N-Acetyl-L-Leucine for Niemann-Pick Disease, Type C (NPC): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for N-Acetyl-L-Leucine for Niemann-Pick Disease, Type C (NPC) (NCT03759639), 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 completed phase II study evaluated IB1001 in people with Niemann-Pick disease, type C. The registry record describes it as multinational, multicenter, prospective, open-label, and rater-blinded. Allocation was nonrandomized and the model was single group, so there was no randomized control arm for a direct between-group estimate. Enrollment was 33.

The study had a Parent Study and an Extension Phase. The Parent Study assessed symptomatic treatment during 6-weeks of oral IB1001. The Extension Phase assessed longer-term treatment during 1-year of oral IB1001. A 6-week post-treatment washout followed both the Parent Study treatment period and the Extension Phase treatment period. The registry record does not report how many participants entered or completed each phase.

Open-label describes the treatment arrangement; rater-blinded describes the assessment arrangement. These features are not contradictory: participants and study personnel may know the treatment being given while a rater assessing recorded performance is kept unaware of the relevant treatment-period information. The registry record does not report the practical blinding procedures or whether blinding was maintained.

The primary endpoint used CI-CS ratings comparing baseline with the end of treatment, and the end of treatment with the end of washout. The described target population for the primary analysis was the mITT Analysis Set, with eligibility based on treatment exposure and videos in both baseline and treatment periods. The registry record does not report the final analysis population size, participant flow, or the number of evaluable videos.

The registry record lists a start date of 2019-09-04, a primary completion date of 2022-11-07, and a completed status. It does not report a separate comparator group or a randomized allocation scheme. As a result, changes across the study periods can be described within the study, but they do not by themselves isolate a treatment effect from changes over time, assessment effects, or other influences.

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: All patients began treatment with N-Acetyl-L-Leucine (IB1001) in this open label study schema. The post-treatment washout period followed the IB1001 treatment period.

Treatment With IB1001

Post-Treatment Washout

Analysis population for the primary outcome, as defined in the registry: Modified Intention to Treat (mITT) Analysis Set - 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 the CI-CS comparing the end of 6-weeks treatment with IB1001 (Approximately Day 42) versus the end of 6-weeks post-treatment washout.

The primary endpoint is the Clinical Impression of Change in Severity (CI-CS), described as a score on a scale and analyzed as a mean with standard deviation. The blinded rater considers whether performance on the 9 Hole Peg Test of the Dominant Hand or 8 Meter Walk Test has improved or worsened between videos. The scale runs from +3, significantly improved, to -3, significantly worse.

The specified endpoint is a contrast between two CI-CS comparisons: baseline to the end of 6-weeks treatment, minus the end of treatment to the end of the 6-weeks post-treatment washout. It therefore represents a summary of ratings across treatment and washout periods, rather than a simple score at a single visit. The subtraction order is important when interpreting any reported estimate: its direction depends on the endpoint definition and the scale coding.

Using a blinded rater for a performance-based assessment can reduce the influence of knowledge about treatment on the rating. It cannot, by itself, address every possible source of bias, such as changes in participant performance over time or the influence of repeated assessment. The registry record does not report the primary endpoint estimate, its standard deviation, or an uncertainty interval, so the size and precision of the observed contrast are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean endpoint describe?

For a continuous measure, the mean is a summary of the values across participants. It gives a central estimate, while the standard deviation describes how spread out individual values are around that mean. A mean can be useful when the study question concerns an average change or contrast, but it does not show whether all participants had similar experiences. The distribution of values, the number of participants contributing data, and the method used to handle incomplete observations also matter.

Here, the specified primary parameter is the mean CI-CS contrast, with standard deviation as the measure of dispersion. The scale is an ordered rating from +3 to -3, with the endpoints described as significantly improved and significantly worse. Treating such a rating as a mean produces a group-level summary; it does not imply that every participant had the same rating or that an individual-level change can be inferred from the mean alone. The numerical mean and standard deviation are not reported in the registry record.

What does the primary contrast compare?

The endpoint subtracts the CI-CS rating comparison from the end of treatment to the end of washout from the comparison between baseline and the end of treatment. In general, subtracting one period's measure from another creates a contrast whose sign depends on the order of subtraction and the coding of the underlying measure. This definition is especially important when the scale has positive and negative values. The registry record gives the scale direction and subtraction order, but it does not report the resulting estimate or further analysis details that would clarify its interpretation.

Because the contrast uses two comparisons within a single-group study, it is not the same as comparing outcomes between randomly assigned treatment groups. A within-study contrast can describe how ratings differed across periods among participants with the relevant observations. It cannot, on its own, establish that treatment caused the difference. A randomized comparison can help balance measured and unmeasured factors between groups; this study's nonrandomized, single-group design does not provide that kind of control.

How should uncertainty be understood?

In general, a confidence interval expresses the uncertainty around an estimate under the statistical model used. A narrower interval indicates greater precision under that model, while a wider interval indicates less precision. A confidence interval does not remove limitations in the design, measurement, or analysis population. The registry record does not report a confidence interval for the primary endpoint, nor does it report a p-value for that endpoint. Consequently, its statistical precision and compatibility with different values cannot be assessed from the registry information described.

In general, a p-value summarizes how unusual data would be under a specified null model and its assumptions. It is not the probability that the null hypothesis is true, nor does it measure clinical importance. Statistical significance, if reported, would need to be interpreted alongside the estimate, its uncertainty, the endpoint scale, and study design. No primary p-value or inferential method is reported in the registry record.

Why does the design matter for analysis?

The study is open-label, nonrandomized, and single group, with a blinded rater for the described primary assessment. Blinding the rater may reduce bias in the assessment, but does not create a randomized control group. Open-label treatment may affect expectations or behavior, and repeated performance tests can be influenced by familiarity or other time-related changes. These are general design considerations, not claims about what occurred among participants.

The primary analysis population is defined using treatment exposure and video availability during baseline and treatment. That definition means the primary analysis is not automatically an analysis of every enrolled participant. The registry record does not report how many participants were included, whether anyone was excluded, or whether the analysis population differed from the enrolled group. Those details matter because results from a subset may not represent all enrolled participants if inclusion is related to outcomes or participant characteristics.

General statistical planning illustrations can describe how many participants per arm might be needed under specified assumptions, but they are not observed power and do not describe the design actually used. The registry record's planning assumptions refer to a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and effects defined as fractions of the observed effect. That planning illustration does not turn this single-group study into a two-arm randomized trial. No trial-specific sample-size justification or design rationale is reported in the registry record.

What can be learned from the adverse-event counts?

Adverse-event counts are descriptive unless the study provides a comparison and analysis capable of estimating relative risk. The serious-event counts identify participants affected during the listed periods, and the other-event counts are reported separately. The registry record does not specify whether participants could contribute events in more than one category, the number of recurrent events, or the event-level observation time. General comparisons of event counts also require attention to exposure and follow-up, which differed in the reported at-risk counts across periods.

Over-dispersion is a general statistical issue that arises when observed variability exceeds what a chosen probability model expects. It can make standard errors and confidence intervals too small if an analysis assumes less variability than the data contain. Whether over-dispersion was relevant to any analysis in this study is not reported in the registry record. The record does not provide a statistical analysis plan, model details, or enough primary outcome results to assess such assumptions.

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(32)
m   <- c(0.86)
sp  <- c(2.52)
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  32  0.860  2.520  -0.049  1.769

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 12 outcome measures and 14 analyses. When a study assesses multiple outcomes or conducts multiple analyses, the chance of at least one apparently notable result arising by chance can increase. Statistical approaches such as pre-specifying a hierarchy of outcomes or adjusting inference can address this concern, but the registry record does not report a multiplicity strategy. It also does not identify which analyses, if any, were intended to be confirmatory versus exploratory.

The primary analysis population is the mITT Analysis Set. It includes participants who received at least one dose and had a video recording during both the baseline period and treatment period. The registry record does not report the number who met these criteria, the number analyzed for the primary endpoint, or the reasons participants may have lacked required recordings.

The registry record does not report how missing endpoint data were handled. It does not specify whether incomplete records were excluded, imputed, or addressed through another method, and it does not report sensitivity analyses for missingness. In general, missing data can affect estimates when the chance of having a recorded outcome is related to the outcome itself or to participant characteristics. Without information on the amount, pattern, and handling of missing data, the potential impact cannot be evaluated.

The record also does not report whether other analysis populations were used for efficacy or safety, or how their definitions differed from the mITT definition. The distinction matters because efficacy and safety summaries may use different eligible participants or observation periods. Those analysis details, along with the multiplicity plan and missing-data methods, are not reported in the registry record.

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: rib fracture (3.0%), head injury (3.0%), fall (3.0%), upper respiratory tract infection (3.0%), lower respiratory tract infections (3.0%).

During treatment with IB1001, 33 participants were at risk for serious adverse events; 4 were affected. The registry record reports 11 participants affected by other adverse events during that period, and 0 deaths. During post-treatment washout, 31 participants were at risk; 0 were affected by serious adverse events, 5 were affected by other adverse events, and 0 deaths were reported.

The registry lists Rib Fracture, Head Injury, Fall, Upper respiratory tract infection, Lower respiratory tract infections, and Dehydration among the top serious-event terms, each at 3.0%. These terms should be read as registry-reported event categories, not as evidence that IB1001 caused those events. The registry record does not provide enough detail to determine whether participants experienced multiple listed terms or to establish the timing and circumstances of each event.

Counts across treatment and washout periods are descriptive, not a randomized comparison. The at-risk participant counts differ between the periods, and the registry record does not report event rates adjusted for exposure time. Serious and other adverse events are distinct reporting categories; the record does not specify whether the same participant could be represented in both. The figures therefore describe recorded safety experience without establishing comparative risk or causation.

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

The registry record identifies a phase II study of oral IB1001 in NPC and describes its primary endpoint, study periods, analysis population, and adverse-event counts. It reports enrollment of 33 and a completed status. It does not report the numerical primary CI-CS result, so the average endpoint contrast and its precision cannot be described from this record.

The primary outcome is a rater-based change-in-severity contrast involving baseline, the end of treatment, and the end of washout. Its scale and direction are described, but without the actual estimate there is no basis to characterize the observed contrast as favoring improvement, worsening, or no change. The absence of a reported estimate is not evidence that the endpoint was unchanged.

The study's single-group, nonrandomized design means it does not provide a randomized between-group comparison. Even if a change were reported, the design would not by itself distinguish a treatment-associated change from natural history, period effects, assessment familiarity, or other influences. Rater blinding may help limit one source of assessment bias, but the registry record does not report enough detail to judge how the blinding operated.

The safety counts describe participants affected by adverse events during treatment and washout, with no deaths reported in either period. They do not establish that IB1001 caused or prevented any listed event, and they do not offer a like-for-like control comparison. The listed serious-event terms are useful as a description of what was recorded, not as causal conclusions.

In sum, the information supports a careful account of study design and reported safety counts, while leaving the primary efficacy result and key analytic details unavailable. It cannot support a conclusion about the magnitude, precision, or causal interpretation of the primary endpoint.

14. Why This Trial Matters Statistically

This study is statistically notable because its primary endpoint is not a single performance-test score at one visit. It is a contrast between two CI-CS comparisons: baseline to the end of treatment, and the end of treatment to the end of washout. The definition makes the order of measurement and subtraction central to interpretation. A reported value would need to be understood alongside the scale direction, the mean and its variability, and the availability of observations across periods.

The rater-blinded assessment addresses a particular measurement concern: the primary rating depends on judging observed performance. Blinding can reduce the influence of knowledge about treatment on a rater's judgment. At the same time, open-label treatment and a single-group design leave other potential influences uncontrolled. Separating the role of measurement safeguards from the causal strength of the design is essential when interpreting an outcome.

The mITT definition also illustrates why analysis populations matter. Eligibility depends on receiving study drug and having video recordings during both baseline and treatment. The number included under that rule is not reported, so readers cannot tell how much of the enrolled group contributed to the primary endpoint. Understanding the relationship between enrollment, follow-up, video availability, and analysis inclusion is important for assessing whether the result represents the intended study population.

Finally, the record lists multiple outcome measures and analyses but does not report multiplicity handling, missing-data methods, or the primary result. Those omissions limit assessment of both the reliability and the scope of any efficacy interpretation. The study therefore offers a useful example of how endpoint construction, blinding, analysis-population definitions, and reporting completeness all shape what can be learned from a clinical study.

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 most consequential limitation for interpreting the primary endpoint is that its numerical result is not reported in the registry record. The mean contrast, standard deviation, confidence interval, and primary p-value are not reported in the registry record. Without those quantities, neither the size nor the precision of the primary finding can be evaluated.

The nonrandomized, single-group design has no separate randomized control arm. This limits causal interpretation of any within-study change across treatment and washout periods. The registry record describes the study as open-label with a blinded rater, but does not report how the rater's blinding was maintained or assessed. It also does not report whether video acquisition or assessment procedures differed across periods.

The registry record does not report the number of participants in the mITT Analysis Set or the number with usable primary endpoint data. It does not report participant flow through the Parent Study, Extension Phase, and washout, or how missing observations were treated. These omissions make it difficult to assess the completeness and representativeness of the analyzed observations.

Although 12 outcome measures and 14 analyses are listed, multiplicity procedures and the distinction between confirmatory and exploratory analyses are not reported in the registry record. The statistical analysis plan, model assumptions, and trial-specific sample-size justification are also not reported in the registry record. Planning illustrations based on an observed effect do not establish the study's original design rationale or observed power.

The safety record provides counts and selected serious-event terms but does not report event-level detail, participant overlap among categories, exposure-adjusted rates, or a control-group comparison. These limits mean the counts should be read descriptively, without causal attribution or direct comparative-risk interpretation.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: N-Acetyl-L-Leucine for Niemann-Pick Disease, Type C (NPC) — NCT03759639.
• Registry record last updated 2023-11-28; status last verified 2023-11.
• Results first posted 2023-11-28.
• 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 NCT03759639, titled N-Acetyl-L-Leucine for Niemann-Pick Disease, Type C (NPC). It is a completed phase II study sponsored by IntraBio Inc, with enrollment of 33 and a start date of 2019-09-04. The primary completion date is 2022-11-07.

The study was prospective, multinational, multicenter, open-label, rater-blinded, nonrandomized, and single group. It evaluated oral IB1001 in a Parent Study with 6-weeks of treatment and an Extension Phase with 1-year of treatment, followed by a 6-week post-treatment washout after each treatment period.

The primary endpoint was a mean CI-CS contrast involving baseline, end of treatment, and end of washout. The registry record does not report its numerical result. During treatment, 4 of 33 participants were affected by serious adverse events and 11 of 33 by other adverse events; during washout, the counts were 0 of 31 and 5 of 31, respectively. No deaths were reported in either period.