Assessing the Safety and Efficacy of MK-5592 (Posaconazole) in Japanese Participants With Fungal Infection (MK-5592-101): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Assessing the Safety and Efficacy of MK-5592 (Posaconazole) in Japanese Participants With Fungal Infection (MK-5592-101) (NCT02180165), a randomized phase 3 study. The primary outcome is Number of Participants With an Adverse Event.

2. Clinical Question

The central clinical question is whether the safety experience recorded for posaconazole differs from that recorded for voriconazole in the study’s Japanese participants. The endpoint is broad: an adverse event could be an unfavorable medical occurrence, symptom, disease, or abnormal laboratory finding temporally associated with treatment or a protocol procedure, regardless of whether it was considered treatment-related. Worsening of a pre-existing condition could also qualify.

The study used two cohorts and specified distinct disease populations for the primary endpoint. Cohort 1 concerned chronic pulmonary aspergillosis; Cohort 2 included invasive and chronic pulmonary aspergillosis. The registry also lists response outcomes for several disease categories as secondary outcomes, but the primary outcome addressed adverse events rather than response. The clinical question therefore needs to be read as a safety question, not as a direct test of antifungal efficacy. The record does not report a primary efficacy endpoint or a formal safety margin for judging the treatments.

3. Trial Design

This was a Phase 3, randomized, parallel-group, open-label study comparing posaconazole with voriconazole. It was conducted in Japanese participants and lists aspergillosis as its condition. The registry records enrollment of 116 participants. The study status is completed; the recorded start date is 2014-07-29 and the primary completion date is 2018-01-24.

The intervention descriptions specify oral tablet or intravenous solution options for both drugs. Posaconazole was described as 300 mg twice on Day 1, followed by 300 mg once daily for up to 84 days. Voriconazole was described as 300 mg twice on Day 1, followed by 200 mg orally twice daily or 4 mg/kg intravenously twice daily for up to 84 days. The registry gives these regimens for both Cohort 1 and Cohort 2.

The primary endpoint description defines separate analysis populations for the cohorts. In Cohort 1, the population was randomized participants with chronic pulmonary aspergillosis who received at least one dose. In Cohort 2, it was randomized participants with invasive aspergillosis and chronic pulmonary aspergillosis who received at least one dose. The primary outcome counts reported by arm are 15 of 15 for Cohort 1 posaconazole, 6 of 7 for Cohort 1 voriconazole, 57 of 57 for Cohort 2 posaconazole, and 27 of 27 for Cohort 2 voriconazole.

Randomization and parallel assignment are recorded, but details of the sequence-generation procedure, allocation concealment, and the randomization ratio are not reported in the registry record. The study was open-label, meaning treatment assignment was not masked. The record describes treatment for up to 84 days and an adverse-event timeframe up to approximately Day 98. It does not report additional details about follow-up procedures or whether treatment duration varied among participants.

The overall enrollment and the endpoint-specific arm counts do not have identical scopes. Safety-group counts elsewhere in the registry are 15, 7, 62, and 31 across the four arms, while the primary-outcome arm counts are 15, 7, 57, and 27. The registry record does not explain the difference between these sets of denominators. They should therefore be kept distinct rather than combined or treated as interchangeable.

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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Cohort 1: All randomized participants with chronic pulmonary aspergillosis who received at least one dose of study treatment. Cohort 2: All randomized participants with invasive aspergillosis and chronic pulmonary aspergillosis who received at least one dose of study treatment.

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: Cohort 1: All randomized and treated participants with chronic pulmonary aspergillosis; Cohort 2: All randomized and treated participants with invasive aspergillosis and chronic pulmonary aspergillosis

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With an Adverse Event, measured over Up to approximately Day 98.

The primary endpoint is the number of participants with at least one adverse event, assessed up to approximately Day 98. The registry defines an adverse event broadly as an untoward medical occurrence after administration of a pharmaceutical product, without requiring a causal relationship to treatment. Events may include unfavorable signs, symptoms, diseases, and abnormal laboratory findings, including events associated with a protocol-specified procedure. A clinically significant worsening of a pre-existing condition may also count when temporally associated with the sponsor’s product.

This endpoint is used to describe the safety experience observed during the study. In general, counting participants with at least one event gives a simple measure of how many people experienced an event, but it does not describe the number of separate events per person, their duration, severity, or relationship to treatment. Those characteristics require additional outcome definitions and results. The endpoint count also does not establish that treatment caused an event: the registry definition explicitly does not require causality.

The posted counts indicate that all 15 Cohort 1 participants assigned to posaconazole and 6 of 7 assigned to voriconazole had an adverse event. In Cohort 2, the counts are 57 of 57 for posaconazole and 27 of 27 for voriconazole. These are counts in the specified endpoint populations, not a complete description of the kinds or seriousness of events. Serious adverse events are recorded separately in the safety information.

The primary objective was safety comparison, but the registry record does not report a prespecified threshold for an acceptable difference or a formal noninferiority or equivalence criterion. Without such a framework, the endpoint counts alone cannot establish that the treatments have equivalent safety profiles.

7. Results Posted in the Registry

• Cohort 2: Posaconazole: 100.0% (57/57) versus 100.0% (15/15) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0), risk ratio 1.00 (1.00–1.00); unadjusted two-proportion z-test p = n/a.
• Cohort 2: Voriconazole: 100.0% (27/27) versus 100.0% (15/15) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0), risk ratio 1.00 (1.00–1.00); unadjusted two-proportion z-test p = n/a.

8. Statistical Interpretation

9. Statistical Methods Explained

The reported primary outcome is binary at the participant level: a participant either had at least one adverse event during the stated timeframe or did not. The arm results are presented as counts of participants with an event and the corresponding arm sizes. This is a straightforward way to describe event occurrence, but its interpretation depends on the endpoint definition, the analysis population, the observation period, and how missing outcome information was handled. Details of missing-data handling are not reported in the registry record.

What does a risk difference describe?

In general, a risk difference is the event proportion in one group minus the event proportion in a reference group. It is expressed on the probability scale, so a value of 0.0 means the reported proportions are equal for the particular groups being contrasted. The registry comparisons report a risk difference of 0.0 for Cohort 2 posaconazole versus Cohort 1 posaconazole, and 0.0 for Cohort 2 voriconazole versus Cohort 1 posaconazole. The corresponding intervals are 0.0 to 0.0.

The identity of the comparison groups matters as much as the arithmetic. These registry comparisons do not place the two randomized treatments against each other within the same cohort: both use Cohort 1 posaconazole as their reference, and each other group is from Cohort 2. Because the endpoint populations differ by cohort, this is not a direct estimate of a randomized treatment effect for either cohort. A valid treatment comparison should preserve the study’s population and randomized-group structure, unless a justified adjustment or other design is reported. Such an analysis is not reported in the registry record.

Why can an event outcome reach a ceiling?

In general, when every participant in a group has at least one event, the observed event proportion is at its maximum. In Cohort 2, all participants in both listed primary-outcome arms had an event. This leaves no event-free participants in either group for the binary endpoint to distinguish. The identical observed proportions are a property of these counts; they do not show that the event types, severity, or timing were identical. Nor do they establish that the underlying risks in a broader population are exactly equal.

When observed proportions are at a boundary, simple interval calculations can be uninformative. The posted intervals of 0.0 to 0.0 accompany the zero differences in the cross-cohort comparisons, but they do not capture all sources of uncertainty, such as differences between disease cohorts or unreported features of the analysis. A confidence interval is generally intended to express uncertainty around an estimate under a specified statistical method and assumptions. The method used for these posted intervals is not reported in the registry record, so their construction cannot be assessed from the record alone.

What is the role of randomization?

General statistical principle: randomization is intended to make treatment groups comparable, on average, within the population and allocation process to which it applies. It does not make distinct disease cohorts interchangeable. The record identifies the study as randomized and parallel, but it does not report allocation concealment, the randomization ratio, or sequence-generation details. Open-label assignment also means participants and study personnel were not masked to treatment, according to the recorded masking status. That design feature can matter for outcomes that involve reporting, assessment, or decisions about whether an event has occurred.

The primary outcome’s broad definition includes events that do not have to be judged treatment-related. This helps make the endpoint an all-event safety count, but it means the count cannot be interpreted as the number of adverse reactions caused by a drug. In general, attribution requires separate assessment and criteria. The registry’s primary count does not supply that attribution.

What is reported about the analysis?

The record lists 20 outcome measures, including secondary response outcomes, and indicates 19 secondary outcomes posted. It reports no analyses in the analysis count. A complete statistical analysis plan, the planned primary comparison, the estimator and interval method, hypothesis tests, model covariates, and multiplicity procedures are not reported in the registry record. The absence of those details makes it difficult to determine whether the displayed contrasts were prespecified or how they relate to a sponsor’s planned analysis.

The outcome population requires at least one dose of study treatment. This is a treatment-received criterion, even though the population description begins with randomized participants. In general, analysis populations can affect comparability if participants are excluded after randomization. The record does not describe exclusions by arm, whether all randomized participants were included in other analyses, or how participants without complete follow-up were handled.

How should planning illustrations be understood?

General statistical principle: a sample-size calculation is a planning exercise, not a measure of what a completed trial has demonstrated. The stated illustration assumptions use a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a fraction of the observed effect. For time-to-event outcomes, the stated convention is total events; for other outcomes, the convention is participants per arm. Such calculations are sensitive to the chosen effect and assumptions. They are not observed power, and they do not remedy limitations in the posted endpoint comparison. The protocol’s own sample-size justification is not reported in the registry record.

10. Confidence Intervals and Precision

The registry gives a risk difference of 0.0 with an interval from 0.0 to 0.0 for each of its two posted comparisons. Both comparisons have an observed event proportion of 1.0 in each group. Numerically, the intervals do not extend away from the observed zero difference. However, those comparisons use Cohort 1 posaconazole as the reference for Cohort 2 treatment groups, rather than comparing the randomized treatments within one cohort. Their numerical precision should not be mistaken for precise evidence about a treatment effect.

A confidence interval is generally a range of values compatible with an estimate under a particular statistical procedure and its assumptions. Its width is commonly used to communicate sampling uncertainty, while its validity depends on whether the method matches the design and data. The registry record does not identify the interval method for the posted risk differences. Because the compared groups belong to different cohorts and the event proportions are at the ceiling, the displayed zero-width intervals are especially limited as a description of uncertainty about a clinically relevant treatment contrast.

The endpoint counts themselves give useful descriptive information about the observed participants: adverse events were recorded in all 15 Cohort 1 posaconazole participants, 6 of 7 Cohort 1 voriconazole participants, and all 57 and 27 participants in the two Cohort 2 arms. The sizes of these groups and the near-universal event occurrence constrain what can be learned from a binary any-event measure. That measure does not distinguish participants with one event from those with multiple events, or less serious events from serious ones.

The serious-event safety groups have their own denominators, including 62 and 31 in Cohort 2, and should not be used to reinterpret the primary endpoint intervals. The reasons for the different Cohort 2 denominators are not reported in the registry record. No adjusted estimates or uncertainty intervals for the serious-event counts are reported. Overall, the posted interval values should be read alongside the design and population definitions, not as proof of equivalence or as a complete measure of precision.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 20 outcome measures, including a primary adverse-event count and secondary outcomes describing successful overall response at different timepoints and for different fungal conditions. It records 19 secondary outcomes posted. Multiple outcomes can create a multiplicity issue: when many hypotheses or contrasts are considered, the chance of at least one apparently notable result can increase. General statistical practice may address this through a prespecified hierarchy, adjusted thresholds, or clearly identified exploratory analyses. The registry record does not report a multiplicity strategy or explain how the posted secondary outcomes were prioritized.

The record reports an analysis count of 0. It does not provide a detailed statistical analysis plan, a primary hypothesis test, adjusted treatment-effect estimates, or a sponsor analysis of the primary endpoint. The specific comparison planned for the primary outcome is therefore not reported in the registry record. The available risk-difference comparisons use Cohort 1 posaconazole as the reference for Cohort 2 arms, so they do not establish a within-cohort randomized comparison of posaconazole and voriconazole.

The primary endpoint population includes participants who received at least one dose, with distinct disease definitions for Cohort 1 and Cohort 2. The registry does not describe a broader intention-to-treat analysis or report how many randomized participants were excluded from each endpoint population. In general, excluding participants after randomization can affect the balance created by random assignment, depending on the reasons for exclusion and the analysis approach.

Handling of missing endpoint data, incomplete follow-up, treatment discontinuation, and censoring is not reported in the registry record. The record also does not report whether the event status was assessed for every participant through approximately Day 98. Without these details, the posted counts cannot show whether missing information could have affected the outcome summaries. Protocol deviations, sensitivity analyses, and methods for any adjusted analysis are likewise not reported in the registry record. These omissions limit assessment of how robust the results are to analytic choices, especially across multiple outcomes and cohort-specific populations.

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: blister infected (14.3%), bronchopulmonary aspergillosis (14.3%), spinal compression fracture (14.3%), pneumonia (13.3%), sepsis (6.7%).

Serious adverse events are reported separately from the primary count of participants with any adverse event. In Cohort 1, serious events were reported for 3 of 15 participants receiving posaconazole and 2 of 7 receiving voriconazole. In Cohort 2, the corresponding safety-group counts were 28 of 62 and 3 of 31. Deaths were recorded for 1 participant in each Cohort 1 arm, 6 in Cohort 2 posaconazole, and 0 in Cohort 2 voriconazole.

These are descriptive counts, not evidence that treatment caused each event or death. The registry’s broad adverse-event definition does not require a causal relationship, and the safety figures do not provide a treatment-effect estimate or a statistical comparison. In particular, Cohort 2 safety denominators differ from the primary outcome denominators of 57 and 27. The registry record does not explain that difference, so the two sets of figures should not be combined.

The listed serious-event terms include Blister infected, Bronchopulmonary aspergillosis, and Spinal compression fracture, each reported as 14.3%; Pneumonia at 13.3%; Sepsis at 6.7%; and Pyrexia at 3.2%. These percentages are reported terms, but the registry entry does not give enough detail to interpret their denominators or determine how participants with multiple serious events are represented. They should not be treated as mutually exclusive categories or summed.

In general, safety counts are best interpreted together with event definitions, exposure time, seriousness, relatedness, and participant-level follow-up. Several of those details are not reported in the registry record.

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

The posted primary endpoint counts establish that adverse events were recorded for all participants in the Cohort 2 endpoint arms and for nearly all participants in Cohort 1. This is a description of event occurrence under a broad definition during the stated observation timeframe. It does not establish that the events were caused by either treatment, and it does not rank the clinical importance of the events.

The reported zero risk differences and intervals arise from comparisons in which both groups had an event proportion of 1.0. One reference group is Cohort 1 posaconazole, and the comparison groups are the two Cohort 2 arms. Since those groups are drawn from different cohort populations, the comparisons are not a direct randomized comparison between treatments. The estimates therefore cannot be interpreted as demonstrating that posaconazole and voriconazole have equal safety or that either is safer.

The separate safety figures show serious adverse events and deaths by arm, but they are also descriptive. They do not include a reported statistical comparison, adjustment, or causal attribution. Differences in the Cohort 2 safety denominators and primary outcome denominators further mean the safety summaries answer distinct descriptive questions. The registry record does not explain the denominator difference.

More broadly, the record does not report the full analysis plan, missing-data methods, a primary statistical test, multiplicity handling, or the method used to construct the posted confidence intervals. Those details are important for assessing the strength and precision of any treatment comparison. The registry also lists numerous secondary response outcomes, but their presence does not turn the primary safety count into an efficacy result.

Accordingly, the results support a narrow conclusion about the recorded counts in the listed endpoint and safety groups. They do not establish equivalence, noninferiority, superiority, or treatment causation. The study’s randomized designation is relevant to the design, but it does not make comparisons across distinct cohorts equivalent to randomized treatment contrasts within a cohort. Any broader interpretation would require additional analyses and design details that are not reported in the registry record.

14. Why This Trial Matters Statistically

This trial illustrates why statistical interpretation depends on matching a numerical contrast to the design that generated the data. The study is recorded as randomized, yet the posted risk differences compare Cohort 2 arms with Cohort 1 posaconazole. Because the cohort populations differ, a numerical equality across those groups is not the same as a randomized comparison between posaconazole and voriconazole within one population. The distinction is central to interpreting the reported zero differences.

It also illustrates a limitation of a broad binary safety endpoint when event occurrence is nearly universal. A count of participants with at least one adverse event is easy to understand, but it can reach a ceiling and then fail to distinguish groups on the measured outcome. Event types, seriousness, repeated events, duration, and attribution may still vary even when both groups have the same participant-level event proportion. The registry’s separate serious-event counts provide different information, but do not by themselves resolve those questions.

Denominators also matter. The primary outcome and the safety summaries have different Cohort 2 arm sizes, and the record does not explain why. A reader who combines these values could confuse distinct populations or outcome summaries. Clear separation of endpoint populations and safety sets is essential for reproducible interpretation.

Finally, the record lists many outcomes but no analysis count and does not report a statistical analysis plan or multiplicity procedure. That limits the ability to identify the intended primary contrast and distinguish confirmatory from exploratory results. The example underscores that a completed randomized trial can still have registry results that are insufficient for a definitive inferential conclusion unless the populations, analysis methods, and uncertainty calculations are clearly described.

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 principal limitation is that the posted treatment contrasts do not compare posaconazole and voriconazole within the same cohort. They use Cohort 1 posaconazole as the reference for each Cohort 2 arm, even though the primary endpoint defines different disease populations for the cohorts. The zero risk differences therefore cannot be treated as direct randomized estimates of a treatment effect.

The primary event outcome is saturated in Cohort 2: every participant in both listed endpoint arms had at least one adverse event. This leaves no variation in the binary outcome within those arms and provides no distinction in the any-event measure. In Cohort 1, the counts are 15 of 15 and 6 of 7, but an inferential comparison is not reported. The method used to calculate the posted intervals is also not reported.

There are different Cohort 2 denominators for the primary endpoint and safety summaries: 57 and 27 for the primary outcome, compared with 62 and 31 in the safety groups. The registry record does not explain the distinction. It also does not report the number of randomized participants excluded from each endpoint population or how missing outcome data and incomplete follow-up were handled.

Further design and analysis details are absent, including the randomization procedure, allocation concealment, statistical analysis plan, primary hypothesis test, adjusted analyses, and multiplicity approach. Open-label assignment may be relevant to event assessment, but the record does not describe procedures used to limit assessment bias. The broad adverse-event definition also does not require causality, so counts cannot be interpreted as treatment-related events without separate evidence.

These limitations restrict conclusions to descriptive summaries of the recorded groups. They do not show that the study lacked procedures or analyses; those details are simply not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Assessing the Safety and Efficacy of MK-5592 (Posaconazole) in Japanese Participants With Fungal Infection (MK-5592-101) — NCT02180165.
• Registry record last updated 2021-01-28; status last verified 2021-01.
• Results first posted 2019-01-11.
• 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

NCT02180165 is a completed Phase 3 randomized, parallel, open-label study of posaconazole and voriconazole in Japanese participants with fungal infection, with aspergillosis listed as the condition. Enrollment was 116. The recorded study start date is 2014-07-29 and the primary completion date is 2018-01-24.

The primary endpoint was the number of participants with an adverse event up to approximately Day 98. Counts were 15 of 15 and 6 of 7 in Cohort 1, and 57 of 57 and 27 of 27 in Cohort 2, for posaconazole and voriconazole respectively. The posted risk differences compare Cohort 2 groups with Cohort 1 posaconazole and are not direct within-cohort treatment contrasts.

Separate safety-group results report serious adverse events and deaths. The registry record does not explain the different Cohort 2 denominators between the primary endpoint and safety summaries. It also does not report a detailed statistical analysis plan, missing-data approach, multiplicity procedure, or method for the posted confidence intervals. The available results are therefore descriptive and do not establish comparative treatment effects.