Treatment of Fragile-X Associated Tremor/Ataxia Syndrome (FXTAS) With Allopregnanolone: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Treatment of Fragile-X Associated Tremor/Ataxia Syndrome (FXTAS) With Allopregnanolone (NCT02603926), a na phase 2 study. The primary outcome is California Verbal Learning Test II (CVLT2) Trial 1-5 Free Recall Total Raw Score.

2. Clinical Question

The study asked whether allopregnanolone could be examined for safety and efficacy as a possible treatment for symptoms of Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). The primary outcome focused on working memory, measured with the California Verbal Learning Test II (CVLT2) Trial 1-5 Free Recall Total Raw Score. The planned comparison was the score at baseline/pre-treatment with the score at 14 weeks/post-treatment.

This framing matters because a before-and-after observation cannot isolate a treatment effect as securely as a randomized comparison. Changes over time may reflect treatment, but they may also reflect other influences, including natural fluctuation, practice with the assessment, or changes in participants’ circumstances. Those are general possibilities, not findings reported for this trial. The registry record does not report a control group or an analysis capable of separating such influences.

3. Trial Design

The registry classifies this as a Phase 2, single-group study with no masking. Allocation is listed as NA, and enrollment is 6. The listed condition is Fragile X-associated Tremor/Ataxia Syndrome, and the intervention is the drug Allopregnanolone. The record identifies Randi J. Hagerman, MD as sponsor. The study start is listed as 2015-10, primary completion as 2016-12, and status as completed.

The treatment description specifies intravenous infusions with escalating doses of 2mg, 4mg, and 6mg once weekly over a three week period. It then describes holding the highest dose tolerated without sedation stable for the remaining weekly infusions, with a total of 12 infusions. This describes a dose-escalation and maintenance schedule; the registry record does not report how many participants reached each dose, what dose was tolerated by each participant, or whether every participant received the full intended course.

The primary outcome was the CVLT2 Trial 1-5 Free Recall Total Raw Score, measured at baseline/pre-treatment and at 14 weeks/post-treatment. The registry lists three secondary outcomes: Behavioral Dyscontrol Scale - 2 (BDS-2) Total Score, CATSYS Dot-to-Dot Tremor Intensity (CATSYS DTD TI), and hippocampal volume measured by structural MRI. The record reports four outcome measures in total, but does not include their numerical results in the information available for interpretation.

Because the design is not randomized and has no concurrent comparison group, the main estimand available from the planned assessments is a within-group change over time. Such a change can describe what happened among participants measured, but it does not by itself estimate what would have happened over the same period without treatment. No masking also means that expectations could potentially influence participant responses or outcome assessment, depending on how the measure was administered. The registry record does not describe procedures intended to limit those influences.

The record does not report the protocol’s sample-size justification, a formal statistical analysis plan, an interim-analysis plan, or a detailed account of the outcome-assessment procedures. These details should not be inferred from the phase, the enrollment, or the treatment schedule.

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

Analysis population for the primary outcome, as defined in the registry: Primary outcome measure (CVLT2) was completed for all enrolled subjects.

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 California Verbal Learning Test II (CVLT2) Trial 1-5 Free Recall Total Raw Score, measured over Baseline/pre-treatment and 14 weeks/post-treatment.

The primary endpoint is the California Verbal Learning Test II (CVLT2) Trial 1-5 Free Recall Total Raw Score. The registry describes the CVLT2 as an assessment of working memory. Trials 1-5 measure the total number of words remembered after 5 repeated trials, and the responses are summed into a raw score ranging from 0 to 80. Higher scores reflect better working memory according to the registry description.

The endpoint is measured before treatment and at 14 weeks/post-treatment. Repeating the same measure allows the study to describe whether participants’ scores changed over that interval. A verbal learning and recall measure is relevant to the stated question because working memory is an aspect of cognitive function, and the registry describes the outcome specifically as a measure of that domain. It is still a measure of performance on an assessment, not a direct measure of every symptom or aspect of daily functioning associated with FXTAS.

The registry specifies means and standard deviations at baseline/pre-treatment and at 14 weeks/post-treatment as the intended summaries. However, those numerical summaries are not reported in the registry record. A mean would describe the group’s average score at a time point, while a standard deviation would describe how spread out individual scores are around that average. Without the posted values, it is not possible to characterize the baseline distribution, the post-treatment distribution, or the magnitude and precision of the observed change.

Even if both time-point means were available, comparing them would describe a group-level change rather than establish that treatment caused that change. A within-person analysis could also account for the pairing of measurements, but the record does not report such an analysis or its result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean describe? A mean is the arithmetic average of the observed scores in a group. For the CVLT2, the mean at baseline/pre-treatment would describe the group’s average raw score before treatment, and the mean at 14 weeks/post-treatment would describe its average score at the later assessment. A mean is a useful summary, but it can hide variation among participants. The registry specifies that means and standard deviations are the intended summaries, but their values are not reported in the registry record.

What does a standard deviation add? A standard deviation describes the spread of scores around a mean. If scores are tightly grouped, the standard deviation is smaller; if they vary more, it is larger. It describes participant-to-participant variation, not the uncertainty in the estimated mean itself. The latter is often expressed through a confidence interval or standard error. Neither the primary endpoint’s standard deviation values nor an uncertainty interval for its change is reported in the registry record, so the variability and precision of the result cannot be assessed from the reported information.

Why is a confidence interval useful? In general, a confidence interval gives a range of values compatible with an estimate under the assumptions of the analysis. Its width communicates precision: a narrower interval indicates more precision, while a wider interval indicates less. A confidence interval for a within-group change would help readers judge how uncertain that estimated change is. It would not, by itself, remove the design limitation created by the lack of a control group. The registry record does not report a confidence interval for the primary outcome.

How should a pre-post comparison be understood? The same participants are assessed at baseline and after treatment, so the observations are paired: each participant’s later score is connected to that participant’s earlier score. A paired analysis generally uses the within-participant changes and their variability. Treating measurements as if they came from unrelated groups would fail to use that pairing and could misrepresent uncertainty. The registry record reports the planned measurement times but does not describe the statistical test or model used to analyze them. No registered analysis is listed.

A difference between group averages at the two time points is not necessarily the same as the average of participants’ individual changes, especially if some participants lack measurements at one time. The analysis population and missing-data handling therefore matter. The primary outcome description says it was completed for all enrolled subjects, but does not report participant-level scores, an analysis method, or details about missing data for secondary outcomes. No imputation method or sensitivity analysis is reported in the registry record.

Why does the single-group design matter? A randomized controlled trial uses a comparison group to help separate treatment effects from background changes over time. This study is classified as single group, and allocation is NA, so the record does not describe a randomized treatment comparison. A baseline score can serve as a reference for later measurement, but it is not a substitute for a concurrent control group. In general, scores can change because of assessment familiarity, natural variation, or other events during follow-up. The record does not determine whether any of these influences occurred; they are reasons to interpret an uncontrolled change cautiously.

No masking is listed. In general, masking can reduce the influence of expectations on reported symptoms, participant behavior, and some outcome assessments. The extent of potential influence depends on the outcome and the way it is collected. The CVLT2 is a standardized assessment, but the record does not describe assessor masking, administration procedures, or other safeguards. It is therefore not possible to characterize those procedures beyond the listed masking status.

What does over-dispersion mean in general? For count outcomes, over-dispersion means the observed variation is greater than a basic statistical model assumes. A model that underestimates variation can make uncertainty intervals too narrow and tests appear more decisive than warranted. This is a general concept; the primary endpoint is a continuous score, and the registry record does not report an analysis involving over-dispersed count data.

How do planning illustrations differ from trial results? Sample-size illustrations can show how many participants per arm might be required under specified assumptions, such as a two-sided significance level of 0.05, equal allocation, a normal approximation, and an effect defined as a stated fraction of an observed effect. The registry’s planning description characterizes such calculations as illustrations based on the observed effect, not as the trial’s own design. The record does not report the observed numerical effect needed to interpret those illustrations. Planning calculations are not observed power, do not establish that an effect exists, and do not replace reporting the outcome estimate and its uncertainty. A justification for the actual enrollment is not reported in the registry record.

What can be concluded when analysis details are absent? Statistical interpretation depends on knowing the outcome estimate, its uncertainty, the analysis population, and the method used. For this study, the record identifies the primary measure and states that it was completed for all enrolled subjects, but the numerical result and registered analyses are absent. It is not possible to verify whether the analysis used paired observations, how secondary outcomes were treated, or whether any adjustment was made. Those omissions constrain reproducibility and make it inappropriate to infer a statistical conclusion from the design description alone.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists the CVLT2 measure as the primary outcome and identifies three secondary outcomes: BDS-2 Total Score, CATSYS DTD TI, and hippocampal volume measured by structural MRI. It also reports four outcome measures in total. When a study evaluates several outcomes, the chance of finding an apparently notable result by chance can increase if many tests are performed. General approaches include identifying a primary outcome in advance, adjusting for multiple comparisons, or treating secondary results as exploratory. The registry record does not report a multiplicity adjustment, a hierarchy among secondary outcomes, or the analysis plan for those outcomes.

Missing-data handling is also not described. The primary outcome is stated to have been completed for all enrolled subjects, but the record does not give the numerical data or state how missing data, if any, were handled for other measures. It does not report imputation, a complete-case analysis, or sensitivity analyses. Those methods should not be assumed.

The analysis population is not described beyond the statement that the primary outcome was completed for all enrolled subjects. The record does not say whether analyses followed an intention-to-treat principle, included only participants with particular observations, or used another defined population. No registered analyses are listed. Consequently, the available information does not show how multiplicity, missing outcomes, or analysis-set choices affected any estimated result.

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.

The registry reports the Allopregnanolone group as having 6 participants at risk for serious adverse events, 0 affected, 6 at risk for other adverse events, 0 affected, and 0 deaths. These are recorded counts for the group, not comparisons against a control group. The registry does not list serious adverse-event terms.

A count of 0 means that no event in the relevant category is recorded among the participants at risk in this entry. It does not prove that the treatment cannot cause an event, and it does not establish that every possible adverse event was detected or reported. Safety interpretation also depends on observation duration, event definitions, collection procedures, and completeness of reporting; these details are not reported in the registry record.

The treatment description includes dose escalation and states that the highest dose tolerated without sedation was to be maintained. The safety counts do not show individual tolerability, the dose reached by each participant, or whether any dose adjustments occurred. Those details are not reported in the registry record. The absence of recorded serious and other adverse events should therefore be read as a narrow summary of the listed counts, not as a comprehensive safety profile.

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

The record establishes that a completed Phase 2 study evaluated intravenous Allopregnanolone in a single group of participants with FXTAS. It specifies a primary working-memory measure, assessment times, a dose-escalation and maintenance schedule, three secondary outcomes, and the reported safety counts. The primary outcome measure is stated to have been completed for all enrolled subjects.

What the record does not establish is the numerical change in CVLT2 score. The means and standard deviations at baseline/pre-treatment and 14 weeks/post-treatment are not reported in the registry record, and no analysis or confidence interval for the outcome is listed. It is therefore not possible to determine from this information whether the group’s average score changed, how large any change was, or how precisely it was estimated. Results for the secondary outcomes are also not reported in the registry record.

Even if a before-and-after change were documented, the single-group design would limit causal interpretation. Without a concurrent control group, a change cannot be separated reliably from other influences that may occur over time. This is a general limitation of this design, not evidence that any particular alternative explanation affected these participants. The lack of masking is another design feature to consider, although the record does not provide details about outcome administration or assessor procedures.

The safety entry records 0 serious adverse events, 0 other adverse events, and 0 deaths in the Allopregnanolone group, with 6 at risk in each adverse-event category. These counts are informative as registry entries but do not establish the absence of all harms or fully describe tolerability over the treatment period.

Thus, this record supports a description of what was planned and a limited account of recorded safety events, but not a conclusion that treatment improved or failed to improve working memory, or that it was effective or ineffective. Those conclusions would require numerical outcome results, uncertainty estimates, and careful consideration of the uncontrolled design.

13. Why This Trial Matters Statistically

This study illustrates the distinction between an outcome being specified and an outcome result being available for interpretation. The registry identifies a defined primary measure, explains how it is scored, and gives the assessment time points. Those details make the intended question understandable. Without the score summaries or an analysis of change, however, readers cannot assess the observed result or its precision. Clear outcome definitions are valuable, but they do not replace reporting the data and analysis.

Its single-group, unmasked design also makes the difference between describing change and attributing change especially important. Repeated measurement can show what happened to the treated group over time, but without a control group it does not establish what would have happened over the same period without the intervention. This distinction applies broadly to clinical research and is particularly important when interpreting pre-post observations.

The record additionally shows why safety counts require context. A zero count is a report about events recorded in the study group, not proof that risk is absent. The treatment schedule includes dose escalation and a tolerability condition for maintaining a dose, but the registry does not report individual dosing or tolerability. More complete reporting would help connect the aggregate safety counts to participants’ actual exposure.

Finally, listing several outcomes raises a statistical reporting issue: readers need to know which outcomes were primary, how secondary outcomes were analyzed, and whether multiple comparisons were considered. The primary outcome is identified, but analysis details are not reported in the registry record. Taken together, these features make the study useful for understanding the planned measurement strategy while underscoring why interpretable results require outcome estimates, uncertainty, analysis methods, and design context.

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 limitation for interpreting outcomes is that numerical results are not reported in the registry record. The primary endpoint description gives the score range, direction, and planned measurement times, but not the group means, standard deviations, or estimated change. The secondary outcome results are likewise not reported. This prevents assessment of effect magnitude, direction, variability, and precision.

The single-group design has no concurrent comparator, and masking is listed as none. These features limit the ability to attribute any observed pre-post change to treatment. They do not show that bias or other influences actually occurred, but they leave those explanations unresolved. The record does not report procedures for assessor masking or other methods to reduce expectation effects.

The treatment schedule describes escalation and maintenance, but participant-level exposure is not reported. It is unknown from this record which doses participants reached, how many received each dose, or whether all intended infusions were completed. The adverse-event counts are aggregate entries and do not provide event descriptions, timing, severity beyond the serious/non-serious categorization, or participant-level details. The registry does not list serious adverse-event terms.

Analysis reporting is limited: no registered analyses are listed, and statistical methods, analysis populations, missing-data procedures, and multiplicity handling are not reported in the registry record. Although the primary outcome is stated to have been completed for all enrolled subjects, the record does not provide details about completion or missing observations for the secondary measures. The protocol’s sample-size justification and any interim-analysis plan are also not reported. These limitations preclude a detailed evaluation of robustness or reproducibility.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Treatment of Fragile-X Associated Tremor/Ataxia Syndrome (FXTAS) With Allopregnanolone — NCT02603926.
• Registry record last updated 2018-12-06; status last verified 2018-11.
• Results first posted 2018-12-06.
• 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

This completed Phase 2 study was a single-group, unmasked evaluation of intravenous Allopregnanolone for Fragile X-associated Tremor/Ataxia Syndrome, with enrollment of 6. The regimen described escalating doses of 2mg, 4mg, and 6mg once weekly over a three week period, followed by maintenance at the highest dose tolerated without sedation, for a total of 12 infusions.

The primary outcome was the CVLT2 Trial 1-5 Free Recall Total Raw Score, assessed at baseline/pre-treatment and 14 weeks/post-treatment. The registry lists three secondary outcomes covering behavioral dyscontrol, tremor intensity, and hippocampal volume. It states that the primary outcome measure was completed for all enrolled subjects.

The registry reports 0 serious adverse events, 0 other adverse events, and 0 deaths in the Allopregnanolone group. Numerical primary and secondary outcome results, statistical analyses, and detailed missing-data and analysis-population methods are not reported in the registry record. The absence of a control group limits causal interpretation of any pre-post change.