This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for A Pharmacokinetic Analysis of Posaconazole in Lung Transplant Recipients (MK-5592-105) (NCT01667107), a non-randomized phase 4 study. The primary outcome is Time to Reach 90% of the Steady State Serum Concentration of Posaconazole.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01667107 |
| Phase | Phase 4 |
| Condition | Fungal Infection |
| Allocation | Non-Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 26 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Merck Sharp & Dohme LLC |
| Results posted | Yes |
2. Clinical Question
Population
Lung transplant recipients with cystic fibrosis (CF) or without cystic fibrosis (non-CF) receiving routine post-operative antifungal prophylaxis. The registry record describes a single-site study with an enrollment of 26.
Intervention
Posaconazole, given as oral solution alongside Calogen® to optimize absorption. The arm descriptions specify 400 mg twice daily for a total of 6 weeks, starting within 12 hours of leaving surgery, with a possible change to 200 mg 4 times per day. The condition for changing the dose is cut off in the registry record.
Comparator
The parallel groups were participants with CF and participants without CF. This was not a randomized comparison, and the groups should not be treated as like-for-like control groups. Both received posaconazole; the distinction was CF status.
Primary question
Could the time to reach 90% of the steady state serum posaconazole concentration be estimated from concentrations measured over time? The registry record says the data did not permit estimation using the modeling proposed in the protocol.
The clinical and pharmacokinetic questions are related but distinct. The study description says it would examine posaconazole levels in plasma and the alveolar compartment in CF and non-CF lung transplant recipients receiving routine post-operative antifungal prophylaxis. It also says invasive fungal infection rates would be assessed following transplantation. The named primary endpoint, however, is a serum concentration timing measure; it is not an infection endpoint.
The registry record does not report comparative serum or alveolar concentration estimates, an estimated time to the stated concentration threshold, or infection-rate results. It therefore does not establish whether concentrations differed between the groups or how the measured concentrations related to invasive fungal infections. A comparison between CF and non-CF participants would also be a comparison of nonrandomized groups, not an isolated comparison of treatment assignments.
3. Trial Design
This was a Phase 4, nonrandomized, parallel study with no masking, conducted at a single site according to the study description. The registry record gives an enrollment of 26 and classifies the study status as terminated. The start date is 2013-01-23, and the primary completion date is 2014-01-16. The reason for termination is not reported in the registry record.
Participants were grouped according to whether they had cystic fibrosis. The arm descriptions identify one group as CF participants and the other as non-CF participants. Both groups were described as receiving posaconazole with Calogen® as part of post-operative antifungal prophylaxis. Consequently, the groups are not a treatment arm and a control arm. They differ by CF status, and the record does not describe random assignment to those groups.
The arm descriptions state that posaconazole oral solution was given at 400 mg twice daily with Calogen® to optimize absorption, for a total of 6 weeks, starting within 12 hours of leaving surgery. They say dosing could be changed to 200 mg 4 times per day, but the text describing the condition for that change is incomplete in the registry record. The summary says participants could be followed in hospital or as outpatients. Details of adherence, dose changes actually made, and treatment exposure by group are not reported in the registry record.
The stated primary endpoint concerned the time to reach 90% of the steady state serum posaconazole concentration. The study description also identifies plasma and alveolar compartment levels and invasive fungal infection rates as interests. The registry record lists six outcome measures and two analyses, but the full details and results for the other measures and analyses are not reported in the registry record. Enrollment is a design characteristic; it does not by itself show how many participants contributed usable measurements to each endpoint.
Because the allocation was nonrandomized and masking was absent, observed group differences, if available, could reflect characteristics besides CF status or posaconazole exposure. The registry record does not report a planned adjustment strategy that would address such differences. No treatment effect should be inferred from the structure of the study alone.
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
| Stage | Cystic Fibrosis Participants | Non-Cystic Fibrosis Participants |
|---|---|---|
| STARTED | 8 | 18 |
| COMPLETED | 4 | 11 |
| NOT COMPLETED | 4 | 7 |
Reasons for not completing this period:
| Reason | Cystic Fibrosis Participants | Non-Cystic Fibrosis Participants |
|---|---|---|
| Adverse Event | 4 | 3 |
| Tolerability issues | 0 | 2 |
| Protocol Violation | 0 | 1 |
| Lack of Efficacy | 0 | 1 |
Analysis population for the primary outcome, as defined in the registry: The population to be analyzed included participants who complied with the protocol sufficiently to ensure that the results would exhibit the effects of 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.
| Characteristic | Unit | Cystic Fibrosis Participants | Non-Cystic Fibrosis Participants | Total |
|---|---|---|---|---|
| Participants analysed | 8 | 18 | 26 | |
| Age, Continuous | Years | 30.0 (SD 7.82) | 52.4 (SD 10.39) | 45.5 (SD 14.22) |
| Sex: Female, Male: Female | Participants | 5 | 7 | 12 |
| Sex: Female, Male: Male | Participants | 3 | 11 | 14 |
6. Primary Endpoint
The registry lists the primary outcome as Time to Reach 90% of the Steady State Serum Concentration of Posaconazole, measured over Four hours after the first daily dose on Days 1-12 and every Monday and Thursday on Days 13-43.
| Element | Registry entry |
|---|---|
| Result type | N/A |
| Measure of spread | not applicable |
| Unit | not stated |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint was the time to reach 90% of the steady state serum concentration of posaconazole. Serum samples were scheduled approximately 4 hours after the first daily dose on Days 1-12 and every Monday and Thursday on Days 13-43. The protocol description says a linear model would be fitted to concentration data over time to estimate when the stated concentration level was reached.
As a general pharmacokinetic concept, a time-to-threshold measure describes how concentration changes during dosing and when it approaches a specified level relative to steady state. It can help characterize the development of drug exposure over time. It is different from a direct comparison of infection outcomes and does not by itself describe clinical benefit or harm.
The registry record explicitly states that the data did not permit estimation of this endpoint from the modeling proposed in the protocol. No numerical estimate, uncertainty interval, or group-specific estimate is reported in the registry record. This is an inability to estimate the planned quantity with that approach; it should not be read as a measured time of zero or as evidence that concentrations did not change.
The study description also refers to plasma and alveolar compartment concentrations, but the primary endpoint is worded as a serum concentration measure. Numerical results for alveolar concentrations and the relationship between serum and alveolar concentrations are not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The central interpretive point is that the planned primary endpoint was not estimable using the stated modeling approach. The protocol description proposed fitting a linear model to serum concentration measurements over time, but the registry record says the data did not permit estimation of the time to reach 90% of the steady state concentration. No estimated time, concentration trajectory, uncertainty interval, or statistical test for this endpoint is reported in the registry record.
That statement does not identify why estimation failed. Possible reasons in studies generally can include sparse or irregular measurements, too few observations to characterize a curve, or data that do not support the selected model. Those are general possibilities only; a reason for this study's failure to estimate the endpoint is not reported in the registry record. The absence of an estimate should not be converted into a claim about the actual concentration pattern.
The two groups were defined by CF status, not randomized treatment assignment. Both were described as receiving posaconazole. Thus, even if group-specific pharmacokinetic estimates were available, any contrast would be observational. Differences could not automatically be attributed to CF status or to a difference in treatment, and the registry record does not describe covariate adjustment that could support a more controlled comparison.
The registry record's study summary says invasive fungal infection rates would be assessed following transplantation, and the listed secondary outcome is the percentage of participants who develop invasive fungal infection. Numerical infection results are not reported in the registry record. The concentration endpoint and infection outcome answer different questions: a concentration profile is a measure of drug exposure, while infection occurrence is a clinical outcome. Without reported results linking the two, no conclusion about their association is supported.
The record lists an enrollment of 26, but the number of participants with analyzable concentration data, the number of measurements per participant, and the analysis population for the primary endpoint are not reported in the registry record. The stated population was participants who complied with the protocol sufficiently to ensure that results would exhibit treatment effects. The criteria used to apply that description and the number meeting them are not reported in the registry record.
The study status is terminated, but the reason is not reported in the registry record. Termination alone does not establish whether the study stopped because of recruitment, data quality, safety, operational issues, or another reason. Those explanations should not be inferred.
Overall, the posted information describes a pharmacokinetic study and a planned endpoint, but it does not provide an estimable primary endpoint result or numerical infection outcome. The study record therefore supports a description of the design and the endpoint-estimation limitation, not a quantitative conclusion about concentration timing or infection incidence.
9. Statistical Methods Explained
The registry record describes a plan to estimate the time to reach 90% of the steady state serum posaconazole concentration by fitting a linear model to concentration data over time. It then states that the data did not permit estimation using the proposed model. The record does not provide the model equation, parameter estimates, diagnostics, uncertainty intervals, or a revised model.
What does a concentration-over-time model do?
As a general statistical explanation, a concentration-over-time model represents how measured drug concentration changes with time. A fitted model can be used to describe a trajectory and, if its shape and data support the calculation, estimate when that trajectory reaches a chosen concentration threshold. Here, the threshold was stated relative to the steady state serum concentration. The registry record does not report a numerical steady state concentration or an estimated time to the threshold.
A linear model is one way to represent a relationship between a response and a predictor. Whether it is suitable depends on the data pattern, the model assumptions, and the intended estimate. Drug concentration profiles need not follow a straight-line pattern across all observation times. That general point does not establish that a linear model was unsuitable in this study; the registry record does not explain why the proposed modeling could not produce the endpoint estimate.
Why can an endpoint be unestimable?
In general, estimation requires enough informative measurements to identify the quantity of interest under the selected model. Incomplete, variable, or poorly positioned measurements can leave the model unable to distinguish a trajectory or threshold-crossing time. Model fit and data structure also matter. These are general statistical considerations, not documented explanations for this study. The registry record says only that the data did not permit the proposed estimation.
An unestimable endpoint is not equivalent to a numerical result of no change. It also does not mean that the threshold was never reached. It means the stated procedure did not yield the planned estimate from these data, as described in the registry record. No substitute analysis or estimate is reported in the registry record.
How should repeated measurements be understood?
As a general concept, repeated measurements from one participant are usually related to one another. They are not necessarily independent observations in the way that measurements from different participants might be treated under a simple model. Analyses of repeated data may need to account for within-participant dependence, observation timing, and variation between participants. The registry record does not report whether or how the proposed model accounted for these features, nor does it provide the number or timing of measurements actually collected for each participant.
The sampling schedule in the endpoint description specified blood collection approximately 4 hours after the first daily dose on Days 1-12 and every Monday and Thursday on Days 13-43. This is the planned schedule described in the record, not confirmation that every scheduled sample was collected. Actual sample completeness and deviations from schedule are not reported in the registry record.
What does the group structure imply?
The study had parallel CF and non-CF groups, but allocation was nonrandomized. In general, randomization helps balance measured and unmeasured characteristics between treatment groups on average; this study's design does not provide that protection through random allocation. The groups are defined by clinical status, and the record does not report a statistical adjustment plan for differences between them. A comparison of group outcomes should therefore be interpreted as observational rather than as a randomized treatment contrast.
No masking was used. As a general matter, masking can reduce the opportunity for knowledge of group assignment to influence some decisions or assessments. The relevance depends on the outcome and study procedures. The registry record does not describe any masking of laboratory staff or outcome assessors separately, so such procedures cannot be assumed.
What do uncertainty intervals and tests add?
In general, a confidence interval describes a range of values compatible with the observed data under a specified statistical model and its assumptions. It conveys uncertainty around an estimate; it does not resolve design limitations or establish causation. A p-value, when reported, summarizes how incompatible the data are with a specified null model under the analysis assumptions. Neither a confidence interval nor a p-value for the primary endpoint is reported in the registry record because the endpoint itself was not estimated as planned.
The registry record gives no standard errors, model coefficients, diagnostics, or alternative analysis. It also does not report a treatment-effect estimate for infection outcomes. Consequently, precision and statistical significance cannot be assessed for these outcomes from the information recorded.
How should planning calculations be read?
The record describes planning illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It states that the effect to detect is a specified fraction of the observed effect. These are planning assumptions, not evidence that the trial was designed around those values. The sample-size justification for the trial is not reported in the registry record.
As a general concept, a sample-size calculation estimates how many participants would be needed under stated assumptions to detect a target effect with a chosen power. It is prospective planning, not a measurement of the power achieved after the study. Any such illustration should not be described as observed power. The exact planning outputs and the observed effect used for them are not reported in the registry record. No new sample-size estimate can be inferred from the enrollment alone.
10. Multiplicity, Missing Data and Analysis Populations
The registry record lists six outcome measures and two analyses, but it does not report the complete outcome list, analysis details, or results for those analyses. It identifies the time to reach 90% of the steady state serum concentration as the primary endpoint and the percentage of participants who develop invasive fungal infection as a secondary outcome. How the remaining outcome measures were defined is not reported in the registry record.
Multiplicity arises when several outcomes, time points, groups, or statistical tests are examined. As a general statistical matter, a larger set of tests can increase the chance of obtaining at least one apparently unusual result even when none of the underlying effects is real. Prespecified primary outcomes, a testing hierarchy, or adjustment procedures can help clarify interpretation. Whether the analyses used such procedures is not reported in the registry record. No multiplicity adjustment should be assumed.
The concentration sampling schedule included repeated time points. The record does not specify whether analyses compared time points individually, modeled all observations jointly, or adjusted for multiple comparisons. It also does not describe whether the primary endpoint was the sole confirmatory analysis or how secondary outcomes were handled.
Missing-data handling is not reported in the registry record. The record does not state how unavailable blood samples, missed visits, withdrawals, or incomplete infection follow-up were handled. It does not give the number of participants included in each outcome analysis. The primary analysis population is described as participants who complied with the protocol sufficiently to ensure that results would exhibit treatment effects, but the operational criteria and resulting participant count are not reported.
These omissions limit assessment of selection into analyses and the robustness of any estimated results. They are especially relevant when the planned primary endpoint could not be estimated. The registry record does not describe sensitivity analyses, imputation, or other methods for assessing the impact of missing measurements.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Cystic Fibrosis Participants | 6 | 8 | 75.0% |
| Non-Cystic Fibrosis Participants | 10 | 18 | 55.6% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Cystic Fibrosis Participants | 1 of 8 |
| Non-Cystic Fibrosis Participants | 2 of 18 |
Most frequent serious adverse event terms
| Event term | Organ system | Cystic Fibrosis Participants | Non-Cystic Fibrosis Participants |
|---|---|---|---|
| Lower respiratory tract infection | Infections and infestations | 0 of 8 | 2 of 18 |
| Cerebral infarction | Nervous system disorders | 0 of 8 | 2 of 18 |
| Renal failure acute | Renal and urinary disorders | 0 of 8 | 2 of 18 |
| Neutropenia | Blood and lymphatic system disorders | 1 of 8 | 0 of 18 |
| Supraventricular tachycardia | Cardiac disorders | 1 of 8 | 0 of 18 |
| Systemic inflammatory response syndrome | General disorders | 1 of 8 | 0 of 18 |
| Liver injury | Hepatobiliary disorders | 1 of 8 | 0 of 18 |
| Immunosuppressant drug level decreased | Investigations | 1 of 8 | 0 of 18 |
| Renal failure | Renal and urinary disorders | 1 of 8 | 0 of 18 |
| Acute respiratory failure | Respiratory, thoracic and mediastinal disorders | 1 of 8 | 0 of 18 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Cystic Fibrosis Participants | Non-Cystic Fibrosis Participants |
|---|---|---|---|
| Nausea | Gastrointestinal disorders | 1 of 8 | 0 of 18 |
| Vision blurred | Eye disorders | 0 of 8 | 1 of 18 |
| Alanine aminotransferase increased | Investigations | 0 of 8 | 1 of 18 |
| Immunosuppressant drug level increased | Investigations | 0 of 8 | 1 of 18 |
| Renal failure | Renal and urinary disorders | 0 of 8 | 1 of 18 |
| Renal failure acute | Renal and urinary disorders | 0 of 8 | 1 of 18 |
Serious events with the highest arm-level rate: neutropenia (12.5%), supraventricular tachycardia (12.5%), systemic inflammatory response syndrome (12.5%), liver injury (12.5%), immunosuppressant drug level decreased (12.5%).
The registry record reports serious adverse event figures separately for CF and non-CF participants. Among the 8 CF participants listed as at risk, 6 were affected by serious adverse events and 1 by other adverse events. Among the 18 non-CF participants listed as at risk, 10 were affected by serious adverse events and 2 by other adverse events. These are counts of participants affected as recorded; they do not establish that every affected participant experienced only one event.
The registry also lists six serious adverse event terms, each with a frequency of 12.5%: Neutropenia, Supraventricular tachycardia, Systemic inflammatory response syndrome, Liver injury, Immunosuppressant drug level decreased, and Renal failure. The denominator and the relation of these percentages to the participant groups are not reported in the registry record. The percentages should not be interpreted as group-specific rates without that information.
Deaths are not reported in the registry record. The listed counts do not establish whether an event was caused by posaconazole, the transplant, another treatment, or an underlying condition. The nonrandomized group structure also does not support a controlled safety comparison. Definitions, event timing, severity grading, and attribution procedures are not reported in the registry record.
12. What the Result Does, and Does Not, Mean
The record describes an attempt to characterize serum posaconazole concentration over time in lung transplant recipients with and without CF. Its main statistical result is a limitation: the planned time-to-threshold endpoint could not be estimated using the proposed modeling. That finding concerns the ability of the data and model to produce the planned quantity. It is not a numerical concentration result and does not establish that the concentration remained below the threshold, reached it at a particular time, or followed any particular pattern.
The registry record also describes an interest in plasma and alveolar compartment levels and in invasive fungal infection rates after transplantation. Numerical results for these outcomes are not reported in the registry record. Without those results, the record does not quantify infection occurrence, compare infection outcomes between groups, or connect drug concentrations with infection outcomes.
The CF and non-CF groups are not randomized treatment arms. Both were described as receiving posaconazole, and group membership reflects CF status. Any difference between their outcomes, if reported, could be associated with other group differences. The record does not report an adjustment strategy that would support a causal comparison.
The adverse event information records participants affected and lists several serious adverse event terms. It does not, on its own, establish causation or comparative risk. The denominators for the listed serious adverse event term percentages are not reported in the registry record, and deaths are not reported there.
Accordingly, this record is informative about the design, sampling plan, endpoint definition, and difficulty estimating the primary endpoint. It does not provide a quantitative basis for conclusions about the time to target concentration, infection rates, or causal safety effects. A missing estimate should not be turned into a positive or negative treatment conclusion.
13. Why This Trial Matters Statistically
This study illustrates an important distinction between specifying an estimand and being able to estimate it from collected data. The primary endpoint was defined as a time to a concentration threshold, and the record described a model intended to estimate it. Yet the registry record states that the data did not permit that estimate. A clearly worded endpoint does not guarantee that the measurements and analysis will identify its value.
It also highlights the need to distinguish pharmacokinetic measures from clinical outcomes. Concentration measurements describe drug exposure; invasive fungal infection is a clinical outcome. The study summary identifies both interests, but numerical infection results and concentration estimates are not reported in the registry record. A pharmacokinetic endpoint cannot stand in for an unreported clinical outcome.
The parallel groups may look like two arms, but they are defined by CF status and were not randomized. That design feature matters when interpreting any group contrast. Statistical adjustment can sometimes address measured differences, but the registry record does not report an adjustment plan, and adjustment cannot guarantee removal of unmeasured confounding.
Finally, the registry record demonstrates why transparent reporting of analysis populations, missing measurements, model performance, and endpoint results is important. Those details would help readers understand why the planned estimate was unavailable and whether an alternative analysis was informative. In this record, those explanations are not reported, so interpretation must remain limited to the stated estimation failure and the design information.
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 primary limitation is that the stated primary endpoint was not estimable from the data using the proposed modeling approach. The registry record does not give the reason, a revised model, or a numerical alternative. It also does not report concentration estimates, uncertainty intervals, or results for the alveolar compartment, despite the study description's interest in those measurements.
The study was nonrandomized and grouped participants by CF status. This does not provide a like-for-like randomized comparison. The registry record does not describe adjustment for differences between groups, and it does not report participant characteristics that could help assess comparability. No causal group interpretation is justified by the design alone.
The record gives a planned blood sampling schedule but does not report sample completeness, actual sampling times, or the number of usable observations. The analysis population is described in general terms, but the criteria and participant count are not reported. Missing-data methods, adherence information, and sensitivity analyses are also not reported in the registry record.
The registry record classifies the study as terminated but does not report the reason. It identifies six outcome measures and two analyses, yet the full analysis details and all outcome results are not reported. The planned infection assessment has no numerical result in the record. The serious adverse event term percentages lack a reported denominator, and deaths are not reported in the registry record.
The arm descriptions are incomplete where they discuss a possible dose change, so the condition for changing the dose is not available. The record also does not report actual dose changes or exposure by group. These limitations restrict what can be concluded about the concentration endpoint, infection outcomes, and safety.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Pharmacokinetic Analysis of Posaconazole in Lung Transplant Recipients (MK-5592-105) — NCT01667107.
- Registry record last updated 2018-10-09; status last verified 2018-09.
- Results first posted 2015-01-05.
- 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.
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18. Record Summary
This Phase 4 study, NCT01667107, examined posaconazole pharmacokinetics in lung transplant recipients with and without CF. It was nonrandomized, unmasked, parallel, and described as single-site, with an enrollment of 26. The study status is terminated; the reason is not reported in the registry record.
The primary endpoint was time to reach 90% of the steady state serum posaconazole concentration, estimated from concentration measurements over time. The registry record states that the data did not permit estimation using the proposed linear model. Numerical concentration and invasive fungal infection results are not reported in the registry record.
The safety record lists serious and other adverse event counts by group and six serious adverse event terms at 12.5% each. The denominator for those term percentages is not reported in the registry record. The record does not support a randomized treatment comparison or a causal interpretation of group differences.