Safety of Intravenous Apramycin in Adults: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety of Intravenous Apramycin in Adults (NCT05590728), a non-randomized phase 1 study. The primary outcome is Area Under the Concentration-time Curve From Time Zero to 8 h (AUC 0-8) of Total Apramycin in Epithelial Lining Fluid (ELF) and Alveolar Macrophage (AM).

2. Clinical Question

3. Trial Design

This was a Phase I, open-label study of a single intravenous apramycin dose in healthy adults. The registry record classifies allocation as non-randomized, masking as none, and the model as parallel. These design features mean that the study was not a blinded randomized comparison of apramycin with another treatment. Its primary purpose, as described in the record, was to assess plasma pharmacokinetics and lung penetration after dosing, alongside safety monitoring.

The brief summary describes five cohorts, T1 through T5, with four subjects planned per cohort. For T1 through T4, the described BAL sampling times were 0.5 h, 2 h, 4 h, and 8 h after dosing, respectively. The T5 cohort was to be enrolled after plasma and lung concentrations and preliminary pharmacokinetic analysis in T1 through T4 were complete. A T5 sampling time is not reported in the registry record. The summary also states that enrollment and dosing depended on the bronchoscopy schedule and that, when two subjects were scheduled on the same day, dosing was to occur sequentially at least 2 hours apart.

The registry record reports enrollment of 16. That differs from the 20 subjects described as planned in the brief summary; a reason for the difference is not reported in the registry record. The record lists the study as completed, with start and primary completion dates recorded. The protocol’s sample-size justification, any interim-analysis plan, and the rationale for the cohort sequence beyond the stated preliminary pharmacokinetic assessment 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.

Before assignment: Participants who signed the Informed Consent Form underwent screening procedures that included medical history, physical exam, clinical laboratory testing (hematology, chemistry, coagulation, urinalysis, viral serology (for HIV, HCV and HBV), and pregnancy testing. Participants who met all the inclusion criteria and none of the exclusion criteria were admitted into the clinical trial unit to confirm eligibility on Day -1 and assigned to one of the study cohorts before dosing on Day 1.

Overall Study

Analysis population for the primary outcome, as defined in the registry: The PK Analysis Subset population includes all participants who completed the lung and plasma PK parts of the trial without any protocol deviations that would likely affect the PK results and who have evaluable plasma PK and BAL PK concentration data for apramycin. All cohorts are reported jointly as all received the same dose, following the same dosing schedule.

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.

Population: The safety population includes all participants who received any amount of apramycin.

6. Primary Endpoint

The registry lists the primary outcome as Area Under the Concentration-time Curve From Time Zero to 8 h (AUC 0-8) of Total Apramycin in Epithelial Lining Fluid (ELF) and Alveolar Macrophage (AM), measured over 0 h through 8 h post dose.

The primary endpoint is AUC 0-8 for total apramycin in ELF and AM, with units of ug*h/mL, over 0 h through 8 h post dose. An area under a concentration-time curve combines concentration information across a specified time interval into a summary measure. In general, it can describe overall exposure during that interval rather than a concentration at one isolated sampling time. The registry record specifies separate ELF and AM endpoint measures.

The record states that each participant contributed only one ELF and AM concentration at one time point. It therefore describes calculating a geometric mean concentration at each BAL sampling time point and using those timepoint means to estimate a single ELF and AM parameter across participants. AUC 0-8 was estimated using Phoenix WinNonlin non-compartmental analysis. These details matter for interpretation: the endpoint is assembled from concentrations observed in different participants at different timepoints, rather than from a complete lung concentration-time profile measured repeatedly in every participant.

The endpoint is relevant to the study’s stated objective of assessing lung penetration after intravenous dosing. However, a numerical estimate, measure of uncertainty, or comparison against a reference value is not reported in the registry record. The endpoint definition alone does not establish the size or precision of the estimated exposure.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies a non-compartmental analysis using Phoenix WinNonlin to estimate AUC 0-8. In general, non-compartmental pharmacokinetic analysis summarizes concentration-time data without requiring a fully specified compartment model. It can use observed concentrations and defined rules for connecting or otherwise summarizing observations over time. The record does not give the detailed calculation settings, concentration values, or numerical AUC outputs, so those aspects cannot be independently described.

How was the lung endpoint assembled?

The record states that each participant contributed one ELF concentration and one AM concentration at one BAL sampling time. Rather than having repeated lung measurements from each participant across the interval, the analysis calculated a geometric mean concentration at each BAL sampling timepoint. Those timepoint means were then used to produce a single parameter estimate for ELF and a single parameter estimate for AM across participants. This is a key feature of the analysis: the estimated lung concentration-time profile draws on different participants at different sampling times.

In general, a geometric mean summarizes positive values on a multiplicative scale, using logarithms to calculate a central value and then returning to the original scale. It can be appropriate for measurements that vary proportionally or are right-skewed. The registry record does not report why this summary was selected, how values below an assay limit were handled, or whether any transformations or additional adjustments were used. Those details are not reported in the registry record.

What does AUC represent?

In general, AUC represents accumulated concentration over a stated time interval. It is a summary across time, so it is distinct from a single concentration measurement at one moment. Here the interval is specified as 0 h through 8 h post dose. The reported unit, ug*h/mL, reflects concentration integrated over time. Without the actual endpoint values or their uncertainty, the registry record does not show how large the estimated exposure was or how precisely it was estimated.

What can be inferred from the design?

The cohorts were intended to obtain BAL samples at different post-dose times, and the study was non-randomized and open-label. In general, distributing sampling times across participants can make a concentration-time summary possible when each participant contributes only one lung sampling timepoint. It also means that the resulting curve does not come from repeated lung measurements in each individual. Differences between participants can contribute to differences among timepoint summaries; the registry record does not report an adjustment for such differences or a model quantifying them.

The record describes a planned sequence in which T5 enrollment followed completion of preliminary concentration and pharmacokinetic analysis in T1 through T4. This is a stated operational feature. Details of any formal interim analysis, decision rules, or statistical consequences of that sequencing are not reported in the registry record. It would be inappropriate to infer a formal adaptive design or an unreported decision process from the stated sequence.

What does the analysis record show?

The registry record lists 25 outcome measures and 0 analyses. The absence of a listed analysis means that statistical tests or model-based comparisons are not described in the record. It does not identify a p-value, confidence interval, or adjusted estimate for the primary endpoint. In general, a point estimate describes the estimated quantity, while an uncertainty interval conveys how much statistical uncertainty accompanies it. Neither numerical endpoint estimates nor corresponding uncertainty measures are reported in the registry record.

The PK Analysis Subset is defined using completion of the lung and plasma pharmacokinetic parts, the absence of protocol deviations likely to affect PK results, and evaluable plasma and BAL concentration data. This definition sets out the intended analysis population, but the number of participants meeting it is not reported. The number with missing or unusable measurements, reasons for any exclusions, and any missing-data handling method are also not reported in the registry record.

How should planning calculations be read?

Any sample-size illustration based on the observed effect is a planning exercise, not an estimate of the trial’s observed power. The stated assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. Such illustrations do not describe the original study design: this study was non-randomized and does not provide a two-arm control comparison. Sample-size justification for the actual trial is not reported in the registry record. These distinctions prevent hypothetical planning calculations from being mistaken for an analysis of the enrolled participants or for evidence that the study was adequately powered for its pharmacokinetic objectives.

10. Multiplicity, Missing Data and Analysis Populations

The record lists a primary pharmacokinetic endpoint and numerous secondary safety outcomes, including frequencies of serious and treatment-emergent adverse events and abnormal examination, vital sign, laboratory, coagulation, and urinalysis findings. It does not report a multiplicity adjustment or a hierarchy for interpreting multiple outcomes. In general, when many statistical tests are conducted, the chance of at least one apparently unusual result can increase; prespecified procedures can address that issue. Whether any such procedure was planned is not reported in the registry record. Since the analysis count is 0 and numerical primary results are not reported, no multiplicity-adjusted interpretation can be made.

The primary analysis population is described as the PK Analysis Subset: participants completing lung and plasma PK parts without protocol deviations likely to affect PK results and with evaluable plasma and BAL concentration data. The number in that subset is not reported. The record does not state how many enrolled participants had evaluable data, whether any were excluded, or how exclusions affected the endpoint estimates.

Missing-data methods are not reported in the registry record. In general, missing observations can affect a summary when the reasons for missingness are related to participant characteristics, timing, or measured concentrations. The record does not describe missing concentration handling, incomplete BAL sampling, or sensitivity analyses. It also does not report a statistical plan specifying how the cohort data would be combined beyond the stated use of geometric mean concentrations at each sampling timepoint. Therefore, the endpoint definition can be described, but the robustness of the estimate to missing or unevaluable data cannot be assessed.

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 non-serious adverse event terms

The registry record reports safety counts for the group titled Apramycin All Participants. For serious adverse events, 16 participants were at risk and 0 were affected. For other adverse events, 16 were at risk and 15 were affected. The listed death count is 0. These are counts as recorded, not percentages or comparative risks; no additional calculation is needed to interpret the entries.

The serious adverse event count should not be conflated with the count for other adverse events. The record lists no top serious-event terms, and the details of the other adverse events are not reported in the registry record. As a result, the posted counts do not describe event types, timing, duration, severity beyond the serious/non-serious distinction, or whether events were considered related to study drug. The record also does not report a comparison group, so these counts cannot be used to estimate a relative safety difference.

In general, safety counts describe events observed and recorded during a study; they do not by themselves establish the probability of future events or prove that an intervention caused or did not cause an event. Here, the registry reports a small single-study group and does not provide further event-level context in the listed safety results. The numbers should be read as the posted counts for this trial, with those reporting limitations in mind.

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

The record describes a completed Phase I study designed to assess plasma pharmacokinetics, lung penetration, and safety after a single intravenous apramycin dose in healthy adults. It specifies an AUC 0-8 endpoint for total apramycin in ELF and AM and outlines how the lung estimates were formed from geometric mean concentrations at BAL sampling times. It also reports safety counts for serious and other adverse events and deaths.

The primary numerical AUC results are not reported in the registry record. Accordingly, the posted information does not establish the estimated ELF or AM exposure, the precision of either estimate, or how the two measures compare. No inferential analysis is listed, and no confidence intervals or p-values are reported. The design and endpoint description explain what the study set out to measure, but do not substitute for the missing numerical outcome.

The safety entries show 0 serious adverse events among 16 participants at risk, 15 participants with other adverse events among 16 at risk, and 0 deaths. Those counts describe the registry record’s safety entries; they do not provide detailed event descriptions or a comparison with another group. The trial’s non-randomized, open-label design also does not support a controlled comparison.

In general, a pharmacokinetic study can characterize concentration patterns and exposure under the conditions studied, while a controlled clinical trial is needed for a comparative treatment-effect question. This record’s stated question concerns pharmacokinetics and safety after one dose in healthy adults. It does not report evidence about clinical effectiveness in people with bacterial infection, repeated dosing, or outcomes in other populations. Such results are not reported in the registry record and should not be inferred from the study’s title or endpoint definitions.

13. Why This Trial Matters Statistically

This study raises an important statistical feature of lung pharmacokinetic work: the endpoint was built from samples collected at different times from different participants. Because each participant contributed one ELF and AM concentration at one timepoint, the concentration-time summary depends on combining information across participants. That structure differs from following a complete series of lung concentrations within each individual, and it makes clear why the sampling schedule and analysis population are central to interpreting the estimate.

The registry record also makes the distinction between an endpoint definition and a reported result visible. It gives a clear AUC 0-8 definition, units, and a method for estimating the endpoint, but the numerical AUC result and its uncertainty are not reported. Statistical methods cannot provide an interpretation of magnitude or precision without those results. A well-described endpoint is necessary for understanding an analysis, but it is not itself the outcome estimate.

The safety counts offer another statistical lesson: event counts need context. The record reports counts at risk, counts affected, and deaths, but does not provide event-level descriptions or a control group. These data can be stated accurately as counts while remaining limited for comparative interpretation.

Finally, the difference between the reported enrollment of 16 and the planned 20 described in the brief summary illustrates why completed enrollment and planned enrollment should not be treated as interchangeable. The record does not explain that difference or state how many participants were included in the PK Analysis Subset. Those details affect how readers assess the available information, and their absence limits conclusions about endpoint completeness and precision.

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 statistical interpretation is that the primary endpoint is defined but its numerical result is not reported in the registry record. No uncertainty measure is given, so neither magnitude nor precision can be assessed. The analysis count is 0, and the record does not list inferential analyses for the endpoint.

The intended design involved 20 subjects in five cohorts, while the registry reports enrollment of 16. The reason for the difference is not reported. The number of participants contributing evaluable PK data, the number included in the analysis subset, and the completeness of sampling at each planned timepoint are also not reported. The T5 sampling time is not reported in the registry record.

Each participant contributed only one lung concentration at one sampling time. The endpoint therefore uses geometric mean concentrations across participants at each BAL timepoint to estimate an overall lung parameter. This approach does not provide repeated lung concentration measurements within each individual. The record does not report estimates of between-participant variability, details of any adjustment for participant differences, or sensitivity analyses.

The trial was non-randomized and open-label, with no reported control group. Its results cannot support a randomized treatment comparison. Safety reporting is limited to the listed counts; event-level details, timing, attribution, and fuller descriptions of other adverse events are not reported in the registry record. Missing-data methods, multiplicity procedures, the original sample-size justification, and formal interim-analysis methods are also not reported.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety of Intravenous Apramycin in Adults — NCT05590728.
• Registry record last updated 2025-03-06; status last verified 2022-10-17.
• Results first posted 2024-12-10.
• 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 NCT05590728, a completed Phase I, open-label, non-randomized study of a single intravenous apramycin dose in healthy adults. Its primary endpoint was AUC 0-8 of total apramycin in ELF and AM. The endpoint was estimated using non-compartmental analysis, with geometric mean concentrations at BAL sampling timepoints used to produce a single parameter estimate across participants.

The brief summary describes 20 planned subjects across five cohorts, while registry enrollment is 16. The reason for this difference is not reported. Numerical primary endpoint results and endpoint uncertainty are not reported in the registry record, and the analysis count is 0.

For safety, the record lists 0 serious adverse events among 16 at risk, 15 participants with other adverse events among 16 at risk, and 0 deaths. Event-level details and a control-group comparison are not reported. The record supports description of the study design, endpoint method, and posted counts, but not conclusions about the size or precision of lung exposure or comparative effects.