A Study of the Effects of Posaconazole on Alectinib (RO5424802) Pharmacokinetics in Healthy Volunteers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of the Effects of Posaconazole on Alectinib (RO5424802) Pharmacokinetics in Healthy Volunteers (NCT01984229), a non-randomized phase 1 study. The primary outcome is Maximum Observed Plasma Concentration (Cmax) of Alectinib: Cohort A.

2. Clinical Question

The study asks a pharmacokinetic interaction question: whether repeated posaconazole administration affects the concentration of alectinib after a single dose. This is a question about drug exposure in healthy volunteers, not a test of clinical benefit or an assessment in people being treated for a disease.

The primary endpoint is Cohort A Cmax, the maximum observed plasma concentration of alectinib. The recorded assessment schedule includes predose and multiple post-dose sampling times through 96 hours in each treatment period. The registry describes the endpoint as a mean with standard deviation, and defines the PK analysis population as participants who received both scheduled alectinib doses and provided adequate PK assessments.

The study also lists secondary pharmacokinetic outcomes, including measures of the metabolite RO5468924 and time to maximum observed concentration for alectinib in both cohorts. Those additional measures broaden the pharmacokinetic description, but the registry record does not report their numerical results. The central question therefore remains clear, while its quantitative answer cannot be recovered from the record summary alone.

3. Trial Design

This was a Phase 1, open-label study with a non-randomized, fixed-sequence crossover model. Participants moved through treatment periods in a planned order rather than being randomly assigned to parallel groups. The study title and summary describe an assessment of multiple oral doses of posaconazole on the pharmacokinetics of a single alectinib dose in healthy volunteers.

The record describes three periods for each cohort. In Cohort A, Period 1 covered Days 1 to 7, Period 2 covered Days 8 to 14, and Period 3 covered Days 15 to 18. Alectinib was scheduled as a 40 mg single oral dose on Day 1 and Day 15, with an identical standardized meal. In Cohort B, the described periods were Days 1 to 7, Days 8 to 14, and Days 15 to 21. Its alectinib dose was to be selected based on Cohort A data. The registry text does not give the selected Cohort B dose in the record excerpt.

The period descriptions identify alectinib alone, posaconazole alone, and alectinib with posaconazole. This sequence allows pharmacokinetic measurements under more than one exposure condition in the same study, but the fixed order matters: treatment condition is not separated from period order by randomization. The design therefore differs from a randomized comparison in which treatment assignment is balanced across participants.

The registry reports enrollment of 23, a completed status, and study dates from 2013-12 to primary completion in 2014-03. It does not report a detailed rationale for enrollment, a sample-size justification, or the full operational dosing details in the available record. These design features should be kept in view when interpreting the descriptive and comparative pharmacokinetic results shown in the tables and plots.

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.

Period 1

Period 2

Period 3

Safety Follow-up Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) Analysis Population \[Cohort A\] consisted of all participants who received both scheduled doses of Alectinib, and provided adequate PK assessments.

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: Safety Analysis Set consisted of all participants who received at least 1 dose of study drug and had at least 1 after dosing safety assessment.

6. Primary Endpoint

The registry lists the primary outcome as Maximum Observed Plasma Concentration (Cmax) of Alectinib: Cohort A, measured over Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period.

Cmax is the maximum plasma concentration observed after a dose. It summarizes the peak concentration captured by the scheduled blood-sampling measurements. In this study, the primary endpoint is the mean Cmax of alectinib in Cohort A, reported in nanograms per milliliter. Sampling was scheduled predose and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period.

Pharmacokinetic studies use Cmax because it describes one aspect of drug exposure: the observed peak concentration. It does not by itself describe the full concentration-time profile, total exposure, duration of exposure, or a clinical outcome. Other measures, such as the listed AUC outcomes and time to maximum concentration, address different features of the profile.

The registry specifies that the endpoint is summarized as a mean with standard deviation. The analysis population for Cohort A is described as participants who received both scheduled alectinib doses and had adequate pharmacokinetic assessments. The numerical mean and standard deviation, as well as a treatment contrast and its uncertainty, are not reported in the registry record. Consequently, the endpoint’s definition and measurement schedule can be described, but the size and precision of any observed difference cannot be assessed from this record summary.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

This study concerns continuous pharmacokinetic measurements. Cmax and AUC are quantities measured on a numerical scale rather than event counts. For the primary outcome, the registry says that the statistic is the mean and that dispersion is summarized using the standard deviation. The mean describes the average measurement in the analysis population; the standard deviation describes the spread of individual measurements around that average. Neither statistic, on its own, describes uncertainty in a comparison between treatment periods.

What does a treatment contrast represent?

A treatment contrast summarizes how an outcome differs between the treatment conditions being compared. For this study’s central question, the contrast would describe the difference in Cmax between the alectinib-alone and alectinib-with-posaconazole conditions in Cohort A. A contrast must be read together with its scale and direction: a difference expressed in concentration units is not the same as a ratio-based comparison. The registry record does not state the contrast estimate or the comparison scale, so neither can be interpreted quantitatively.

In crossover studies, measurements from the same participant can be related. This dependence is a central feature of the design: the observations from one participant should not automatically be treated as if they came from unrelated people. A suitable analysis can account for within-participant comparisons, but the registry record does not report the specific statistical model used, its assumptions, or its handling of period and sequence. Those details should not be inferred from the word “crossover” alone.

Why does the fixed sequence matter?

A fixed-sequence design administers conditions in a planned order rather than randomizing their order. That feature means treatment and period can be linked. As a general statistical point, if the measured outcome changes over time for reasons other than treatment, a fixed order can make it difficult to distinguish those changes from a treatment-associated difference. This does not show that period effects occurred; the registry record does not report such an assessment. It explains why the sequence is relevant when judging the limits of the comparison.

Randomization is often used to reduce systematic differences between assigned groups, while masking can limit the influence of treatment knowledge on parts of study conduct or assessment. This trial was non-randomized and open-label. These labels describe design choices; they do not, without further information, quantify the direction or size of any resulting bias. In particular, the objective nature of a measured concentration does not remove the need to understand the study’s collection, processing, and analysis procedures, which are not detailed in the registry record.

How should variability and precision be distinguished?

Standard deviation describes variability among measurements. A confidence interval describes uncertainty around an estimated quantity, such as a mean or treatment contrast, under the chosen analysis and assumptions. A narrow interval generally indicates greater statistical precision than a wide interval, but precision is not the same as freedom from bias. The registry entries for this page do not include a confidence interval for the primary endpoint, so the uncertainty around the comparison cannot be described from the registry record.

Pharmacokinetic measurements can vary across participants, and their distribution may be uneven. General statistical practice sometimes uses transformations or models suited to the distribution and comparison scale. However, the analysis method, any transformation, and any model diagnostics are not reported in the registry record. It would be inappropriate to attribute a particular method to the investigators without documentation.

What is the role of the other outcomes?

The listed secondary outcomes include Cmax, AUClast, and AUC0-inf for RO5468924 in each cohort, along with Tmax for alectinib in each cohort. These measures describe distinct features: peak concentration, area under the concentration-time curve over specified ranges, and timing of the observed peak. They complement the primary Cmax endpoint rather than duplicating it. The registry record does not provide the outcome estimates or detailed analysis methods for these measures.

When many outcomes or comparisons are examined, multiplicity can increase the chance of obtaining an apparently notable result by chance if each is tested independently at a chosen threshold. General approaches include prespecifying a primary comparison, adjusting thresholds, or treating secondary analyses as descriptive. The record lists 21 outcome measures and six analyses, but it does not report a multiplicity procedure or enough detail to determine how the analyses relate to one another. The count alone does not establish how many formal hypothesis tests were conducted.

What do planning illustrations mean?

The sample-size section is a planning illustration based on an observed effect, not a report of observed power. Its stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect defined as a fraction of the observed effect. Such illustrations show how a hypothetical design might perform under selected assumptions. They are not evidence that the actual study had that power, and they do not replace a design-stage sample-size justification. The registry record does not report the trial’s own sample-size justification. Any planning values displayed on the page should be interpreted as hypothetical participants-per-arm illustrations, not as observed trial outcomes or a retrospective measure of success.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Cohort A: Alectinib (Period 1)", "Cohort A: Alectinib + Posaconazole (Period 3)")
n   <- c(5, 5)
m   <- c(27.6, 35)
sp  <- c(6.61, 10.8)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Cohort A: Alectinib (Period 1)  5  27.600  6.610  19.393  35.807
CARM  Cohort A: Alectinib + Posaconazole (Period 3)  5  35.000  10.800  21.590  48.410

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 21 outcome measures and six analyses. It identifies a primary endpoint and several secondary pharmacokinetic outcomes, but the record does not report a multiplicity adjustment, a testing hierarchy, or a complete statistical analysis plan. The presence of multiple outcomes makes it important to distinguish the primary question from additional descriptive or exploratory questions. Without documented testing procedures, the reader cannot determine how the investigators controlled the overall chance of false-positive findings across analyses.

The record also does not report a missing-data method, imputation procedure, or detailed account of missing pharmacokinetic samples. The primary analysis population is defined as participants who received both scheduled alectinib doses and provided adequate PK assessments. This definition indicates that the analysis depends on receipt of treatment and the availability of usable measurements, but the record does not say how adequacy was determined or how many participants were excluded from the relevant analysis.

The enrollment count is 23, while the adverse-event groups list different numbers at risk by cohort and period. Those safety counts should not be substituted for the endpoint-specific analysis population. The record does not provide enough information to reconcile enrollment with the number contributing to every pharmacokinetic outcome.

General statistical principle: complete-case analysis can be affected if the availability of measurements is related to the outcome or treatment condition. That is a potential concern to consider, not a claim about what happened in this study. The missingness pattern and its reasons are not reported in the registry record. Without those details, the extent to which missing measurements could influence the estimated comparison is unknown.

The planning illustrations use stated assumptions and should remain separate from the analysis of missing data and multiplicity. They are hypothetical design calculations rather than a substitute for a prespecified analysis plan or a description of the observed endpoint population.

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 non-serious adverse event terms

The adverse-event summary lists serious adverse events separately from other adverse events for each cohort and period. In the listed groups, the number of participants affected by serious adverse events is zero. The numbers at risk are shown by group: Cohort A has 6 in the Alectinib (Period 1) and Posaconazole (Period 2) groups, and 5 in the Alectinib + Posaconazole (Period 3) group; Cohort B has 17 in each listed period group. These are period-specific entries and should not be added together to infer a count of unique participants.

The record lists other adverse events affecting 3 participants in Cohort A during Posaconazole (Period 2), 2 during Alectinib + Posaconazole (Period 3), and none during Alectinib (Period 1). For Cohort B, the corresponding affected counts are 3, 4, and 5. These are descriptive counts, not comparative estimates adjusted for exposure duration or other factors.

The death fields are not populated with a numerical result, and the registry record does not report the death counts. A zero count for participants affected by serious adverse events in the listed groups should not be interpreted as proof that a risk is absent. The study enrolled healthy volunteers and was focused on pharmacokinetics; these safety entries are limited summaries and do not establish safety in other populations or settings.

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

This record describes a study designed to examine whether multiple oral doses of posaconazole affect the pharmacokinetics of a single alectinib dose in healthy volunteers. It identifies the primary outcome as Cohort A Cmax, defines the sampling schedule, and describes the crossover sequence. Those details explain the scientific question and the structure of the measurements.

What the record does not provide is the numerical primary outcome or its treatment contrast. Without those values, the direction, magnitude, and precision of the Cmax comparison cannot be stated. The same limitation applies to the listed secondary outcomes: their definitions appear in the registry, but their numerical estimates are not reported in the registry record. The tables and plots can organize posted results, but no values beyond those in the record details can be asserted in this explanation.

The study is not a randomized trial of clinical outcomes. It is a non-randomized, open-label, fixed-sequence pharmacokinetic study in healthy volunteers. Its results, even if numerical estimates are available elsewhere on the page, should be interpreted as evidence about measured drug concentrations under the studied conditions, not as evidence about clinical effectiveness or outcomes in patients. No medical advice follows from this study description.

General statistical principle: an estimate is most useful when considered alongside its uncertainty, the population analyzed, the design, and the assumptions of the model. A point estimate alone cannot show how precisely an effect has been measured. Here, the registry entries do not include the primary estimate or its uncertainty, and they do not describe the model used to obtain a comparison. These omissions limit interpretation.

The safety summary reports no participants affected by serious adverse events in the listed groups, while the death fields are not reported. Those entries are descriptive and should not be treated as proof of absence of risk. In combination, the record supports a clear account of the intended pharmacokinetic question and some safety counts, but not a quantitative conclusion about the primary pharmacokinetic effect.

14. Why This Trial Matters Statistically

This trial is statistically interesting because it uses a fixed-sequence crossover approach to study a pharmacokinetic interaction. Repeated measurements under different treatment conditions can help characterize within-participant variation, which is often important when studying concentration profiles. The same design also makes treatment order relevant: because conditions were not randomized, period and treatment effects may be difficult to separate. Recognizing both features is central to reading the comparison responsibly.

The primary endpoint focuses on Cmax, one interpretable feature of a concentration-time profile. The study also lists AUC and Tmax outcomes, which address other aspects of that profile. Considering multiple measures can provide a broader pharmacokinetic description, but it also raises questions about how analyses were prioritized and how multiplicity was handled. Those procedures are not reported in the registry record.

The study further illustrates the distinction between an endpoint’s definition and its result. The record specifies units, summary statistic, sampling times, and an analysis-population description. These are necessary for understanding what was intended to be measured, but they do not convey the observed effect or its precision. Numerical estimates and uncertainty are essential for evaluating the size and reliability of a comparison.

Finally, planning illustrations based on an observed effect are not the same as a prospective design justification, nor do they provide observed power. This distinction matters because a hypothetical calculation answers a different question from the analysis of the completed study. The registry record does not report the trial’s own sample-size justification. Keeping design, estimation, and planning calculations separate helps prevent an attractive-looking calculation from being mistaken for evidence about the actual 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.

Several limitations are specific to the information and design described for this study. First, allocation was non-randomized and the sequence was fixed. Consequently, treatment conditions are tied to period order, and the comparison does not have the protection against systematic allocation differences that randomization is intended to provide. The registry record does not report an assessment of period effects or other sequence-related influences.

Second, the study was open-label. The endpoint is an objective concentration measurement, but the record does not give enough detail about sample handling, laboratory methods, or quality-control procedures to assess those aspects. The absence of masking should be understood as a design characteristic, not as proof that measurements were biased.

Third, this was a Phase 1 study in healthy volunteers, with enrollment of 23. The record does not establish how the pharmacokinetic findings would generalize beyond the studied population. The primary endpoint is also limited to Cmax, while other listed measures address different features of exposure. No clinical outcome is identified as the primary question.

Fourth, the registry text for Cohort B says the alectinib dose was selected based on Cohort A data but does not state the selected dose in the available record. Some arm-description text is incomplete, so the full dosing details cannot be reconstructed. The registry does not report the analysis model, missing-data procedures, multiplicity handling, or the trial’s sample-size justification.

Finally, the numerical primary pharmacokinetic estimates and their uncertainty are not reported in the registry record. This prevents assessment of the observed effect’s direction, size, and precision. The listed adverse-event counts are limited summaries, and the death results are not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of the Effects of Posaconazole on Alectinib (RO5424802) Pharmacokinetics in Healthy Volunteers — NCT01984229.
• Registry record last updated 2016-10-11; status last verified 2016-08.
• Results first posted 2016-10-11.
• 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

This is a completed Phase 1, open-label, non-randomized, fixed-sequence crossover study of posaconazole and alectinib in healthy volunteers. The record reports enrollment of 23 and describes three treatment periods in each of Cohort A and Cohort B. Its primary outcome is mean Cmax of alectinib in Cohort A, with standard deviation as the dispersion measure and scheduled sampling through 96 hours after dosing.

The study’s central purpose was to investigate whether multiple oral doses of posaconazole affect the pharmacokinetics of a single alectinib dose. Secondary outcomes include measures of RO5468924 and Tmax of alectinib. The registry record does not report the numerical primary endpoint results, treatment contrast, confidence interval, detailed analysis model, multiplicity procedure, missing-data method, or sample-size justification.

The adverse-event listing reports no participants affected by serious adverse events in the displayed groups; death counts are not reported in the registry record. The fixed sequence, lack of randomization, healthy-volunteer population, and unavailable numerical pharmacokinetic results all limit what can be concluded from this record summary.