A Study to Evaluate the Effect of the Potent Cytochrome P-450 3A4 (CYP3A4) Inhibitor Itraconazole on the Pharmacokinetics (PK) of TAK-954 in Healthy Adult Participants: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate the Effect of the Potent Cytochrome P-450 3A4 (CYP3A4) Inhibitor Itraconazole on the Pharmacokinetics (PK) of TAK-954 in Healthy Adult Participants (NCT03173170), a na phase 1 study. The primary outcome is Cmax: Maximum Observed Plasma Concentration for TAK-954.

2. Clinical Question

3. Trial Design

The registry describes a Phase 1, single-sequence, open-label, two-period crossover trial. It enrolled 10 healthy adult participants and is listed as completed. The recorded study start was 2017-05-31, and the primary completion date was 2017-07-24. Allocation is listed as not applicable, and masking was none. These features distinguish the study from a randomized, masked comparison between separate groups.

The stated intervention schedule begins with TAK-954 0.2 mg by intravenous infusion once on Day 1 of the first intervention period. This was followed by a minimum 7-day washout period. In the second intervention period, the description specifies itraconazole 200 mg capsules taken orally once daily on Days 1 to 8, with TAK-954 0.2 mg given by intravenous infusion on Day 4. The registry description is cut off after its reference to the second intervention period, so additional scheduling details are not reported in the registry record.

A crossover design compares exposures within the same participant across periods, rather than comparing separately randomized groups. That can be useful in pharmacokinetic research because each participant can serve as their own reference. It also means that the sequence, period timing, washout, and completeness of measurements matter when interpreting the comparison. The record identifies a single sequence and a washout but does not report a rationale for the washout duration, procedures for handling period effects, or details of the analysis model.

Open-label means the study was not masked. The registry record does not report a random assignment of treatment order, and allocation is listed as not applicable. Consequently, the exposure groups should not be treated as like-for-like randomized controls. The record also does not report a sample-size justification or explain whether the enrollment was selected for precision, feasibility, or another design objective.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Healthy participants were enrolled in this single sequence 2-period crossover study to receive TAK-954 0.2 milligram (mg) in Intervention Period 1 followed by itraconazole 200 mg + TAK-954 0.2 mg in Intervention Period 2.

First Intervention Period (6 Days)

Washout Period (at Least 7 Days)

Intervention Period 2 (9 Days)

Analysis population for the primary outcome, as defined in the registry: The pharmacokinetic (PK) set included all participants who received at least 1 dose of study drug and had at least 1 measurable plasma concentration.

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: The safety analysis set included all participants who were randomized and received at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Cmax: Maximum Observed Plasma Concentration for TAK-954, measured over TAK-954 0.2 mg: Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose; Itraconazole 200 mg and TAK-954 0.2 mg: Day 4 pre-dose and at multiple time points (up to 120 hours) post-dose.

The primary endpoint was Cmax, the maximum observed plasma concentration of TAK-954, measured in nanograms per milliliter. Cmax describes the highest measured concentration after dosing. For a pharmacokinetic question, it is relevant because it characterizes peak exposure and can be compared across the TAK-954-alone and coadministration periods.

The registry specifies that Cmax was summarized as a geometric mean with standard deviation. A geometric mean is a way to summarize positive measurements when values are better represented on a multiplicative scale than by an arithmetic average. The registry record does not explain the rationale for selecting that summary, report a transformation, or give details of the inferential analysis. Standard deviation describes variability in the measurements under the stated summary; it is not a confidence interval and does not by itself express the precision of a treatment comparison.

Measurements were scheduled before dosing and at multiple time points after dosing, up to 120 hours, for both the TAK-954-alone and coadministration conditions. The endpoint is therefore based on measured concentrations over time, with Cmax taken as the maximum observed value. The record defines the pharmacokinetic population as participants who received at least one dose of study drug and had at least one measurable plasma concentration. It does not report the number included in that population, the individual concentration profiles, or numerical Cmax results. Thus, the endpoint’s definition and planned measurement windows are available, but the observed peak concentrations and their comparison are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The endpoint and design can be understood using general statistical concepts, but the registry record does not describe the full analysis plan. The following explanations distinguish general principles from what is documented for this study.

What does a crossover design compare?

In general, a crossover study observes participants under more than one condition and compares their measurements across periods. Because the same person contributes measurements under each condition, stable characteristics of that person do not vary between those measurements. This can make within-participant comparisons informative in pharmacokinetic studies. The method depends on suitable scheduling and on an analysis that reflects the repeated measurements and treatment sequence.

For this study, the registry describes a single sequence: TAK-954 alone in the first intervention period, followed by a washout and then TAK-954 with itraconazole in the second period. This is not a randomized comparison of independent groups. Treatment condition and period therefore cannot be separated by random assignment in the way they could be in a design with multiple randomized sequences. General crossover analyses may account for period and participant effects, but whether and how those were handled is not reported in the registry record.

What does Cmax measure?

In general, Cmax is the highest observed concentration in a participant’s concentration-time measurements after a dose. It is a summary of peak exposure, not a description of the entire concentration profile. The measured value depends on the timing and availability of samples, which is why the registry’s measurement schedule is relevant. The stated schedule includes pre-dose measurements and multiple post-dose time points up to 120 hours. The record does not report the observed concentration profiles or explain how missing or unevaluable time points were handled.

Why use a geometric mean?

In general, concentration measurements are positive and may be more naturally compared on a multiplicative scale. A geometric mean summarizes measurements using that scale and is often used for pharmacokinetic quantities. A contrast on a multiplicative scale is commonly interpreted differently from an arithmetic difference. However, the registry record does not state the exact contrast used for this endpoint or provide a numerical estimate, so a particular interpretation of the comparison cannot be attributed to this study.

The registry lists standard deviation as the dispersion measure accompanying the geometric mean. In general, standard deviation describes variability among observations under the chosen summary. It is distinct from a confidence interval: a confidence interval is used to express uncertainty about an estimated quantity, while a standard deviation describes variation in the data. The registry record does not report a confidence interval for Cmax or for a comparison between conditions.

What would an uncertainty measure add?

In general, a point estimate describes the estimated size and direction of a contrast, while an uncertainty interval describes how compatible a range of values is with the data and the analysis assumptions. A p-value, when reported, addresses a specified statistical test and should be interpreted alongside the estimate and its uncertainty. Neither an estimate nor a test alone establishes the practical importance of a finding. For this study, the relevant numerical contrast, confidence interval, and p-value are not reported in the registry record, so these aspects cannot be interpreted.

How should planning calculations be read?

In general, sample-size calculations based on an observed effect are planning illustrations. They explore the number of participants that might be needed under stated assumptions to detect an effect of a chosen size. They are not evidence that the completed study had a particular probability of detecting its effect, and they are not a substitute for the study’s observed estimate and uncertainty. The stated planning assumptions for this record include a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and effects defined as fractions of an observed effect. The actual observed effect and the numerical planning results are not reported in the registry record. The record’s design is a single-sequence crossover, so an equal-allocation illustration between arms should not be read as a description of the study’s actual allocation or design.

General statistical interpretation also depends on the analysis population and the handling of incomplete measurements. Here, the registry defines the pharmacokinetic set by receipt of at least one dose and at least one measurable plasma concentration. It does not report exclusions, missing-data procedures, model assumptions, adjustment for period, or sensitivity analyses. Without those details and the endpoint results, the analysis cannot be independently evaluated beyond the design and endpoint information recorded.

10. Multiplicity, Missing Data and Analysis Populations

The registry identifies two outcome measures and two analyses, but does not report the full analysis plan or explain how the analyses relate to each other. In general, multiplicity arises when several outcomes, contrasts, or tests are assessed: without an appropriate plan, the chance of at least one apparently unusual result can increase. Methods for addressing that issue depend on the hypotheses and analysis structure. Whether multiplicity was considered or adjusted for is not reported in the registry record.

The primary endpoint is identified as Cmax for TAK-954. The record specifies a geometric mean and standard deviation, but it does not provide the numerical results or a comparison estimate. The endpoint measurement window includes pre-dose and multiple post-dose measurements up to 120 hours. The procedures for deriving Cmax when measurements are missing, delayed, or otherwise unavailable are not reported in the registry record.

The pharmacokinetic population is defined as participants who received at least one dose and had at least one measurable plasma concentration. The record does not report how many participants met this definition, whether any participants were excluded from the analysis, or how incomplete participation was handled. The enrolled count is 10, but enrollment alone does not establish the number contributing endpoint data.

General missing-data methods depend on why data are missing and on the structure of the measurements. The registry does not report a missing-data assumption, imputation procedure, or sensitivity analysis. It also does not report whether all scheduled sampling time points were available for each participant. Consequently, the completeness of the concentration data and the possible influence of missing measurements on Cmax cannot be assessed from the registry record.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent non-serious adverse event terms

The registry safety figures list 10 participants at risk in each of the three exposure groups. The serious adverse event count is 0 in each listed group, and deaths are 0 in each group. The record provides no serious adverse event terms. These figures describe what is recorded for the listed groups; they do not establish that an event was impossible or that a broader safety conclusion can be drawn.

For other adverse events, the registry lists 3 affected participants for TAK-954 0.2 mg alone, 0 for itraconazole 200 mg alone, and 1 for itraconazole 200 mg with TAK-954 0.2 mg. The record does not name those other events in the information available for this summary. It also does not provide event severity, timing, or an assessment of relationship to study treatment.

Because the study used a single-sequence crossover design, the exposure groups should not be interpreted as independent, randomized groups. The same participants may contribute safety observations under more than one exposure condition. The registry figures therefore should be read as descriptive counts associated with the listed exposures, not as a causal comparison of treatment risks. The record does not provide enough detail to determine whether participants with events experienced more than one event or how events were assigned across periods.

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

The study addresses a focused pharmacokinetic question: how TAK-954 exposure, represented by Cmax, was evaluated when TAK-954 was given alone and when it was given with itraconazole. The registry record gives the Phase 1 crossover design, the intervention schedule, the endpoint definition, and the pharmacokinetic population definition. This information explains what the study set out to examine and how the endpoint was framed.

The record does not report numerical Cmax findings or a quantified comparison. It therefore does not support describing an increase, a decrease, or no change in peak concentration. It also does not provide uncertainty estimates that would show how precisely the comparison was measured. Missing numerical results should not be mistaken for evidence of no effect; they leave the effect undetermined from the registry information.

The trial’s enrollment of 10 and its single-sequence, open-label design also limit what can be inferred from the recorded information. A crossover comparison can use each participant’s measurements across conditions, but the fixed sequence means period and condition are linked. Details of the analysis used to address that structure are not reported in the registry record. The number of participants included in the pharmacokinetic analysis is also not reported.

The safety counts are descriptive and show no recorded serious adverse events or deaths in the listed exposure groups. They also record other adverse events in the TAK-954-alone and coadministration groups. The available record does not name those events or establish whether they were caused by a study drug. These counts should not be treated as a randomized safety comparison.

Overall, the record supports an account of the study’s question, design, endpoint, and listed safety counts. It does not support a conclusion about the size or direction of the pharmacokinetic effect, its precision, or a causal safety difference. Those questions would require results and analysis details not reported in the registry record.

13. Why This Trial Matters Statistically

This study is statistically notable because it uses a crossover structure to examine a pharmacokinetic interaction question. In general, repeated measurements from the same participant can help distinguish changes associated with exposure conditions from stable differences between participants. That strength depends on the design and analysis: the schedule, period, washout, and handling of within-participant measurements all matter.

The recorded design is single-sequence and open-label, with TAK-954 alone in the first period and coadministration with itraconazole in the second period. Since the order was not randomized across sequences in the registry description, the contrast is not equivalent to a randomized comparison between parallel groups. Any interpretation would need to account for the fact that treatment condition and period are linked. The analysis approach for that issue is not reported in the registry record.

The endpoint also illustrates a distinction between defining a measurement and reporting a result. Cmax is a clear pharmacokinetic summary of peak observed concentration, and the record specifies how it was summarized and when samples were scheduled. But without numerical estimates and uncertainty, the endpoint definition cannot answer the study’s substantive comparison question.

For researchers, this record highlights why design details and complete results are both necessary. The stated enrollment and population definition identify who was intended to contribute, while the absence of reported analysis counts and endpoint estimates leaves precision and completeness unclear. The safety counts add descriptive context but do not permit a causal comparison in this single-sequence design. The registry record is informative about the study framework, but limited as a source for judging the magnitude and uncertainty of the pharmacokinetic findings.

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.

Several limitations specific to this study affect interpretation of the registry record. The first is that numerical results for the primary endpoint are not reported in the registry record. Without the Cmax estimates, a comparison between TAK-954 alone and TAK-954 with itraconazole cannot be described in terms of direction, magnitude, or precision.

The single-sequence design is another important limitation for interpreting a treatment contrast. The two exposure conditions occurred in a stated order, so treatment condition is associated with period. The record does not describe an analysis addressing period effects or potential carryover, nor does it explain the rationale for the minimum 7-day washout. The design is also open-label, with no masking listed.

The enrollment is 10, but the number of participants included in the pharmacokinetic population is not reported. The record defines that population by receipt of at least one dose and at least one measurable plasma concentration, but does not describe exclusions or missing concentration data. It also does not report the model, comparison estimate, confidence interval, p-value, or sensitivity analyses for the primary endpoint.

The intervention description is incomplete at its ending, so additional schedule details are not reported in the registry record. The record also does not provide a sample-size justification. Its stated planning assumptions concern illustrations based on an observed effect, but the observed effect and numerical planning results are not reported in the registry information used for this analysis.

Finally, the safety information is limited to group counts. Serious adverse event counts and deaths are recorded as zero, while other adverse event counts are given without event terms or attribution details. The crossover design also means exposure-group counts should not be interpreted as independent randomized comparisons.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study to Evaluate the Effect of the Potent Cytochrome P-450 3A4 (CYP3A4) Inhibitor Itraconazole on the Pharmacokinetics (PK) of TAK-954 in Healthy Adult Participants — NCT03173170.
• Registry record last updated 2019-01-15; status last verified 2018-07.
• Results first posted 2019-01-15.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

This completed Phase 1 study enrolled 10 healthy adult participants and evaluated the effect of itraconazole on the single-dose pharmacokinetics of TAK-954. The registry describes an open-label, single-sequence, two-period crossover, with TAK-954 alone in the first period and TAK-954 given with itraconazole in the second period after a minimum 7-day washout.

The primary endpoint was maximum observed plasma concentration of TAK-954, summarized as a geometric mean with standard deviation. The pharmacokinetic population included participants who received at least one dose and had at least one measurable plasma concentration. Numerical Cmax results, the comparison estimate, and its uncertainty are not reported in the registry record.

The safety record lists 0 serious adverse events and 0 deaths in each exposure group. Other adverse events were recorded for 3 participants with TAK-954 alone, 0 with itraconazole alone, and 1 with the combination. The event terms and further analysis details are not reported in the registry record.