified denominator in the information available. These limitations restrict causal and comparative interpretation; they do not alter the descriptive counts that are posted.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study to Evaluate SAGE-547 Injection as Adjunctive Therapy for the Treatment of Super-Refractory Status Epilepticus — NCT02052739.
• Registry record last updated 2025-09-15; status last verified 2022-04.
• Results first posted 2022-05-03.
• 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 identifies a completed, open-label, randomized, parallel-group Phase 1/Phase 2 study of SAGE-547 in super-refractory status epilepticus. Planned enrollment was 25. The primary safety endpoint was the number of participants with treatment-emergent adverse events through Day 29, among participants who started an infusion.

The posted primary counts are 17 of 19 participants in the standard-dose group and 6 of 6 in the high-dose group. Serious adverse events, other adverse events, and deaths are also reported. The record does not provide a comparative estimate or uncertainty interval for the primary two-arm outcome. The study began on 2014-03-21, with primary completion on 2015-05-03.