First-In-Human Study to Evaluate Safety, Tolerability, and PK of Intravenous ATB200 Alone and When Co-Administered With Oral AT2221: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for First-In-Human Study to Evaluate Safety, Tolerability, and PK of Intravenous ATB200 Alone and When Co-Administered With Oral AT2221 (NCT02675465), a non-randomized phase 1, phase 2 study. The primary outcome is Incidence of Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Adverse Events (AEs) Leading to Discontinuation of Study Drug.

2. Clinical Question

The study is described as a first-in-human assessment of safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of ATB200 with AT2221 in adults with Pompe disease. Its primary endpoint, however, is a safety endpoint: it counts participants with specified adverse-event categories during the two-year treatment period and extension. The registry gives the combined Stage 3 and Stage 4 timeframe as a mean of 71 months on treatment.

Several secondary outcomes concern change from baseline in walking distance, pulmonary function, muscle strength, fatigue, and patient- or physician-rated physical wellbeing. The listed outcomes indicate that the study also sought to describe functional and patient-centered measures. The registry record does not report analysis results for those outcomes. Because participants were not randomized to a concurrent control and the study was open-label, the main question is descriptive: what events and changes were observed in the study groups, rather than whether a treatment caused a difference compared with a randomized control.

3. Trial Design

This is an international, multicenter, open-label, fixed-sequence, ascending-dose, first-in-human study. The registry lists Phase 1 and Phase 2. Allocation is non-randomized, masking is absent, and the model is single-group. The study enrolled 29 participants with Pompe disease, and its status is completed.

The record describes sequential single ascending doses of intravenously infused ATB200 for three dosing periods. It also describes ATB200 co-administered with AT2221, which is identified as Miglustat. The cohort labels include ATB200 dose levels and combinations with Miglustat. These categories reflect the study’s dose and cohort structure; they should not be read as randomized treatment arms or as equivalent groups assigned to provide a control comparison. The record does not give a detailed account of how participants moved between cohorts or dosing periods.

The primary safety timeframe combines Stage 3, described as a two-year treatment period, with Stage 4, described as an extension. The timeframe is reported as a mean of 71 months on treatment. The record’s primary outcome counts participants with treatment-emergent adverse events, treatment-emergent serious adverse events, and adverse events leading to discontinuation of study drug. The listed secondary outcomes include changes from baseline in six-minute walk distance, pulmonary function tests, muscle strength tests, fatigue severity, and global impressions of physical wellbeing by subjects and physicians.

Open-label means masking was not used, and non-randomized means assignment was not random. Those design features are important when interpreting changes over time and differences among cohorts: the study does not provide the protection against confounding that random allocation to a concurrent control can offer. The registry record does not report a detailed statistical analysis plan, sample-size justification, interim analyses, or specific analysis populations.

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: The study was conducted in 4 stages and 4 cohorts, with Stages 1 and 2 only for Cohort 1 and Stages 3 and 4 for all 4 cohorts.

Stage 1 SAD (Cohort 1 Only)

Stage 2 MAD (Cohort 1 Only)

Stage 3: 2 Year Treatment

Reasons for not completing this period:

Stage 4: Long Term Extension

Reasons for not completing this period:

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 Incidence of Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Adverse Events (AEs) Leading to Discontinuation of Study Drug, measured over Stage 3 (2 year treatment) and Stage 4 (Extension) combined, (mean = 71 months on treatment).

The primary endpoint counts participants with treatment-emergent adverse events, treatment-emergent serious adverse events, and adverse events that led to study-drug discontinuation. The registry describes these events over the two-year treatment period and extension, combining Stage 3 and Stage 4; the stated mean time on treatment for this combined timeframe is 71 months. The endpoint unit is participants, so the intended summaries concern how many participants experienced events in each category, rather than the total number of event episodes.

Safety endpoints are used in early studies to describe the types and occurrence of harms observed during exposure. A count of participants with at least one event can help characterize how many people were affected, while serious-event and discontinuation categories identify events with particular clinical or study-conduct significance. These general purposes do not establish that an event was caused by a study drug. Attribution, event definitions, and adjudication procedures are not reported in the registry record.

The record gives the endpoint definition and timeframe but does not provide a primary endpoint result for the combined Stage 3 and Stage 4 period. The separate adverse-event listings report affected participants in dose and cohort categories, but they do not supply the missing combined endpoint breakdown, including the count of participants with events leading to discontinuation.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count represent?

The primary endpoint uses participants as its unit. In general, a count of participants with an event records whether a person experienced an event in the specified category, rather than counting every episode separately. This distinction matters because one participant may experience more than one event, but the count of participants remains a person-level summary. The registry describes counts for treatment-emergent adverse events, serious treatment-emergent adverse events, and events leading to study-drug discontinuation. It does not report the combined primary endpoint results or explain the event-level rules used to classify and count them.

The posted cohort listings give both the number at risk and the number affected for serious and other adverse events. In general, a denominator helps readers understand the group to which an affected-participant count pertains. Here, those denominators are specific to the listed cohort categories. They do not convert the data into a randomized comparison, and they should not be treated as evidence that one cohort’s regimen caused more or fewer events than another’s.

Why does design affect interpretation?

In general, random allocation helps balance known and unknown participant characteristics between comparison groups, while masking can limit some differences in care or assessment. This study is listed as non-randomized and open-label, with a single-group model. Its sequence of dose and cohort categories is therefore not a randomized control structure. Comparisons across those categories can be influenced by who entered each cohort, their prior exposure, the time at which events occurred, and other factors. The registry record does not report enough detail to evaluate those influences.

In a single-group study, observations can describe what happened among participants receiving study treatment, but they do not by themselves show what would have happened without that treatment. General changes over time, concurrent care, disease course, and measurement conditions can all affect outcomes. For the same reason, a difference between cohorts is not automatically a treatment effect. The record does not report an adjusted or causal analysis that would address these issues.

What can confidence intervals and tests add?

General explanation: a confidence interval describes statistical uncertainty around an estimated quantity under a specified analysis. A narrow interval indicates greater precision than a wide interval, while neither width nor location alone determines whether a finding is clinically important. A hypothesis test evaluates compatibility of data with a specified statistical null model. These tools require a defined estimate, analysis population, and method. The registry record lists no analyses for the outcomes, so no corresponding confidence intervals or test results are available to interpret.

General explanation: for event-count outcomes, the choice of statistical model depends on the question and the data structure. A simple count may describe how many participants were affected. A comparative model would require an appropriate comparison and a specified approach to account for group membership and exposure. Repeated exposure or follow-up can also affect how event data are summarized. The registry record does not report a model for the primary safety outcome, person-time methods, covariate adjustment, or a plan for repeated observations.

Why is the follow-up timeframe relevant?

The primary endpoint combines Stage 3 and Stage 4, covering the two-year treatment period and extension, with a reported mean of 71 months on treatment. General explanation: a longer observation period can provide more opportunity to detect events, but a simple participant count does not account for different lengths of observation. A time-to-event or exposure-adjusted analysis can address follow-up duration when its assumptions and data are available. The registry record does not report such an analysis, the distribution of individual follow-up times, or the handling of participants who did not complete the combined timeframe.

The listed cohort counts must also be read in light of the study’s fixed-sequence and ascending-dose description. General explanation: when people receive treatments in sequence, outcomes observed during a later period can reflect prior exposure as well as the current dose or combination. A concurrent randomized control can help separate treatment differences from time and sequence effects; these listings do not provide such a control comparison. Details of sequence-specific statistical handling are not reported in the registry record.

How should sample-size planning be understood?

General explanation: sample-size planning uses assumptions about the outcome, target effect, variability, error rates, and design to estimate how many participants might be needed for a planned analysis. A planning illustration based on an observed effect is not the same as the trial’s original design calculation, and it is not observed power. No sample-size justification or protocol-based calculation is reported in the registry record. A small or large planning estimate would not change the observed event counts or establish a treatment effect.

For this study, a planning illustration cannot substitute for a randomized comparison or for missing endpoint analyses. The listed enrollment is 29, while adverse-event summaries are organized by cohort. The record does not report the statistical procedures used to combine cohorts, account for sequence, or handle exposure time. Any interpretation should therefore remain tied to the descriptive information actually reported, rather than treating a planning calculation as evidence of precision or efficacy.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple outcome measures: the primary safety endpoint and secondary outcomes covering walking distance, pulmonary function, muscle strength, fatigue severity, and overall physical wellbeing as rated by subjects and physicians. Considering multiple outcomes creates a general multiplicity issue: when many hypotheses are tested, the chance of at least one apparently unusual result can increase unless the analysis plan addresses that possibility. The registry record does not report a multiplicity procedure, a hierarchy among secondary outcomes, or a detailed statistical analysis plan. It also does not list analysis results for the outcomes.

Missing-data methods are important when outcomes are measured over time or participants do not complete all assessments. General explanation: complete-case analysis, imputation, and other approaches make different assumptions about missing observations, and those assumptions can affect estimates. The registry record does not report missingness by outcome, reasons for missing assessments, an imputation method, or sensitivity analyses. It is therefore not possible to assess how missing data affected any endpoint.

The record also does not define the analysis populations used for safety or secondary outcomes, such as which participants were included in each summary or how exposure and discontinuation were handled. The primary outcome timeframe combines Stage 3 and Stage 4, but the posted material does not provide a complete participant flow or the endpoint-specific denominator for that combined period. These omissions limit the assessment of completeness and reproducibility. They do not imply that a particular method was or was not used outside what the registry reports; the analysis-population details and handling of missing observations are not reported in the registry record.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: supraventricular tachycardia (33.3%), acute myocardial infarction (16.7%), arrhythmia (16.7%), cardiac arrest (16.7%), colitis (16.7%).

The safety listings give the number of participants at risk and the number affected by serious and other adverse events within each cohort label. For example, the listing for Cohort 1 at ATB200 20 mg/kg plus Miglustat 260 mg reports 7 of 11 participants with serious adverse events and 11 of 11 with other adverse events. The corresponding listings for Cohorts 2, 3, and 4 report serious-event counts of 4 of 6, 4 of 6, and 6 of 6, and other-event counts of 6 of 6 for each. Earlier Cohort 1 dose categories list no serious adverse events, with other-event counts of 7 of 11, 5 of 11, 4 of 11, and 9 of 11.

These are descriptive cohort counts. The study is non-randomized, and the registry cautions that the categories are not like-for-like control comparisons. The counts do not establish that dose or co-administration caused an event, and they are not a comparison of randomized groups. The record lists one death in Cohort 2; it does not report a causal relationship to study treatment.

The serious-event term listing gives supraventricular tachycardia at 33.3%, with acute myocardial infarction, arrhythmia, cardiac arrest, colitis, and femoral hernia each at 16.7%. The denominator and term-counting convention for those percentages are not reported in the registry record. They should not be interpreted as participant-level risks without that information. The primary endpoint also includes adverse events leading to discontinuation, but the corresponding count is not reported in the registry record.

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

The study addresses an early clinical evaluation of ATB200 alone and with AT2221 in adults with Pompe disease. It is described as first-in-human and includes safety, tolerability, pharmacokinetic, pharmacodynamic, and efficacy aims. The primary endpoint is safety-focused and covers treatment-emergent events during the combined Stage 3 and Stage 4 period. The adverse-event listings show that affected-participant counts varied across the named cohorts, including serious events in several of the later combination cohorts. The record also lists serious-event terms and one death in Cohort 2.

Those details do not establish that ATB200, AT2221, or a particular dose caused any event. The cohort structure is non-randomized, open-label, and not a like-for-like control comparison. The counts cannot distinguish treatment effects from differences among participants, prior exposure, follow-up, or other influences. The record does not give a causal attribution for the death or the event terms.

The posted information also does not establish whether treatment improved functional outcomes. Although secondary outcomes include walking distance, pulmonary function, muscle strength, fatigue, and wellbeing, their results are not reported in the registry record. No inferential analyses are listed for the outcomes, and no confidence intervals or hypothesis-test results are available. The primary endpoint’s combined-period result and the count of events leading to study-drug discontinuation are not reported in the registry record.

Accordingly, the statistical meaning is limited to descriptive safety information for the listed cohorts. A participant count is not a comparative treatment effect, and the absence of a reported analysis is not evidence that no events occurred or that a treatment effect was absent. Any conclusions about efficacy, comparative safety, or precision would require results and methods not reported in the registry record.

13. Why This Trial Matters Statistically

Statistically, the record illustrates how study design defines the questions that can be answered. A first-in-human, open-label, non-randomized study can describe exposure and observed events in its participants. It can also organize observations across dose and cohort categories. Without randomized allocation and a concurrent control, however, the category counts do not isolate the effect of a regimen from other differences between participants or study periods.

The study’s safety focus is visible in its primary endpoint: participant counts for treatment-emergent adverse events, serious treatment-emergent adverse events, and events leading to discontinuation. The combined Stage 3 and Stage 4 timeframe, with a reported mean of 71 months on treatment, emphasizes that interpretation depends not just on event counts but also on how exposure and follow-up are summarized. The registry gives cohort-level affected counts but does not report a combined endpoint analysis or an exposure-adjusted method.

The record also makes an important distinction between an outcome being named and an outcome having a reportable result. Walking distance, pulmonary function, strength, fatigue, and global impressions are listed, but their analysis results are not reported. Without estimates and uncertainty measures, readers cannot assess the magnitude or precision of changes. Likewise, descriptive event percentages do not by themselves provide a causal comparison.

These features make the record useful for understanding the scope and structure of the investigation, while also showing the limits of registry summaries. Clear reporting of analysis populations, missing-data handling, endpoint-specific denominators, and prespecified statistical methods would help readers evaluate completeness and uncertainty. Those details are not reported in the registry record, so conclusions must remain narrow and descriptive.

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 most important limitation for interpretation is the absence of a randomized control comparison. The registry describes non-randomized allocation, no masking, and a single-group model, and cautions that the cohort categories are not like-for-like controls. Consequently, apparent differences in event counts between dose or cohort labels cannot be interpreted as causal treatment differences.

The registry gives adverse-event counts by cohort but does not report the combined Stage 3 and Stage 4 primary endpoint result. It also does not report the count of participants with adverse events leading to study-drug discontinuation, despite including that category in the primary endpoint. The serious-event term percentages are listed without a denominator or counting convention in the record. One death is listed in Cohort 2, but its relationship to study treatment is not stated.

The primary timeframe combines the two-year treatment period and extension, with a mean of 71 months on treatment. The record does not report individual follow-up duration, exposure-adjusted event rates, or the handling of participants who did not complete follow-up. It does not report the analysis populations, missing-data methods, detailed statistical analysis plan, sample-size justification, or interim analyses. The secondary outcomes are named, but their results are not reported.

The study enrolled 29 participants, and the listed cohort counts are limited in size. In general, limited group sizes can make descriptive estimates imprecise, but the registry does not provide uncertainty intervals for these counts. The sequence of ascending doses and combination treatment also means that prior exposure or timing may matter; the registry does not report sequence-specific analyses. These limitations constrain both causal interpretation and assessment of statistical precision.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: First-In-Human Study to Evaluate Safety, Tolerability, and PK of Intravenous ATB200 Alone and When Co-Administered With Oral AT2221 — NCT02675465.
• Registry record last updated 2025-10-23; status last verified 2025-10.
• Results first posted 2025-10-23.
• 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

The registry record describes NCT02675465, a completed first-in-human, open-label study of intravenous ATB200 alone and with oral AT2221 in adults with Pompe disease. It lists Phase 1 and Phase 2, non-randomized allocation, no masking, a single-group model, and enrollment of 29 participants. The study began in 2016-04, and primary completion is listed as 2024-08-22.

The primary outcome counts participants with treatment-emergent adverse events, serious treatment-emergent adverse events, and adverse events leading to study-drug discontinuation during Stage 3 and Stage 4 combined. The timeframe is described as a two-year treatment period and extension, with a mean of 71 months on treatment. Cohort-level safety counts and selected serious-event terms are listed, but the combined primary endpoint result and inferential analyses are not reported in the registry record.

Secondary outcomes concern walking distance, pulmonary function, muscle strength, fatigue, and overall physical wellbeing. Their analysis results are not reported in the registry record. The non-randomized cohort structure limits comparative interpretation of the posted safety counts.