Phase 1 Three Part SAD, MAD & Cross-Over Study of ZP-059 in Healthy and Asthmatic Subjects: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 1 Three Part SAD, MAD & Cross-Over Study of ZP-059 in Healthy and Asthmatic Subjects (NCT04229303), a randomized phase 1 study. The primary outcome is Number of Participants With Treatment-Emergent Adverse Events (TEAE).

2. Clinical Question

This is a phase one study, not a trial designed in the registry record around a stated clinical-benefit comparison. Its safety questions differed by part: whether single inhaled doses were tolerated in healthy subjects, whether repeated inhaled doses were tolerated in subjects with mild stable asthma, and whether a single inhaled dose could be assessed alongside oral voriconazole in subjects with mild to moderate stable asthma. The pharmacokinetic objectives likewise varied, with the first two parts assessing inhaled treatment and the crossover part assessing inhaled and oral dosing.

The registry record describes randomization and a crossover model, with no masking. It does not report the randomization method, allocation details within the separate parts, or a formal hypothesis for comparing treatments. Accordingly, the central statistical question is descriptive: what adverse-event counts were posted for the listed groups, and how much can those counts establish about comparative safety? The record gives group-level counts, but does not provide a single estimate of a treatment effect, confidence interval, or test for the primary endpoint.

3. Trial Design

The record describes NCT04229303 as a completed phase one study, titled “Phase 1 Three Part SAD, MAD & Cross-Over Study of ZP-059 in Healthy and Asthmatic Subjects.” It lists randomized allocation, no masking, and a crossover model. Enrollment was 58. The study began on 2020-02-11, and primary completion was 2020-08-31. Zambon SpA is listed as sponsor.

The study had three parts with different populations and dosing schedules. Part 1 enrolled healthy subjects for single ascending doses of inhaled ZP-059. Its listed groups received 5mg, 10mg, 20mg, or 40mg as a single dose. Part 2 involved subjects with mild stable asthma and multiple ascending doses: 10mg twice daily or 20mg twice daily, or 40mg once daily. The treatment schedules ran through Day 10, with the twice-daily schedules given for 9 days and once on the morning of Day 10. Part 3 involved subjects with mild to moderate stable asthma and compared a single inhaled 20 mg dose with a single oral 200 mg dose using a crossover sequence. A washout period of at least 96 hours is described.

The safety objective in each part was to assess safety and tolerability for that part’s population and dosing schedule. The pharmacokinetic objectives concerned voriconazole and N-oxide voriconazole. The stated assessments included systemic pharmacokinetics after inhaled dosing and, in Part 3, after inhaled and oral dosing.

Although randomization is recorded, the record does not report the randomization procedure or explain whether and how it applied within each part. It also does not report a masking procedure, which is consistent with the recorded designation of no masking. The protocol’s sample-size justification, any interim analyses, and the detailed statistical analysis plan are not reported in the registry record. The parts should therefore be understood as distinct assessments rather than assumed to be one uniform comparison across all participants.

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: Subjects were screened for eligibility to participate in the study within 28 days before dosing (Day 1). Part 2 and Part 3 subjects who had completed the initial screening visit attended the study site on Day -4 or Day -3, for Covid-19 reverse transcriptase - polymerase chain reaction (RT-PCR) test, together with additional daily tympanic temperature measurements, and other tests as applicable. Subjects were then be admitted to the study site on the evening of Day -1.

Only the first 6 of 9 groups are shown.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Safety Analysis Set (SAF): subjects who received at least 1 IMP dose, analyzed according to the treatment actually taken.

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: Enrolled Set: subjects who passed screening irrespective of whether they received study treatment.

Only the first 6 of 10 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment-Emergent Adverse Events (TEAE), measured over Part 1: screening (Day -28 to -1) to follow-up (8 to 12 days after last dose); part 2: screening (Day -28 to -1) to follow-up (11-17 days after last dose); Part 3: screening (Day -28 to -1) to follow-up (8-12 days after last dose of study drug)..

The primary endpoint is the number of participants with treatment-emergent adverse events. The registry defines an adverse event as an untoward medical occurrence temporally associated with use of the investigational medicinal product, whether or not it was considered related to that product. The safety analysis population is described as subjects who received at least one dose of investigational medicinal product, analyzed according to the treatment actually taken.

This endpoint is useful in an early-phase study because it records whether participants experienced adverse events during exposure and follow-up. A count of participants with an event is a binary outcome at the participant level: a participant either contributes to the count or does not, under the endpoint’s specified definition. It is not the same as counting every event, because one participant may experience more than one occurrence. The registry record does not specify in the primary endpoint description how repeated events within a participant were handled for the posted count.

The assessment windows differ by part. Each begins at screening, described as Day -28 to -1, and continues through follow-up after the last dose. The record gives follow-up windows of 8 to 12 days for Part 1, 11-17 days for Part 2, and 8-12 days for Part 3. These windows define the period covered by the safety assessment; they do not establish that events outside those periods were absent.

The endpoint supports descriptive safety reporting, but a count alone does not indicate severity, causation, duration, or comparative risk. Those questions require the relevant event definitions and analyses, which are not fully reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study’s statistical structure matters because its three parts do not represent one common comparison. Part 1 assesses single-dose escalation in healthy subjects. Part 2 assesses repeated dosing in subjects with mild stable asthma. Part 3 uses a crossover sequence in subjects with mild to moderate stable asthma, comparing inhaled ZP-059 with oral voriconazole. The registry records randomization, no masking, and a crossover model, but does not report enough detail to reconstruct the allocation procedure or all analysis decisions.

What does a participant count represent?

The primary endpoint counts participants with treatment-emergent adverse events. This differs from a count of total event occurrences: a participant may have more than one event, while the endpoint title describes the number of participants affected. The registry gives the endpoint definition and population, but does not report further rules for handling repeated events, events that begin before treatment, or events spanning more than one treatment period. The safety population includes subjects who received at least one investigational dose and uses the treatment actually taken for analysis. This is an exposure-based description, rather than an assignment-only description.

For binary outcomes, a group count is usually interpreted in relation to the number of participants at risk, and comparisons can be expressed using measures such as a risk difference or a relative measure. General statistical explanation: estimates of this kind quantify the observed contrast, while confidence intervals express the uncertainty around that estimate under the analysis assumptions. The registry results do not include a reported contrast or interval for the primary endpoint. No new comparative estimate should be inferred from the counts alone.

Why do the study parts need separate interpretation?

Part 1 and Part 2 vary dose and schedule across groups, and their populations differ. Part 3 has two treatment periods and treatment sequences. A crossover design can allow within-participant comparison, which may reduce the influence of stable differences between participants. General statistical explanation: such an analysis must account for the paired nature of observations and consider period and sequence effects where relevant. A washout period is intended to separate treatment periods, but the presence of a washout alone does not establish that carryover was absent. The registry record does not report a crossover analysis method, tests for period or sequence effects, or a carryover assessment.

Randomization can reduce systematic allocation differences when implemented appropriately, but the registry record does not specify its procedure or its application by part. No masking is recorded. General statistical explanation: lack of masking can affect reporting or assessment of subjective outcomes, although the extent of such influence depends on the outcome and trial conduct. The record does not describe safeguards for outcome assessment.

What can sparse safety counts establish?

Counts are valuable for describing what was observed, particularly in an early-phase safety assessment. They are less informative about uncommon outcomes when groups are small. General statistical explanation: sparse binary data can produce imprecise estimates, and conventional large-sample approximations may perform poorly when event counts are very low. Exact methods or other approaches may be considered in suitable analyses, but the registry record does not identify a method used for the posted safety results. It also does not report confidence intervals for the group-level event frequencies.

The serious-event entries are zero for each listed group. A zero observed count is not proof of no underlying risk. The precision of a risk estimate depends on the number of exposed participants and the observation period, as well as on the event process. The registry record lists group-specific numbers at risk and follow-up windows, but does not report an uncertainty interval for serious-event risk. It is also not appropriate to combine the groups casually: populations, regimens, and study parts differ, and the Part 3 treatments are repeated within a crossover framework.

What do pharmacokinetic outcomes require?

The stated pharmacokinetic objectives include systemic measures for voriconazole and N-oxide voriconazole. Listed secondary outcomes include exposure measures, peak concentration, time to peak, half-life, elimination rate, clearance, volume of distribution, and metabolite-to-parent measures. General statistical explanation: pharmacokinetic outcomes often have skewed distributions, and analyses may use transformations or geometric summaries when appropriate. These choices affect how estimates and intervals should be interpreted. The registry record does not report the analytic transformation, summary approach, missing-sample handling, or numeric pharmacokinetic results in the registry record for this analysis.

The registry lists 33 outcome measures and 50 analyses. The presence of many outcomes and analyses raises questions about selective emphasis and multiplicity. General statistical explanation: when many hypotheses are tested, the chance of at least one nominally unusual result can increase unless the analysis plan accounts for the testing structure. The registry record does not report a multiplicity adjustment or identify a prespecified hierarchy for interpreting secondary outcomes. The number of listed analyses alone does not establish which results were confirmatory.

The record also states a planning illustration based on the observed effect, using a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the target effect expressed as a fraction of the observed effect. Such an illustration is a planning aid, not observed power and not evidence that the trial was designed with those assumptions. The registry record does not report the original sample-size justification, and no planning result should be treated as the trial’s own design rationale.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 33 outcome measures and 50 analyses, while the primary endpoint is not reduced to one comparison because it has several categories or time points. This creates an interpretation challenge: different outcomes, time windows, parts, dose regimens, and treatment sequences may each generate separate findings. A nominal result from one analysis would need to be interpreted in the context of the full set of planned and reported analyses.

General statistical explanation: multiplicity refers to the increased chance of finding at least one apparently notable result when many hypotheses are examined. A prespecified hierarchy, adjustment procedure, or clear distinction between confirmatory and exploratory analyses can help readers understand that risk. The registry record does not report a multiplicity adjustment, an outcome hierarchy, or which analyses were designated confirmatory. It also does not report whether any interim analyses were planned or conducted. These details are not reported in the registry record.

Missing-data handling is likewise not described in the registry record reported for this analysis. The record defines the safety analysis set as subjects who received at least one investigational dose, analyzed according to treatment actually taken. It does not state how incomplete follow-up, missing event assessments, or unavailable pharmacokinetic samples were handled. For a safety endpoint, incomplete observation can matter because participants may differ in how long they were followed or in whether events were captured. The listed follow-up windows vary by part, which should be kept in mind when interpreting counts across parts.

The registry record does not report the number of participants with missing endpoint data, reasons for missingness, or sensitivity analyses. It also does not provide a full statistical analysis plan. As a result, the posted counts can be described, but the robustness of comparisons to missing data or multiple testing cannot be assessed from the information reported.

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 serious adverse-event entries are zero for every listed group: the Part 1 groups at 5mg, 10mg, 20mg, and 40mg; the Part 2 groups at 10mg twice daily, 20mg twice daily, and 40mg once daily; and the Part 3 inhaled and oral treatments. The registry reports 6 participants at risk in each Part 1 and Part 2 group, and 16 at risk for each Part 3 treatment entry. These are group-specific counts and should not be added or treated as independent groups across the crossover periods.

Other adverse events are listed separately. The posted counts are 0, 3, 2, and 2 in the Part 1 dose groups; 5, 4, and 4 in the Part 2 regimen groups; and 9 for Part 3 inhaled treatment and 7 for Part 3 oral treatment. These counts do not by themselves identify event type, severity, relatedness, duration, or whether an individual experienced multiple events. The registry record does not report those details in the registry record for this analysis.

A zero serious-event count means no serious event was recorded for that group in the posted results; it does not mean the underlying risk is zero. The group sizes and follow-up periods limit what can be concluded about uncommon events. No risk estimates or confidence intervals are reported, so the precision of the serious-event findings cannot be quantified from the registry record.

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

The posted results describe safety observations during exposure to inhaled ZP-059 and, in Part 3, oral voriconazole. They give the number of participants at risk and the counts of participants with serious and other adverse events for each listed group. This is useful descriptive information for understanding what was recorded during the study’s defined observation windows. It does not by itself establish a treatment effect.

The results do not show that inhaled ZP-059 caused or did not cause any particular event. The primary endpoint definition includes events regardless of whether they were considered related to study treatment. Event-level descriptions, severity, relatedness, and timing are not reported in the registry record for this analysis. The counts also do not establish whether a difference between groups is larger than could plausibly arise from chance, because the registry record does not report a formal comparative estimate or confidence interval for the primary endpoint.

Interpretation should remain specific to each part. Healthy subjects receiving single doses are not interchangeable with subjects with stable asthma receiving repeated doses. The crossover comparison in Part 3 has a different structure from the dose-escalation groups in the earlier parts. The treatment regimens and assessment windows also differ, so raw group counts should not be read as if they arose from one common trial population and exposure period.

The record does not provide numeric pharmacokinetic results in the registry record, nor does it report a clinical-benefit endpoint. The study’s stated purposes were safety, tolerability, and pharmacokinetics. The posted safety counts therefore cannot answer questions about clinical benefit, comparative effectiveness, or risks in populations outside those enrolled. They also cannot establish that serious adverse events are impossible, given the limited group sizes and follow-up.

In short, the counts are observations from a completed early-phase study, not a definitive ranking of treatment options. Their interpretation is constrained by the absence of reported inferential analyses, event detail, and fuller methods for handling missing data and multiple outcomes.

13. Why This Trial Matters Statistically

This study illustrates why statistical interpretation must follow the design rather than focus on a single count. Its parts address different populations and exposures: single-dose escalation in healthy subjects, repeated dosing in subjects with mild stable asthma, and a crossover comparison in subjects with mild to moderate stable asthma. A pooled summary could obscure those differences, while a simple comparison of group counts could ignore the pairing in the crossover part.

It also illustrates the role of descriptive safety reporting in early-phase research. Reporting participants with adverse events gives readers a direct account of observed events within the study’s follow-up windows. Yet small group-level counts provide limited information about rare outcomes, and zero serious events cannot establish zero risk. Precision matters alongside the observed count; the registry record does not provide confidence intervals for these safety results.

The endpoint is broad by design: treatment-emergent events are counted whether or not considered related to treatment. That makes the definition inclusive, but also means counts should not be interpreted as product-caused events. Event-level context and a clearly described analysis are necessary for stronger causal or comparative conclusions. The record does not report those details in the registry record for this analysis.

Finally, the record lists many outcomes and analyses without reporting a multiplicity strategy or complete analysis plan. This is a reminder that readers need to know which comparisons were prespecified, how missing observations were handled, and how uncertainty was quantified. Without those details, the responsible statistical reading is descriptive and limited to the posted observations, rather than confirmatory.

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 registry record does not report the detailed statistical analysis plan, the original sample-size justification, or the randomization procedure. Although randomization is recorded, its implementation within each part is not described. The trial is recorded as unmasked, but the record does not describe outcome-assessment safeguards or how awareness of treatment may have affected event reporting.

The posted safety information provides group counts, but the registry entries available for this analysis do not include event-level descriptions, severity categories, relatedness assessments, duration, or reasons for treatment discontinuation. No confidence intervals or formal comparative estimates are reported for the primary safety endpoint. The serious-event counts are zero in the listed groups, but limited group sizes and follow-up prevent those observations from establishing absence of risk.

The three parts differ in population, dose schedule, and design. Comparisons across parts may therefore be confounded by those design differences. The Part 3 crossover sequence requires methods that account for within-participant pairing and potentially period or sequence effects; those methods are not reported in the registry record. The washout period is described, but the record does not report an assessment of carryover.

The record lists multiple outcome measures and analyses but does not report a multiplicity strategy, an outcome hierarchy, or whether any interim analyses were performed. It also does not report how missing safety assessments or pharmacokinetic samples were handled, the amount of missing data, or sensitivity analyses. Numeric pharmacokinetic findings are not included in the registry record for this analysis. These limitations mean the posted counts support descriptive interpretation, while broader comparative and causal conclusions remain uncertain.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Phase 1 Three Part SAD, MAD & Cross-Over Study of ZP-059 in Healthy and Asthmatic Subjects — NCT04229303.
• Registry record last updated 2021-11-15; status last verified 2019-12.
• Results first posted 2021-11-15.
• 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

NCT04229303 is a completed phase one study of inhaled voriconazole, ZP-059, in healthy subjects and subjects with stable asthma. The registry records randomized allocation, no masking, a crossover model, and enrollment of 58. The study began on 2020-02-11 and reached primary completion on 2020-08-31; Zambon SpA is the listed sponsor.

Its three parts assessed single ascending doses in healthy subjects, multiple-dose regimens in subjects with mild stable asthma, and a crossover comparison of inhaled ZP-059 with oral voriconazole in subjects with mild to moderate stable asthma. The primary safety endpoint counts participants with treatment-emergent adverse events. No serious adverse events are reported in the listed groups; other adverse-event counts vary by group. The registry record does not report a single comparative estimate, confidence interval, or full analysis plan for interpreting those counts.