Safety and Pharmacokinetics of AT-007 in Healthy Subjects and in Adult Subjects With Classic Galactosemia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Pharmacokinetics of AT-007 in Healthy Subjects and in Adult Subjects With Classic Galactosemia (NCT04117711), a randomized phase 1, phase 2 study. The primary outcome is Number of Participants With Treatment-emergent Adverse Events.

2. Clinical Question

3. Trial Design

NCT04117711 is a completed Phase 1-2 study titled “Safety and Pharmacokinetics of AT-007 in Healthy Subjects and in Adult Subjects With Classic Galactosemia.” The longer official title describes a dose-escalating, four-part study of single and multiple doses in healthy adults and adults with classic galactosemia. Its brief description calls it first-in-human, randomized, and placebo-controlled, with single ascending dose and multiple ascending dose parts.

The registry identifies the design as randomized, triple-masked, and parallel-group. It lists AT-007 and placebo as drug interventions. The sponsor is Applied Therapeutics, Inc. The recorded start date is 2019-06-21, and the primary completion date is 2021-12-14. Total enrollment is 114.

The posted dose cohorts span 0.5mg/kg, 5mg/kg, 10mg/kg, 20mg/kg, and 40mg/kg in different parts of the study. Part A also has a placebo comparator group. Safety listings additionally identify Part B & C, Part D, and Part D Extension groups. The information in the registry record does not establish how healthy participants and participants with classic galactosemia were distributed among all those cohorts, or give the detailed sequence of dose escalation.

The primary outcome is a count of participants with treatment-emergent adverse events, with a stated timeframe of events after 1 day of administration. The record lists pharmacokinetic outcomes and plasma galactose-related outcomes as secondary measures. Detailed procedures, dose-specific follow-up schedules, randomization methods, and masking roles are not reported in the registry record.

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.

Only the first 6 of 22 groups are shown.

Part A Cohort 1

Part A Cohort 2

Part A Cohort 3

Part A Cohort 4

Analysis population for the primary outcome, as defined in the registry: All subjects dosed were analyzed.

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.

Only the first 6 of 23 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment-emergent Adverse Events, measured over Events after 1 day of administration..

The primary endpoint is the number of participants with treatment-emergent adverse events. It is a binary participant-level outcome: for each participant, the relevant question is whether an event meeting the study’s treatment-emergent definition was recorded. The registry gives the timeframe as events after 1 day of administration. It does not provide a more detailed operational definition of treatment emergence, event severity thresholds for this endpoint, or a complete follow-up window.

The stated purpose of the endpoint is to evaluate safety and tolerability of AT-007 after administration to healthy subjects. The description specifies clinically significant changes in clinical laboratory test results, physical examination findings, vital sign evaluations, and electrocardiogram results. Such a count provides a broad summary of how many participants experienced at least one qualifying event; it does not by itself describe the number of events per participant, their duration, their severity, or their relationship to treatment.

For this endpoint, the registry says that all subjects dosed were analyzed. The posted primary outcome values list counts for the Part A dose cohorts and placebo comparator. The detailed endpoint definition and outcome values for other parts are not reported in the primary outcome listing. The count is a safety measure rather than a measure of pharmacokinetic exposure or clinical benefit.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

For a binary safety endpoint, each participant is classified according to whether the defined outcome occurred. The primary measure in this study counts participants with treatment-emergent adverse events. This is different from counting every event: one participant with multiple events still contributes as a participant with the outcome, unless the analysis specifies a different method. The registry record reports the participant count, but does not give a separate event-level analysis.

What do the raw counts show?

The counts provide a direct description of each listed group. For example, the Part A outcome listing reports 1 participant for AT-007 0.5mg/kg and 2 for placebo. The other Part A dose groups have their own posted counts. These observations are not, on their own, a treatment-effect estimate. A count depends both on the number of participants in a group and on how many experience the outcome. Comparisons are ordinarily more interpretable when the denominators, outcome definitions, and analysis population are clearly specified alongside the counts.

General statistical explanation: a confidence interval expresses uncertainty around an estimate under the assumptions of the method used. It can help readers understand how compatible the data are with a range of possible effects. No confidence intervals for the primary endpoint are reported in the registry record. A p-value, if reported, would address compatibility with a specified null model; it would not measure the probability that a treatment works or establish clinical importance. No p-values are reported for this endpoint.

Why are small counts difficult to compare?

General statistical explanation: when an outcome is uncommon or groups are small, a change of only a few participants can materially alter a group’s apparent pattern. Standard large-sample approximations may be unreliable in sparse data, so a suitable method depends on the prespecified analysis plan and data structure. The registry record does not report an inferential method for the primary outcome. No unadjusted recalculation or treatment comparison is available in the posted results.

Counts also leave out important clinical detail. A binary endpoint combines events regardless of their type unless the study’s definition or analysis separates them. It does not show whether participants had one event or several, when events occurred, how long they lasted, or whether they led to treatment interruption. Those details are not reported for the primary endpoint in the information. The adverse-event listings add some safety categories, but do not replace a complete event narrative or an analysis of event severity and attribution.

How should the study design inform interpretation?

Randomization can support a fair comparison when groups are analyzed as assigned, the randomization process is implemented as intended, and the analysis preserves the planned comparison. The registry identifies the study as randomized and parallel-group, but does not report the random sequence method, allocation concealment, or the analysis used to preserve randomized groups. Triple masking is recorded, but the identities of the masked parties and any exceptions are not reported. It is therefore possible to describe the registered design, but not to assess its implementation from these results alone.

The study includes multiple parts, dose levels, and populations. In general, comparing groups across parts requires attention to differences in eligibility, dosing, follow-up, and analysis populations. The registry record does not give enough information to establish that all listed cohorts were intended for direct comparison. In particular, the results should not be collapsed across parts or doses without a prespecified rationale and compatible populations.

What does the planning illustration represent?

General statistical explanation: a sample-size calculation is a planning exercise based on assumptions about a target effect, variability or event frequency, significance level, allocation, and analysis method. It is not a measure of the trial’s observed power after results are known. The planning assumptions described for the accompanying illustration use a two-sided significance level of 0.05, equal allocation, a normal approximation, and an effect to detect expressed as a fraction of the observed effect. These are illustration assumptions, not evidence of the original trial’s design rationale. The registry record does not report the trial’s own sample-size justification, and no inferred sample-size requirement should be read as an observed result.

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("Part A Cohort 1: AT-007 0.5mg/kg", "Part A Cohort 2: AT-007 5mg/kg", "Part A Cohort 3: AT-007 10mg/kg", "Part A Cohort 4: AT-007 20mg/kg", "Part A Cohort 5: AT-007 40mg/kg", "Part A: Placebo Comparator")
n      <- c(6, 6, 6, 6, 6, 10)
events <- c(1, 0, 0, 2, 1, 2)
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  Part A Cohort 1: AT-007 0.5mg/kg  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Part A Cohort 2: AT-007 5mg/kg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Part A Cohort 3: AT-007 10mg/kg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Part A Cohort 4: AT-007 20mg/kg  6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0
ARM  Part A Cohort 5: AT-007 40mg/kg  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Part A: Placebo Comparator  10  2  20.0  2.5  55.6  5.7  51.0  6.0  51.8

11. Multiplicity, Missing Data and Analysis Populations

The study lists a primary safety endpoint and secondary outcomes that include AT-007 pharmacokinetic measures, maximal plasma galactitol reduction, and plasma galactose and Gal-1p concentrations. The registry lists 12 outcome measures, of which 8 secondary outcomes are posted. It does not report a multiplicity procedure, such as an adjustment or hierarchy for interpreting results across multiple outcomes, doses, or study parts. Without a stated strategy, any set of outcome findings should be treated as descriptive rather than as a single confirmatory testing family.

The analysis population for the primary endpoint is described as all subjects dosed. The record does not explain how participants with incomplete outcome follow-up, missing measurements, protocol deviations, or withdrawals were handled. Missing-data methods and the amount or pattern of missing data are not reported in the registry record. It is therefore not possible to assess whether incomplete observations could affect the reported counts.

The registry identifies the trial as randomized, but does not report whether the primary analysis followed intention-to-treat, per-protocol, or another named principle beyond the statement that all subjects dosed were analyzed. It also does not report a statistical analysis plan, a prespecified analysis population for each secondary outcome, or methods for handling multiplicity across dose cohorts. These omissions limit the ability to distinguish prespecified analyses from exploratory descriptions and to evaluate the robustness of any comparisons.

The listed primary counts are not accompanied by inferential analyses. The registry records 0 analyses for the posted outcomes. No adjustment, imputation, or sensitivity analysis is reported for the primary endpoint.

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: liver injury (11.1%).

The serious adverse-event listing separates participants at risk from participants with a serious event in each listed group. The groups cover Part A, Part B & C, Part D, and Part D Extension. In the listed groups, 0 participants with serious adverse events are reported except for Part D Extension Cohort 1, which reports 1 participant with a serious event among 9 at risk. The listing reports 0 deaths in every group.

The registry identifies Liver Injury as the top serious event term and reports 11.1%. That term and figure should be read as the record’s reported safety detail; they do not establish causation or a treatment effect. The record does not provide a full account of seriousness criteria, timing, relatedness assessments, or event-level narratives in the information used for this analysis.

These serious-event figures are distinct from the primary endpoint counts for treatment-emergent adverse events. They should not be added together or treated as interchangeable outcomes. A serious adverse event is a specific safety category, while the primary endpoint is a count of participants with the broader treatment-emergent outcome. Each group’s size and study part matter when reading the reported counts.

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

The registry results document safety observations from a dose-escalating Phase 1-2 study of AT-007 in healthy adults and adults with classic galactosemia. The primary endpoint is a participant count, and the Part A listing reports outcome counts for five AT-007 dose cohorts and a placebo comparator. The broader safety listing also gives serious adverse-event counts and reports no deaths in the listed groups.

These results do not establish that AT-007 is safer or less safe than placebo. The registry does not report an inferential comparison, confidence intervals, or p-values for the primary endpoint. Raw counts cannot show the precision of a difference, and comparisons across parts may not be valid because cohort composition and follow-up details are not fully reported. The data also do not establish whether any event was caused by treatment.

The results are not evidence of efficacy. Although the record lists pharmacokinetic and plasma biomarker outcomes, the primary endpoint is a safety measure, and the posted information described for this analysis does not include inferential efficacy results. No conclusion about clinical benefit, long-term safety, or outcomes outside the studied groups can be drawn from the listed participant counts alone.

General statistical explanation: early dose-escalation studies can characterize observations within the tested groups and help describe which questions warrant further study. They are not automatically designed or powered to make definitive comparisons across many doses, populations, and outcomes. The registry record does not report its sample-size rationale or complete analysis plan. The appropriate reading is therefore descriptive: the listed events occurred in the recorded cohorts, with substantial limits on comparisons and causal interpretation.

14. Why This Trial Matters Statistically

This trial is statistically notable for combining dose escalation, single and multiple dosing, healthy adults, and adults with classic galactosemia within a four-part study. Such a structure can generate useful safety and pharmacokinetic observations, but it also makes the choice of comparison important. A dose cohort in one part should not be assumed to be directly comparable with a cohort in another part without information about eligibility, exposure, follow-up, and analysis.

The primary safety outcome is a participant count rather than a continuous measurement. That makes the result straightforward to describe, but a count alone does not quantify precision or distinguish event types. The posted Part A data give small group counts, while the registry’s broader serious-event listing spans additional parts and extension cohorts. Separating these sources prevents an apparent pooled comparison from being mistaken for a randomized contrast.

The record also illustrates the difference between a registered design and a fully documented analysis. Randomization and triple masking are recorded, but operational details, inferential methods, missing-data handling, and multiplicity procedures are not reported. Without these details, readers can describe the trial’s design and observed counts but cannot independently evaluate all assumptions behind a treatment comparison.

Finally, the registry includes secondary pharmacokinetic and biochemical outcomes alongside the safety endpoint. This makes it especially important to distinguish descriptive monitoring from formal hypothesis testing. The available record supports a careful account of what was measured and posted, while leaving key questions about precision, analysis, and generalizability unresolved.

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 primary endpoint information is limited to participant counts, without confidence intervals, p-values, adjusted estimates, or a reported method of comparison. The registry does not provide a detailed operational definition of treatment-emergent events or the full follow-up period beyond the stated timeframe of events after 1 day of administration. Event severity, duration, recurrence, and treatment attribution are not described for the primary endpoint.

The posted primary outcome values cover Part A dose cohorts and placebo. The safety listings for other parts provide additional serious and other adverse-event counts, but the record does not explain how those listings correspond to the primary endpoint analysis or establish comparability between cohorts. The distribution of healthy participants and participants with classic galactosemia by group is not reported in the information available for this analysis.

The registry describes randomization and triple masking but does not report the randomization method, allocation concealment, masked roles, or details of implementation. The analysis population is described as all subjects dosed, but handling of missing data, withdrawals, and protocol deviations is not reported. Multiplicity control and the statistical analysis plan are also not reported.

Serious adverse-event data do not include full event narratives or reported relatedness assessments. The record’s top serious event term and reported percentage do not establish causation. Overall, these limitations mean the safety counts are best treated as descriptive registry results, not as precise comparative estimates or a complete account of the trial’s safety experience.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Pharmacokinetics of AT-007 in Healthy Subjects and in Adult Subjects With Classic Galactosemia — NCT04117711.
• Registry record last updated 2024-05-30; status last verified 2024-05.
• Results first posted 2024-05-30.
• 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

NCT04117711 is a completed, randomized, triple-masked, parallel-group Phase 1-2 study of AT-007 and placebo in healthy adults and adults with classic galactosemia. The registry describes a four-part, dose-escalating study with single and multiple ascending dose components and reports enrollment of 114.

The primary outcome counts participants with treatment-emergent adverse events. Part A counts range across AT-007 dose cohorts and the placebo comparator. The broader safety listing reports 1 participant with a serious adverse event in Part D Extension Cohort 1 and 0 deaths in all listed groups. Liver Injury is the top serious event term, reported as 11.1%.

No inferential primary outcome analysis, confidence intervals, p-values, multiplicity procedure, missing-data method, or trial sample-size justification is reported in the registry record. The posted counts therefore describe recorded observations but do not establish a comparative treatment effect or causation.