N-Acetyl-L-Leucine for GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for N-Acetyl-L-Leucine for GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease) (NCT03759665), a non-randomized phase 2 study. The primary outcome is Clinical Impression of Change in Severity (CI-CS) [Fields et al 2021].

2. Clinical Question

3. Trial Design

This was a multinational, multicenter, open-label, rater-blinded Phase II study sponsored by IntraBio Inc. The registry classifies its allocation as non-randomized and its model as single group. Enrollment was 30, and the study status is completed. The registry record lists a start date of 2019-06-07 and a primary completion date of 2023-01-09.

The Parent Study evaluated N-Acetyl-L-Leucine, or IB1001, for symptomatic treatment. It included 6-weeks of oral treatment, followed by a 6-week post-treatment washout. The Extension Phase involved 1-year of oral treatment and was described as exploratory, with a focus on long-term safety and efficacy for neuroprotective, disease-modifying treatment. The record’s primary endpoint is defined around the Parent Study treatment and washout periods.

Open-label means participants and the treating team were not blinded to treatment assignment. Rater-blinded means the person judging the videos was blinded, as described in the endpoint assessment. This distinction matters because a blinded rater may reduce some assessment bias, but it does not turn the study into a randomized or placebo-controlled comparison. The registry record does not report a separate control arm.

The primary endpoint compares mean change in CI-CS across the treatment period with mean change across the post-treatment washout period. This is a comparison of periods within a single-group study, not a randomized between-group treatment effect. The registry record does not report the protocol’s sample-size justification, statistical plan, interim analyses, or details of how treatment and washout data were modeled.

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.

Treatment With IB1001

Post-Treatment Washout

Analysis population for the primary outcome, as defined in the registry: Modified Intention to Treat (mITT) Analysis Set is defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both).

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 Clinical Impression of Change in Severity (CI-CS) [Fields et al 2021], measured over (CI-CS comparing Baseline [Day 1] with IB1001 versus the end of 6-weeks treatment with IB1001 [approximately Day 42]) MINUS (CI-CS comparing the end of 6-weeks treatment with IB1001 [approximately Day 42] versus end of 6-weeks post-treatment washout);.

The primary endpoint is the difference between mean CI-CS change during IB1001 treatment and mean CI-CS change during post-treatment washout. The CI-CS is a clinical rating of change in severity, based on a blinded rater’s comparison of videos of performance on the 9 Hole Peg Test of the Dominant Hand or the 8 Meter Walk Test. Its 7 point Likert scale runs from +3, significantly improved, to -3, significantly worse.

For each period, the endpoint description defines change by comparing the relevant video assessments. The mean change in the washout period is then subtracted from the mean change during treatment. A positive value is defined in the registry as improvement in the treatment period relative to the washout period. This contrast is intended to distinguish change during treatment from change after treatment has stopped, rather than to compare IB1001 with a concurrent control group.

A rater-blinded assessment is relevant because the endpoint depends on judgment of recorded performance. The registry record does not report the primary endpoint’s numerical result, its standard deviation, confidence interval, or p-value. Without those results, the size and precision of the observed contrast cannot be interpreted from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study’s main statistical contrast uses a continuous outcome summarized as a mean and standard deviation. The primary outcome is not a direct comparison of separate randomized groups. Instead, the registry defines a treatment-period change and a washout-period change, then subtracts the latter mean change from the former. The direction is defined so that a positive contrast indicates improvement during treatment relative to washout. The registry record does not report the estimate or its uncertainty.

What does a mean describe?

In general, a mean represents the average value in an analysis population. It gives a compact summary of the center of the observed measurements, but does not show how widely individual measurements vary. The standard deviation describes that spread. It is not the same as the uncertainty in the estimated mean: uncertainty in an estimate depends on the data and analysis, and is commonly conveyed using a confidence interval. The registry record identifies mean and standard deviation as the primary outcome’s summary measures, but does not report their numerical values.

How should the period contrast be read?

The endpoint definition first considers change during treatment and change during washout. The mean change in the washout period is then subtracted from the mean change during treatment. A positive value therefore means the average change favored the treatment period according to the endpoint’s stated direction. It does not, by itself, show that treatment caused the difference. In a non-randomized single-group design, changes over time and differences between periods can have explanations other than the intervention.

The registry’s assessment uses videos and a blinded rater. Blinding the rater can reduce the possibility that knowledge of treatment influences the rating. However, blinding the assessor does not remove other sources of bias, and it does not make the treatment allocation randomized. The trial is described as open-label and rater-blinded, so participants and the treating team were not blinded in the way a fully blinded controlled study would be.

What does a confidence interval add?

In general, a confidence interval describes the range of values compatible with the observed data and the method’s assumptions. A narrower interval indicates greater precision, while a wider interval indicates more uncertainty. It is useful to consider the interval’s direction and span alongside the point estimate, rather than relying only on whether a p-value crosses a threshold. No confidence interval for the primary endpoint is reported in the registry record, so its precision cannot be assessed from this record.

What does a p-value address?

In general, a p-value measures how incompatible the observed data are with a specified null hypothesis under the statistical model. It does not measure the probability that the null hypothesis is true, the size of an effect, or the probability that a result will repeat. Interpretation depends on the design, endpoint, assumptions, and analysis plan. The registry record does not report a primary endpoint p-value or the inferential procedure used for it.

How should planning calculations be understood?

The study’s planning illustration is described as a calculation based on the observed effect, not the trial’s own design. Its stated assumptions include a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; it describes planning for a stated fraction of the observed effect. For non-time-to-event outcomes, the illustration is expressed as participants per arm. Such calculations are hypothetical planning aids. They are not observed power, do not change the study’s single-group design, and do not establish that the trial was prospectively designed to detect the observed effect. The registry record does not report the trial’s own sample-size justification.

General statistical practice also considers whether the model’s assumptions fit the outcome and data structure. For example, over-dispersion matters when variability is greater than a model expects; ignoring it can make uncertainty appear too small. The primary outcome is described as continuous and summarized with a mean and standard deviation, but the registry record does not report the model used or diagnostic checks. It is therefore not possible to assess model fit or whether an alternative approach was considered.

Because the endpoint combines changes from two periods, interpretation also depends on which observations were available in each period and how incomplete assessments were handled. The record defines the mITT analysis set using drug exposure and video availability across baseline and treatment. It does not report a missing-data method, sensitivity analysis, or a numerical flow of participants through the endpoint analysis. Those omissions limit evaluation of the robustness of any treatment-period versus washout contrast.

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("Parent Study")
n   <- c(29)
m   <- c(0.71)
sp  <- c(2.09)
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  Parent Study  29  0.710  2.090  -0.085  1.505

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 12 outcome measures and 10 analyses. The primary endpoint is the CI-CS contrast between treatment and washout. Listed secondary measures include individual CI-CS components, average CI-S severity change, alternative CI-CS presentations, SCAFI, SARA, EQ-5D VAS, and mDRS. When a study examines multiple outcomes, the chance of at least one apparently notable result can increase. Statistical methods may address this through a prespecified hierarchy or adjustment, but the registry record does not report whether multiplicity was controlled or how the outcomes were prioritized in analysis.

The primary analysis population is defined as the modified Intention to Treat (mITT) set: patients who received at least one dose and had a video recording during both the baseline period and the treatment period. This definition requires usable video information from each period, so it is not simply all enrolled patients. The registry record does not report how many participants met the definition, how many contributed to the primary analysis, or how missing outcome data were handled.

Missing-data methods can affect estimates when observations are unavailable, particularly if missingness is related to health status or observed outcomes. In general, analysts may use assumptions or sensitivity analyses to examine how conclusions change under different missing-data scenarios. The registry record does not report imputation, a missing-data model, sensitivity analyses, or reasons for missing assessments. It also does not report whether the extension-phase outcomes used the same analysis population.

The statistical analysis plan, any interim analyses, and any prespecified multiplicity procedure are not reported in the registry record. Without these details and numerical results, it is not possible to determine how strongly the reported analyses were prespecified or how uncertainty across outcomes was handled.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: fall (3.3%), lumbar vertebral fracture (3.3%), psychotic disorder (3.3%), bipolar disorder (3.3%).

During the IB1001 treatment period, 2 participants were affected by serious adverse events among 30 at risk, and 17 were affected by other adverse events among 30 at risk. During post-treatment washout, 0 were affected by serious adverse events among 30 at risk, and 15 were affected by other adverse events among 30 at risk. The reported deaths were 0 in each period.

The registry lists Fall, Lumbar vertebral fracture, Psychotic disorder, and Bipolar disorder as the top serious adverse event terms, each at 3.3%. These event terms and percentages describe what the record lists; they do not establish that IB1001 caused an event. The registry record does not give further detail about timing, severity beyond the serious classification, recurrence, or attribution for each term.

These period-specific figures should not be read as a randomized safety comparison. The study was non-randomized and single-group, and treatment and washout are different periods rather than concurrently assigned arms. “Other adverse events” is a separate category from serious adverse events in the posted figures; the counts indicate participants affected, not a total number of event episodes. The record does not report additional detail needed to assess exposure-adjusted rates or compare risk across other populations.

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

The registry record establishes that a completed Phase II, open-label, rater-blinded, non-randomized, single-group study examined oral IB1001 in GM2 Gangliosidosis. It defines a primary endpoint contrasting CI-CS change during treatment with change during post-treatment washout, and reports period-specific adverse event figures. It does not report the numerical primary endpoint result, a confidence interval, or a p-value. The record therefore does not allow the magnitude, direction, or precision of that primary contrast to be assessed.

The endpoint’s positive direction is defined as greater improvement during treatment relative to washout. Even if a numerical contrast were available, the single-group period comparison would not provide the same causal evidence as a randomized comparison with a concurrent control. Changes over time, the order of study periods, and other influences could contribute to the contrast. Rater blinding may help protect the assessment from some bias, but does not resolve these design limitations.

The safety figures describe participants affected during treatment and during washout. They should be interpreted descriptively, not as proof that an event was caused by treatment or as a reliable head-to-head safety comparison. The record does not report enough contextual detail to characterize the listed serious events fully.

The results described in the registry record do not establish whether IB1001 benefits or harms people with GM2 Gangliosidosis. They also cannot be generalized automatically to people outside the study population or to treatment schedules beyond those described. The study’s exploratory Extension Phase is identified as a longer-term component, but its numerical outcomes are not reported in the record.

14. Why This Trial Matters Statistically

This trial is statistically notable because its primary question is framed as a contrast between treatment and washout periods within a single-group study. That design can describe how measured performance changed across periods, but it does not provide the protection against confounding that random allocation to a concurrent control group can offer. The distinction is central when interpreting any period contrast as evidence about treatment.

The primary measure also relies on a rater’s judgment of video-recorded performance. Blinding the rater is an important design feature for an assessment that involves rating change, while the open-label design leaves participants and the treating team aware of treatment. Considering both features gives a more accurate picture than labeling the study simply blinded or unblinded.

The registry supplies a specific direction for the primary contrast and defines an mITT population based on drug exposure and video availability. Those details help clarify what the outcome is intended to represent and who qualifies for the primary analysis. At the same time, the record does not report the numerical endpoint result, the analysis method, missing-data handling, or multiplicity procedures. These omissions prevent a reader from assessing effect size, precision, and robustness from the registry record.

The safety reporting also illustrates why study periods should not be treated as randomized arms. Counts during treatment and washout are useful descriptions, but they do not alone establish comparative risk or causation. Reading the design, endpoint definition, analysis population, and reporting limitations together is essential to avoid interpreting descriptive study results as stronger evidence than the record supports.

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 principal limitation for statistical interpretation is that the registry record does not report a numerical result for the primary endpoint. It also does not report a confidence interval, standard deviation, or p-value for that endpoint. As a result, neither the estimated contrast nor its precision can be evaluated from the record.

The non-randomized, single-group design limits causal interpretation. The primary endpoint contrasts treatment and washout periods, so the study does not provide a randomized concurrent control comparison. The open-label design may also affect participant experience and behavior, although the rater was blinded for the video assessment. The record does not describe additional measures used to address these design concerns.

The mITT definition requires at least one dose and video recordings in both baseline and treatment periods. The registry record does not report how many participants met this definition or contributed endpoint data, nor does it explain how missing video assessments or other incomplete observations were handled. That makes it difficult to assess selection into the analysis population or the influence of missing data.

The record lists multiple secondary outcomes but does not report a multiplicity strategy or the statistical analysis plan. It also does not report the sample-size justification, interim analyses, or model diagnostics. Safety figures lack detailed context about event timing, recurrence, and attribution. The Extension Phase is described as exploratory, and the record does not provide its numerical results in the registry record described. These limitations restrict assessment of both the strength and scope of the evidence.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: N-Acetyl-L-Leucine for GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease) — NCT03759665.
• Registry record last updated 2024-03-12; status last verified 2024-02.
• Results first posted 2024-03-12.
• 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

NCT03759665 is a completed, multinational, multicenter Phase II study of oral N-Acetyl-L-Leucine (IB1001) for GM2 Gangliosidosis, including Tay-Sachs and Sandhoff disease. The study was open-label, rater-blinded, non-randomized, and single group, with enrollment of 30. The Parent Study included 6-weeks of treatment and a 6-week post-treatment washout; the exploratory Extension Phase involved 1-year of treatment.

The primary outcome was the difference between mean CI-CS change during treatment and mean change during washout. The registry record does not report a numerical result or uncertainty estimate for this endpoint. It reports serious adverse events affecting 2 during treatment and 0 during washout, other adverse events affecting 17 and 15, respectively, and 0 deaths in each period. These descriptive safety figures do not establish causation or provide a randomized comparison.