Adjunctive Ganaxolone Treatment (Part A) in TSC Followed by Long-term Treatment (Part B): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Adjunctive Ganaxolone Treatment (Part A) in TSC Followed by Long-term Treatment (Part B) (NCT04285346), a na phase 2 study. The primary outcome is Percent Change From Baseline in 28-day Seizure Frequency Through the End of 12-Week Treatment Period.

2. Clinical Question

Primary seizures were defined to include atonic/drop, bilateral clonic, bilateral tonic, focal motor without impairment of consciousness or awareness, focal with impairment of consciousness or awareness, focal to bilateral tonic-clonic, and generalized tonic-clonic seizures. The study aimed to assess preliminary safety and efficacy of ganaxolone as adjunctive therapy. Because the study had no concurrent control group, its primary question is a within-participant comparison with baseline, not a randomized estimate of the difference between ganaxolone and another treatment.

3. Trial Design

This was a Phase 2 open-label study of adjunctive ganaxolone for tuberous sclerosis complex-related epilepsy. The registry record classifies the design as single-group, with allocation listed as NA and masking as none. It reports enrollment of 23 and a completed status. The listed start date is 2020-04-08, and the primary completion date is 2021-06-25.

The intervention was ganaxolone. The arm description states that participants received ganaxolone suspension (50 mg/ml) TID for 12 weeks with a 24 week extension. The primary outcome timeframe is baseline and up to Week 12. The registry describes the study aim as assessing preliminary safety and efficacy through the end of the 12 week treatment period.

With a single group and no masking, participants and study staff knew the treatment being used. There is no randomized control group against which to compare seizure frequency or adverse events. The pre-treatment baseline provides a reference for the primary endpoint, but changes from baseline can reflect influences other than treatment, including the natural course of seizure frequency and changes in observation or reporting.

The registry record lists two outcome measures and 0 analyses. These entries do not establish whether analyses were conducted outside the registry record. A numerical primary endpoint estimate, its 95% confidence interval, and the results for the listed secondary outcome are not reported in the registry record. The record also does not report a statistical analysis plan or a sample-size justification for the trial itself.

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 23 participants were enrolled in the study.

Treatment Period (Up to 12 Weeks)

Reasons for not completing this period:

Open Label Period (Week 12 to 38)

Analysis population for the primary outcome, as defined in the registry: Intention to Treat (ITT) Population comprised of all participants who received at least one dose of Ganaxolone and have at least one post-Baseline efficacy assessment.

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 comprised of all participants who have received at least one dose of Ganaxolone.

6. Primary Endpoint

The registry lists the primary outcome as Percent Change From Baseline in 28-day Seizure Frequency Through the End of 12-Week Treatment Period, measured over Baseline and Up to Week 12.

The primary endpoint is percent change from baseline in 28-day seizure frequency through the end of the 12-week treatment period. The registry specifies that the summary measure is a median and the dispersion measure is a 95% confidence interval. It defines primary seizures as a set of seizure types, including atonic/drop, bilateral clonic, bilateral tonic, several focal seizure categories, focal to bilateral tonic-clonic, and generalized tonic-clonic seizures.

The frequency calculation puts seizure counts on a 28-day scale. At baseline, the registry says the total number of primary seizures in the baseline period is divided by the number of days with non-missing seizure data in that period and multiplied by 28. The baseline visit is defined as Week 0. Percent change is defined by comparing the post-baseline 28-day frequency with the baseline 28-day frequency, dividing the difference by the baseline frequency, and multiplying by 100. The registry’s wording describes the difference as post-baseline frequency minus baseline frequency, so a negative change corresponds to a lower frequency relative to baseline.

Standardizing the observation period is useful when participants have different amounts of recorded seizure data: it expresses frequency on a common time scale rather than comparing raw counts from unequal observation periods. The median summarizes the middle of the participant-level distribution and is less affected by unusually large values than the mean. These are general statistical properties, not evidence about the observed trial results. The numerical median and confidence interval are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary summary as a median percent change and its dispersion as a 95% confidence interval. It does not report the numerical estimate, the interval limits, or the method used to calculate that interval. The method should therefore not be inferred from the endpoint description alone.

What does a median change describe?

In general, the median is the middle value when participant-level observations are ordered. For a change endpoint, it describes the center of the distribution of individual changes, not the arithmetic average. This can be useful when participant responses are uneven or when a few unusually large changes would have a strong influence on a mean. A median does not, by itself, describe the spread of individual responses or show whether most participants changed in the same direction.

The endpoint is expressed as percent change from baseline. According to the registry definition, the post-baseline 28-day frequency is compared with the baseline 28-day frequency, and the difference is divided by baseline frequency and multiplied by 100. Under that convention, a value below zero represents a lower frequency after baseline, while a value above zero represents a higher frequency. This explains the sign of the endpoint; it does not indicate the observed sign or size in this study, because the numerical result is not reported in the registry record.

Why express seizure counts per 28 days?

The registry calculates baseline 28-day seizure frequency using the total number of primary seizures divided by the number of days with non-missing seizure data in the baseline period, then multiplied by 28. In general, this kind of rate standardization makes observations with different amounts of recorded follow-up more comparable. A raw count over a longer observation period would generally have more opportunity to include events than a raw count over a shorter period. The registry defines the baseline visit as Week 0 and describes the endpoint as extending through up to Week 12.

That calculation depends on the observed seizure data and the days considered to have non-missing data. The registry description does not explain how gaps in recording were handled beyond this denominator definition, nor does it report any imputation approach. A standardized rate is not the same as a complete record of every seizure that might have occurred during unobserved days. The magnitude of any resulting influence cannot be assessed without further information about missingness and the analysis.

What does the confidence interval add?

In general, a confidence interval communicates statistical uncertainty around an estimated quantity, taking account of the data and the method used to construct the interval. It should be read alongside the point estimate: a narrow interval indicates greater precision under the method’s assumptions than a wide interval. A 95% confidence interval is not a statement that there is a 95% probability that a fixed true value lies inside the particular interval. The registry specifies a 95% confidence interval for the primary endpoint, but the interval and its construction method are not reported in the registry record. Its precision therefore cannot be evaluated.

The use of a median can require methods tailored to the distribution of the data, especially when sample sizes are limited or observations are highly skewed. This is a general methodological point. The record does not state whether the interval was based on a distribution-free method, a model, resampling, or another approach. No method should be assigned to the trial without a report of it.

How does the design affect statistical interpretation?

In general, a single-group baseline comparison estimates change over time among the people observed; it does not estimate a treatment contrast against a control group. Random allocation can help balance measured and unmeasured factors between treatment groups, but this record lists allocation as NA and describes a single group. It therefore does not support a randomized between-group treatment effect. Since masking is listed as none, outcome recording and other study processes may also be susceptible to awareness of treatment. These design features limit causal interpretation, irrespective of the statistical summary used.

The endpoint is a participant-level percentage change, summarized by its median. The registry does not state whether all planned assessments were included, how multiple post-baseline measurements were reduced to a participant-level value, or how the end-of-treatment observation was selected when data were available at different times. Those details are not reported in the registry record. The phrase “through the end of 12-week treatment period” defines the endpoint window, but does not provide a full analysis algorithm.

The primary analysis population is described as the Intention to Treat (ITT) Population comprising all participants who received at least one dose of ganaxolone and had at least one post-baseline efficacy assessment. This is the population definition in the registry, although it requires a post-baseline assessment and thus does not include people without one. The record does not report the number included in the primary endpoint analysis or whether the analyzed population differed from this definition.

The registry’s planning illustration assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a stated fraction of the observed effect. These are planning assumptions for an illustration, not a description of the design of this single-group trial. The record does not report that this trial used two arms or that the illustration’s assumptions formed its statistical plan. Sample-size planning under an assumed effect is not observed power and does not establish the precision or significance of the study’s unreported result.

10. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a multiplicity procedure for handling more than one outcome or analysis. It lists the primary percent change endpoint and a secondary outcome based on the percentage of participants experiencing a >=50 Percent Reduction in 28-day Primary Seizure Frequency through the end of the 12-week treatment period. No hierarchy, adjustment method, or testing sequence is reported in the registry record. Without that information, the results cannot be interpreted as if a particular multiplicity strategy had been used.

The record lists 0 analyses. This describes the analysis information recorded there; it does not establish whether analyses were performed elsewhere. Numerical results for the primary endpoint and secondary outcome are not reported in the registry record, and no p-values or confidence interval limits are available for interpreting statistical evidence.

The primary population is defined as participants who received at least one dose and had at least one post-baseline efficacy assessment. The registry does not report the number included in the primary analysis, the amount or pattern of missing seizure data, or whether participants with incomplete follow-up were handled in a particular way. The baseline frequency calculation uses the number of days with non-missing seizure data, but this does not specify how missing post-baseline observations were addressed. Imputation, sensitivity analyses, and rules for incomplete outcome data are not reported in the registry record.

In general, missingness can affect estimates when the chance that data are unavailable is related to seizure frequency or participant characteristics. Sensitivity analyses can examine how conclusions change under different assumptions, but the registry does not report such analyses. These general considerations identify questions for interpretation; they do not establish that missing data caused bias in this study.

11. 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: thalamic infarction (11.1%), seizure (4.3%), aspiration (4.3%), angioedema (4.3%).

The registry lists serious adverse events for two labeled periods: “Treatment Period: Ganaxolone” and “Open Label: Ganaxolone.” For the first, 23 participants are listed at risk, 3 are listed with serious adverse events, and deaths are listed as 0. For the second, 9 are listed at risk, 1 is listed with serious adverse events, and deaths are listed as 0. These entries should be read separately by period; the record does not establish how participants may relate across the periods, so the figures should not be added or treated as independent groups.

The most common serious adverse event terms listed are Thalamic infarction, 11.1%; Seizure, 4.3%; Aspiration, 4.3%; and Angioedema, 4.3%. The registry record does not specify in this summary how these term percentages relate to the period-specific denominators. The listed terms may not represent mutually exclusive participants, and they should not be summed to infer a total.

Other adverse events are listed for 20 of 23 at risk in the treatment period and 3 of 9 at risk in the open-label period. These are descriptive counts, not comparative estimates against a control group. The registry record does not provide a causal attribution method, exposure-adjusted rates, or a basis for estimating comparative risk. The figures alone do not establish whether an event was caused by ganaxolone.

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

The record establishes that a Phase 2 open-label, single-group trial was designed to assess adjunctive ganaxolone in tuberous sclerosis complex-related epilepsy, with a primary endpoint based on change from baseline in 28-day primary seizure frequency through the end of the 12-week treatment period. It also defines a secondary outcome based on a threshold reduction in seizure frequency and records safety information for named treatment periods.

It does not report the numerical primary endpoint estimate or its 95% confidence interval. It therefore does not show how large the median change was, whether the estimate was above or below baseline, or how precisely the change was estimated. The secondary outcome’s numerical result is also not reported in the registry record. Without these results, the record cannot support a conclusion about the observed size or distribution of seizure-frequency changes.

Even if a change from baseline were available, the single-group design would not distinguish treatment-associated change from other changes over time. In general, seizure frequency can vary over time, and baseline comparisons can be affected by that variation, changes in observation, or regression to the mean. The study is open-label, so treatment awareness is another consideration when outcomes are recorded. These are general interpretive cautions, not claims that a particular bias occurred in this trial.

Safety counts provide a description of recorded events among participants at risk in the named periods. With no concurrent control group, they do not provide a comparative estimate of adverse-event frequency. The registry’s zero death entries describe the recorded counts for those periods; they do not by themselves characterize every aspect of safety or establish causal relationships.

Accordingly, the registry record supplies useful information about the question, design, endpoint definitions, and recorded safety counts, but not the numerical efficacy results needed to judge the observed change or its precision. It cannot establish a causal treatment effect or a comparison with another therapy.

13. Why This Trial Matters Statistically

This trial is statistically informative as an example of how an epilepsy endpoint can be defined and standardized. The primary measure uses seizure frequency expressed on a 28-day scale and compares the post-baseline frequency with a baseline rate calculated using days with non-missing seizure data. That structure makes the time unit explicit and ties the outcome to primary seizure types specified in the registry.

The record also illustrates the difference between defining an estimand and reporting its result. It specifies a median percent change and a 95% confidence interval, but does not report the estimate or interval. Readers can identify the intended summary and time window, yet cannot judge its magnitude, direction, or precision. Reporting the numerical result and its analysis method would be necessary for that statistical interpretation.

The design is important to the question the data can answer. An open-label, single-group baseline comparison can describe change over time in the analyzed population. It does not provide a randomized contrast with a control group. That distinction is central when interpreting clinical trial evidence: a clearly defined change measure does not, by itself, identify how much change is attributable to the intervention.

The registry record also makes the analysis population definition and safety periods visible. These details help readers ask whether participants with incomplete outcome data were included and how event counts relate to the follow-up period. The record does not supply all the information needed to resolve those questions, including missing-data methods and the numerical efficacy analyses.

14. 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 trial-specific limitation for interpretation is the absence of a reported numerical primary endpoint result. Although the registry specifies a median and a 95% confidence interval, neither the estimate nor interval limits are reported in the registry record. The secondary outcome’s numerical result is also not reported. This prevents assessment of effect direction, magnitude, and precision.

The study is identified as single-group, open-label, with allocation listed as NA and masking as none. There is no concurrent control group, so a baseline comparison cannot separate change during treatment from other influences over time. Treatment awareness may also affect how outcomes are observed or recorded. These are design limitations for causal interpretation, not evidence that a particular bias occurred.

The primary population requires at least one dose and at least one post-baseline efficacy assessment. The registry does not report how many participants contributed to the primary endpoint, how many had incomplete follow-up, or whether the analysis population matched the stated definition. It gives a baseline rule using days with non-missing seizure data but does not report methods for missing post-baseline data, imputation, or sensitivity analyses.

The registry record lists 0 analyses and does not report the statistical analysis plan, interval-construction method, multiplicity approach, or sample-size justification for the trial. The planning assumptions recorded for an illustration should not be treated as this study’s design or analysis plan. The available safety counts are descriptive and lack a randomized comparator; the relationship between listed serious-event terms and the period-specific denominators is not specified in the summary.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Adjunctive Ganaxolone Treatment (Part A) in TSC Followed by Long-term Treatment (Part B) — NCT04285346.
• Registry record last updated 2023-04-04; status last verified 2023-03.
• Results first posted 2023-04-04.
• 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.

18. Record Summary

NCT04285346 is a completed Phase 2, open-label, single-group trial of adjunctive ganaxolone in tuberous sclerosis complex-related epilepsy. The registry lists enrollment of 23, a start date of 2020-04-08, and a primary completion date of 2021-06-25. The intervention description specifies ganaxolone suspension (50 mg/ml) TID for 12 weeks with a 24 week extension.

The primary endpoint is median percent change from baseline in 28-day primary seizure frequency through the end of the 12-week treatment period, with a specified 95% confidence interval. The numerical primary result and interval are not reported in the registry record. A secondary outcome concerns the percentage experiencing a >=50 Percent Reduction in 28-day Primary Seizure Frequency, but its numerical result is also not reported.

The record lists safety counts by treatment period, including serious adverse events, other adverse events, and deaths. Because the design has no concurrent randomized control group, efficacy changes and safety counts are descriptive rather than controlled comparisons.