The Relationship of Defeverscence and Itraconazole Plasma Level Study in Immunocompromised Participants: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for The Relationship of Defeverscence and Itraconazole Plasma Level Study in Immunocompromised Participants (NCT01021683), a registered phase not stated study. The primary outcome is Percentage of Participants Achieving Plasma Level of Itraconazole at 1000 Nanogram Per Milliliter (ng/mL) or Higher After Administration of Study Treatment.

2. Clinical Question

The study's stated purpose was to examine whether sufficient itraconazole concentration could influence fever disappearance in participants receiving intravenous itraconazole for unknown neutropenic fever under general treatment conditions. That purpose is broader than the primary endpoint as described: the primary endpoint is a concentration-threshold measure, while fever disappearance appears among the secondary outcomes. A concentration endpoint can describe drug exposure, but by itself it does not establish whether fever resolved or whether exposure caused a change in fever.

The registry also lists outcomes involving time to defervescence, duration of neutropenia, absolute neutrophil count, plasma concentration in relation to overall success, and fungal infection. Numerical results for these outcomes are not reported in the registry record. Accordingly, the central question that can be evaluated from the record is how the primary endpoint was defined, not what percentage achieved it or how it related to clinical outcomes.

3. Trial Design

This was an observational study sponsored by Janssen Korea, Ltd., Korea. The registry lists the study as completed, with a start date of 2009-07 and primary completion in 2010-07. Enrollment was 203. The condition terms are hematologic neoplasms, neutropenia, and fever.

The study description concerns participants who had received itraconazole oral solution as prophylaxis and subsequently received intravenous itraconazole for unknown neutropenic fever. The intervention is listed as itraconazole. The treatment description specifies an infusion over one hour at 200 mg per dose twice daily for 2 days, followed by 200 mg once. The record does not give further detail after that final phrase, so the complete treatment schedule is not reported in the registry record.

The registry does not state how treatment allocation occurred. It does not establish a randomized comparison, and the record identifies no like-for-like control comparison. The presence of a listed treatment group therefore should not be interpreted as evidence of random assignment or as a controlled contrast. The observational description also means that comparisons between participants, if made, could reflect differences other than plasma concentration or treatment exposure; the registry record does not report an adjustment strategy.

The primary endpoint was assessed on Day 5 and concerned the percentage reaching an itraconazole plasma level of at least 1000 ng/mL. The registry defines the endpoint population as eligible participants who received the study drug at least once and had the primary efficacy endpoint measured at least once. It also lists secondary outcomes addressing fever, neutropenia, neutrophil count, plasma concentration, and fungal infection. The registry lists 9 outcome measures and 0 analyses. Numerical outcome estimates and detailed analysis methods are not reported in the registry record.

The record does not report a protocol-level explanation for enrollment, a sample-size justification, or the methods used to select or analyze participants. Those details should not be inferred from the completed status or the enrollment count.

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: The intent-to-treat (ITT) population included the participants who satisfied the eligibility criteria, received the study drug at least once, and in whom the primary efficacy endpoint was measured at least once.

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: Baseline characteristics were reported only for intent-to-treat (ITT) population which included 150 participants.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants Achieving Plasma Level of Itraconazole at 1000 Nanogram Per Milliliter (ng/mL) or Higher After Administration of Study Treatment, measured over Day 5.

The primary endpoint is the percentage of participants who achieved an itraconazole plasma level of at least 1000 ng/mL after study treatment, assessed on Day 5. For this endpoint, plasma level is defined as the sum of itraconazole concentration and hydroxyitraconazole concentration. The registry specifies a 95% confidence interval as the measure of uncertainty around the percentage.

This threshold endpoint describes whether measured exposure crossed a prespecified concentration boundary, rather than the actual concentration distribution or a change from baseline. A binary threshold can be useful when a clinical question concerns the proportion of participants reaching a defined exposure level. It also discards some information: participants just below and well below the threshold are counted alike, as are those just above and well above it. That is a general property of turning a continuous measurement into a yes-or-no outcome.

Concentration is relevant to the study's stated interest in whether sufficient itraconazole exposure is related to defervescence. However, the primary endpoint itself is not fever resolution. Defervescence is listed as a secondary outcome, and the registry record does not report numerical results linking concentration to fever outcomes. The endpoint therefore indicates how the study intended to classify exposure, but the posted record does not show the percentage meeting the threshold or its precision. The endpoint's numerical result and the details of how plasma samples were handled are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary percentage: whether each participant did or did not reach the defined plasma concentration threshold on Day 5. A percentage estimates the proportion of the analyzed population classified as reaching that threshold. The registry describes the threshold as at least 1000 ng/mL and defines plasma level as the sum of itraconazole concentration and hydroxyitraconazole concentration. The record identifies the intended summary as a percentage with a 95% confidence interval, but does not report the estimate, interval limits, or the number of participants included in the calculation.

In general, a confidence interval communicates sampling uncertainty around an estimate. It is not a guarantee that a particular range contains the true value, and it does not account automatically for bias from study design, measurement, or missing observations. Its interpretation depends on the method used to calculate it and on the assumptions underlying that method. The specific confidence-interval procedure is not reported in the registry record. Without the interval itself, readers cannot judge how precise the primary estimate would have been.

Converting concentration into a threshold outcome has a practical interpretation: it classifies participants according to whether their measured level reached the stated boundary. As a general statistical trade-off, dichotomizing a continuous measurement can make a result easier to communicate in threshold terms, but it removes information about how far measurements lie from the boundary and about variation within each category. The registry record does not report the distribution of plasma concentrations or the number of participants near the threshold.

The study description identifies an intent-to-treat population, defined as participants who met eligibility criteria, received study drug at least once, and had the primary efficacy endpoint measured at least once. This definition is specific to the record and includes a requirement that the endpoint was measured. It is therefore not possible to assume that every enrolled participant contributed to the primary analysis. Enrollment was 203, but the number satisfying this endpoint-population definition is not reported in the registry record. The record also does not explain how participants without a Day 5 measurement were handled.

For a binary percentage, the denominator is consequential: it determines which participants contribute to the estimate. Excluding participants with missing measurements, treating them as not reaching the threshold, or using another approach can lead to different estimates. These are general possibilities, not reported methods for this study. The registry record does not state the missing-data rule, describe the amount or pattern of missingness, or say whether any sensitivity analysis was performed. A reader should not infer a particular approach from the intent-to-treat label alone, especially because the stated population definition requires the primary endpoint to have been measured at least once.

The registry lists 9 outcome measures, including the primary plasma-level threshold and secondary outcomes about defervescence, neutropenia, absolute neutrophil count, plasma concentration, and fungal infection. It lists 0 analyses. No detailed statistical analysis plan, model, subgroup method, adjustment procedure, or hypothesis-testing approach is reported in the registry record. In particular, the record does not establish whether secondary outcomes were analyzed descriptively or with formal comparisons.

Multiplicity is a general concern when many outcomes or comparisons are examined: the chance of at least one apparently notable finding can increase as the number of tests grows. Statistical methods can address that issue through prespecified prioritization or adjustment, but no multiplicity strategy is reported in the registry record. The existence of several listed outcomes does not itself demonstrate that formal tests were carried out or that any adjustment was necessary or used.

The study is observational, and allocation is not stated. A comparison of participants with different measured plasma levels, if performed, would not automatically be a randomized treatment contrast. General confounding can occur when participant characteristics influence both the exposure measure and the outcome. Adjustment may help address measured factors under appropriate assumptions, but it cannot establish that unmeasured factors are absent. The registry record does not report an adjusted model, covariates, or a plan for confounding control.

Over-dispersion is a general issue for some count or rate models when observed variability exceeds what a simple model assumes. It is not a reported feature or method in this registry record, and the primary endpoint is presented as a percentage rather than a count-rate outcome. No model choice is reported, so there is no basis for claiming that over-dispersion was assessed or that a particular model was used.

The record includes a planning illustration framework based on an observed effect, with two-sided significance level 0.05, equal allocation between two arms, and a normal approximation; it specifies that the effect to detect is a stated fraction of the observed effect. For non-time-to-event outcomes, such illustrations are expressed as participants per arm for 80% power or other stated power levels. These are planning assumptions, not observed results or observed power. No numerical planning estimates are reported in the registry record, and no sample-size justification for the study itself is reported. The record also does not establish the two-arm randomized comparison assumed in that general planning framework as the actual study design.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Itraconazole")
n      <- c(150)
events <- c(102)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Itraconazole  150  102  68.0  59.9  75.4  60.2  74.9  60.1  74.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 9 outcome measures: a primary plasma-level threshold and secondary measures covering defervescence, time to defervescence, neutropenia, absolute neutrophil count, and fungal infection or success-related outcomes. It lists 0 analyses. This does not provide a set of numerical estimates or explain how outcomes were statistically analyzed. The analysis plan, including any prespecified hierarchy among outcomes, is not reported in the registry record.

When multiple outcomes or comparisons are tested, multiplicity can make apparently unusual results more likely by chance. This is a general statistical concern, not a finding about this study. A prespecified primary outcome can help focus interpretation, while formal adjustment or other planning may be used when appropriate. Whether any strategy was chosen or applied is not reported in the registry record. The presence of listed secondary outcomes should not be mistaken for evidence that every outcome was formally tested.

The registry defines the intent-to-treat population as eligible participants who received study drug at least once and had the primary endpoint measured at least once. It does not report how many of the 203 enrolled participants met that definition for the primary analysis. The handling of participants with missing endpoint measurements, the extent of missing data, and any imputation or sensitivity analyses are not reported in the registry record.

These omissions matter because the denominator and missing-data approach can influence a percentage. The intent-to-treat label does not, by itself, specify how missing measurements are handled; the record's own definition explicitly requires at least one primary endpoint measurement. The statistical model, confidence-interval procedure, covariate adjustment, and analysis population for secondary outcomes are likewise not reported in the registry record.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pneumonia (3.0%), sepsis (3.0%), septic shock (2.5%), renal failure acute (1.0%), bacterial sepsis (0.5%).

For the itraconazole group, the registry lists 203 participants at risk for serious adverse events and 28 affected. It also lists 203 at risk for other adverse events and 49 affected. These are the adverse-event figures posted in the record; they are separate from the primary plasma-level endpoint. The record does not report deaths in this group information.

The listed serious adverse event terms and percentages are pneumonia, 3.0%; sepsis, 3.0%; septic shock, 2.5%; renal failure acute, 1.0%; bacterial sepsis, 0.5%; and cardiac arrest, 0.5%. These entries should be read as the registry's reported term percentages. The record does not provide further detail in this information about event timing, severity criteria, recurrence, or whether a participant could contribute to more than one term. Individual term percentages therefore should not be summed to infer a total number of affected participants.

Adverse events recorded during a study do not by themselves establish that the study treatment caused them. The registry record does not report causal attribution for these events, nor does it provide a comparator suitable for a like-for-like safety contrast. The figures describe what was listed in the itraconazole group, not a causal treatment effect or a comparison with an untreated group.

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

The registry record makes clear what the primary endpoint was intended to measure: the percentage of participants reaching at least 1000 ng/mL for the defined combined itraconazole and hydroxyitraconazole plasma level on Day 5. It also identifies the target population and gives the registry's definition of the intent-to-treat population. These details allow the endpoint's meaning to be described, but they do not supply its observed value.

The primary percentage and its 95% confidence interval are not reported in the registry record. Therefore, the posted information does not show how many participants reached the threshold, how precisely that percentage was estimated, or whether exposure varied across participants. It also does not establish whether threshold attainment was related to defervescence. Fever disappearance and mean time to defervescence are listed as secondary outcomes, but their numerical results are not reported in the registry record.

The study's observational design is important when interpreting any proposed relationship between drug concentration and fever. Participants were not described as randomly allocated, and allocation is not stated. If participants with higher or lower concentrations differed in clinical characteristics, those differences could also relate to fever outcomes. This is a general limitation of observational associations; the registry record does not describe methods that would address it.

The listed adverse-event counts and terms describe events recorded in the itraconazole group, but they do not demonstrate that treatment caused those events. The record does not provide a like-for-like control comparison or report deaths in the adverse-event group information. The efficacy endpoint and safety entries answer different descriptive questions and should not be combined into a single conclusion about benefit or harm.

Accordingly, the record supports an account of the study question, endpoint definition, design, and listed safety information. It does not support a conclusion about the observed concentration-threshold percentage, the association with fever resolution, or a causal treatment effect. Those numerical efficacy results and analysis details are not reported in the registry record.

14. Why This Trial Matters Statistically

This study illustrates a distinction that matters in clinical research: a pharmacokinetic threshold and a clinical outcome are related concepts but are not interchangeable endpoints. The primary measure asks what percentage reached a defined plasma concentration on Day 5. The study's stated motivation concerns whether concentration might influence disappearance of fever. To evaluate that relationship, concentration and fever outcomes would both need to be reported with enough detail to understand their analysis. The registry record does not report the numerical results for either.

The endpoint also demonstrates the interpretive trade-off in turning a continuous measurement into a threshold classification. A threshold can make a result concrete, but it does not reveal the full range of concentrations or distinguish participants close to the boundary from those farther away. The registry record defines the threshold and the combined concentration, while the concentration distribution is not reported in the registry record.

The observational design is statistically important because an exposure-outcome association is not equivalent to a randomized treatment comparison. Allocation is not stated, and no like-for-like control comparison is established. If clinical factors are related to both measured concentration and defervescence, an observed association could reflect those factors rather than a direct concentration effect. The registry record does not report an adjustment strategy or detailed analysis plan.

The record also demonstrates why endpoint definitions and analysis populations need to be read together. The intended population excludes, by definition, participants without at least one primary endpoint measurement. Yet the number meeting that definition and the missing-data approach are not reported in the registry record. Without those details and the estimate with its confidence interval, the precision and representativeness of the primary percentage cannot be assessed.

Finally, several outcomes are listed, but no analyses are listed. This makes clear the difference between an outcome being named in a registry and a numerical result being available for interpretation. The record can support a careful description of the intended research question, but not a conclusion about the magnitude or certainty of the primary result.

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 central limitation for interpreting efficacy is that the primary endpoint's numerical percentage and 95% confidence interval are not reported in the registry record. Although the endpoint definition and Day 5 timeframe are stated, the number of participants reaching the threshold and the analysis denominator are not reported in the registry record. The result's precision therefore cannot be assessed.

The study is described as observational, allocation is not stated, and a like-for-like control comparison is not established. The record does not report a strategy for accounting for differences between participants. Consequently, the design as described cannot support a causal interpretation of any potential relationship between plasma concentration and defervescence. The numerical results for defervescence and the other secondary outcomes are also not reported in the registry record.

The treatment description is incomplete: it specifies infusion over one hour at 200 mg per dose twice daily for 2 days, followed by 200 mg once, but does not continue beyond that phrase. Further dosing details are not reported in the registry record. The record also does not report the plasma sampling procedures, assay details, or handling of measurements, which limits assessment of how the exposure endpoint was obtained.

The intent-to-treat population requires that the primary endpoint was measured at least once, but the number meeting this definition and the handling of missing measurements are not reported in the registry record. The statistical analysis plan, confidence-interval method, adjustment strategy, and multiplicity approach are likewise not reported. Although 9 outcome measures are listed, 0 analyses are listed, leaving no numerical outcome estimates to evaluate.

Safety interpretation is also limited to the listed counts and terms. The record does not report causal attribution or deaths in the adverse-event group information, and it does not establish a suitable control comparison. The adverse-event figures therefore cannot be interpreted as comparative risk estimates.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: The Relationship of Defeverscence and Itraconazole Plasma Level Study in Immunocompromised Participants — NCT01021683.
• Registry record last updated 2013-08-12; status last verified 2013-07.
• Results first posted 2013-07-03.
• 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

The registry describes a completed observational study sponsored by Janssen Korea, Ltd., Korea, with enrollment of 203. The listed study dates are start 2009-07 and primary completion 2010-07. Participants had received itraconazole oral solution as prophylaxis and were observed while receiving intravenous itraconazole for unknown neutropenic fever.

The primary endpoint was the percentage achieving an itraconazole plasma level of at least 1000 ng/mL on Day 5, where plasma level was defined as the sum of itraconazole and hydroxyitraconazole concentrations. The registry specifies a 95% confidence interval, but the numerical estimate and interval are not reported in the registry record.

The registry lists 9 outcome measures and 0 analyses. It describes an intent-to-treat population requiring eligibility, at least one study-drug dose, and at least one primary endpoint measurement. Allocation, missing-data handling, detailed analysis methods, and numerical efficacy outcomes are not reported in the registry record. Serious adverse events affected 28 of 203 participants in the itraconazole group; other adverse events affected 49 of 203.