A Study to Investigate the Relative Bioavailability of Entrectinib Capsule Formulations F1 and F06 Under Fed Conditions in Healthy Participants: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Investigate the Relative Bioavailability of Entrectinib Capsule Formulations F1 and F06 Under Fed Conditions in Healthy Participants (NCT03796260), a randomized phase 1 study. The primary outcome is Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Entrectinib and M5 Metabolite.

2. Clinical Question

Relative bioavailability concerns the amount and rate at which a drug reaches systemic circulation from one formulation compared with another. This study addressed that question in healthy participants under a fed condition, rather than evaluating treatment outcomes in people with a disease. The primary endpoint was pharmacokinetic: AUC0-inf for both entrectinib and M5. The registry also lists treatment-emergent adverse events as a secondary outcome.

The randomized crossover structure means participants were assigned to a treatment sequence involving both formulations. In principle, comparing formulations within participants can account for stable differences between people, because each participant receives each formulation. That general advantage depends on complete and appropriately analyzed measurements, and does not by itself establish that the treatment periods or sequences were handled without bias. The analysis details needed to assess those issues are not reported in the registry record.

The record does not report the AUC0-inf estimates, their uncertainty, or a direct statistical comparison. It therefore does not establish the size or precision of any difference in relative bioavailability. The clinical question is identifiable from the endpoint and design, but the posted registry information is insufficient to draw a statistical conclusion about the comparison.

3. Trial Design

This was a Phase 1 randomized, open-label, two-treatment, two-period, two-way crossover study of entrectinib capsule formulations F1 and F06 under fed conditions. The registry lists an enrollment of 14 and identifies healthy volunteers as the study population. The study status is completed. The recorded start date is 2019-01-09, and the primary completion date is 2019-02-04.

Participants were assigned to a sequence: F1 followed by F06, or F06 followed by F1. According to the arm descriptions, the first formulation was given as a single oral dose on Day 1 of Period 1 after a standardized meal. A minimum 14-day washout period separated dosing, after which the other formulation was administered. The registry record does not include the complete text of both arm descriptions, so details beyond the stated sequence, meal condition, single-dose schedule, and washout are not available.

A crossover design differs from a parallel-group design because participants receive both treatments in separate periods. Randomizing the order helps avoid systematically assigning one formulation first. The washout is intended, as a general design principle, to reduce the influence of an earlier treatment on measurements after the next treatment begins. Whether the washout was adequate for this study, and how possible period or sequence effects were assessed, are not reported in the registry record.

Open-label means the study was not masked. The registry records no masking. It does not report the rationale for this choice or whether any outcome assessment was blinded. The primary outcome timeframe is described as sampling at pre-defined intervals from study Day 1 through Day 5 of each period, with the registry also stating “Periods 1 and 2 = 6 days.” The exact sampling schedule is not reported in the registry record.

The registry identifies the primary endpoint as AUC0-inf for entrectinib and M5. It lists percentage of participants with treatment-emergent adverse events as a secondary outcome and four outcome measures overall. The precise outcome-measure specifications, statistical analysis plan, and rationale for enrollment are not reported in the registry record.

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

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

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.

6. Primary Endpoint

The registry lists the primary outcome as Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Entrectinib and M5 Metabolite, measured over At pre-defined intervals from study Day 1 through Day 5 of each Period (Periods 1 and 2 = 6 days).

AUC0-inf measures total drug exposure over time, extrapolated from observed concentration measurements to infinity. The registry defines it as AUC0-t + (Ct/λz), where Ct is the last measurable concentration and λz is the apparent terminal elimination rate constant. The endpoint is specified for entrectinib and its M5 metabolite, with units of nmol*h/L.

As a general pharmacokinetic concept, area under the concentration-time curve combines information across multiple concentration measurements rather than describing concentration at a single sampling time. Extrapolation beyond the last measurable concentration estimates the remaining exposure after the observed part of the profile. This can support a comparison of overall systemic exposure between formulations. The extrapolated component can also add uncertainty, particularly when the terminal portion of the concentration profile is not well characterized; the registry does not report the extent of extrapolation or its uncertainty for these results.

The primary outcome is summarized using geometric means and geometric coefficients of variation. Geometric summaries are commonly used for pharmacokinetic measurements because such data can be skewed and are often interpreted on a multiplicative scale. The geometric coefficient of variation describes relative variability around the geometric mean; it is not a confidence interval and does not, by itself, quantify the precision of a comparison between formulations.

The endpoint is relevant to relative bioavailability because it captures exposure after administration of each formulation. However, a numerical endpoint definition does not indicate whether the formulations had similar exposure. The registry record does not report the geometric mean values, variability estimates, confidence intervals, or a treatment comparison for AUC0-inf.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a randomized crossover design, geometric mean summaries, and geometric coefficients of variation. It does not report a full statistical analysis plan, model specification, inferential procedure, or numerical primary outcome results. The explanations below describe general statistical concepts and do not establish which procedures were used in this study.

What does a crossover design contribute?

In a crossover study, each participant receives the treatments in separate periods. A comparison can therefore use within-participant differences, which may remove some variability associated with stable characteristics of participants. Random assignment to treatment sequence helps prevent the order of administration from being systematically tied to participant characteristics. These are general design properties. The actual analysis must still account for the structure of the observations and consider whether period, sequence, or carryover effects matter.

A washout period separates treatment periods. As a general matter, it is intended to reduce residual influence from the first treatment before the next treatment is administered. The arm descriptions specify a minimum 14-day washout. The registry does not report a formal assessment of carryover or the assumptions used to interpret the periods as comparable. A crossover is also most informative when participants contribute usable measurements under both treatments; the registry does not report the completeness of paired endpoint data.

Why use geometric summaries?

Pharmacokinetic exposure measures can vary multiplicatively and may have a right-skewed distribution. A geometric mean is the exponentiated mean of log-transformed observations, a general method that expresses a central value on the original scale while analyzing proportional rather than additive variation. A geometric coefficient of variation describes relative spread. It is different from a standard deviation and does not express uncertainty in the estimated treatment contrast.

The registry names geometric means and geometric coefficients of variation for AUC0-inf. It does not say whether the primary comparison was performed on log-transformed values, how the treatment contrast was defined, or how uncertainty was estimated. Those procedures should not be inferred solely from the kind of summary statistic selected.

What does a confidence interval add?

In general, a confidence interval gives a range of effect estimates compatible with the observed data under a specified statistical method and its assumptions. For a formulation comparison, it helps show whether the estimated relative exposure is precise or remains compatible with materially different values. A point estimate alone would not describe that uncertainty. The registry record does not report a confidence interval for the primary comparison.

A p-value, when used, addresses compatibility with a specified null hypothesis under the chosen model; it is not the probability that the null hypothesis is true and does not measure the magnitude or clinical importance of an effect. The registry does not report a p-value for the primary endpoint. No p-value or confidence interval should be reconstructed without the necessary results and analysis details.

Why can over-dispersion matter?

As a general concept, over-dispersion occurs when variability in observed outcomes exceeds what a model assumes. It can make standard errors too small if the model does not allow for the extra variation, which can make inferential results appear more precise than warranted. This issue is more commonly relevant to count or binary outcomes than to a geometric summary of a continuous pharmacokinetic measure. The registry does not report an over-dispersion assessment, and there is no basis to claim that it was relevant to the primary analysis.

How should the adverse-event summaries be understood?

Adverse-event counts are descriptive unless an inferential comparison and its method are reported. With repeated treatment periods, the same participant may contribute observations under both formulations. A comparison that treats group counts as if they came from independent participants could ignore the crossover structure. The registry does not report a comparative safety model or enough event-level detail to determine how within-participant dependence was handled. The serious adverse event figures can be described as recorded counts, but they do not demonstrate a formal between-formulation safety test.

What can be concluded from the available analysis information?

The record gives a named endpoint and summary-statistic types, but not numerical results or analysis details sufficient to reproduce an inferential comparison. It reports zero analyses in the registry’s analysis listing. That listing does not explain whether analyses were conducted elsewhere, and no such analyses should be assumed from the completed status. Statistical interpretation therefore remains limited to the design description, endpoint definition, and reported safety counts.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists four outcome measures and identifies AUC0-inf for entrectinib and M5 as the primary outcome. It also lists percentage of participants with treatment-emergent adverse events as a secondary outcome. The primary outcome is described as involving several categories or time points and is not reduced in the registry record to one comparison. The record does not report how multiplicity across endpoints, analytes, or time points was handled, or whether any adjustment was planned.

Multiplicity matters when several statistical hypotheses are tested: without an appropriate plan, the chance of at least one apparently notable result can increase. This is a general concern, not evidence that a particular error occurred in this study. The registry does not report hypothesis tests or an adjustment method, so the impact of multiplicity cannot be assessed.

The pharmacokinetic population is defined as participants who received at least 1 dose and had at least 1 evaluable postdose PK sample. The endpoint description says its presented values are based on all 14 participants receiving F1 in the crossover pattern. The record does not report missing-sample counts, missingness reasons, exclusions from individual analyses, or methods for handling incomplete observations. It also does not report whether all participants contributed usable data under both formulations.

The analysis populations for safety and other outcomes, and the relation between those populations and the pharmacokinetic population, are not reported in the registry record. A complete statistical plan—including prespecified contrasts, handling of period and sequence, missing-data rules, and multiplicity procedures—is also not reported. These omissions limit assessment of whether the posted summaries address the intended comparisons in a consistent and reproducible way.

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 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports zero serious adverse events among 14 participants at risk for F1 and zero among 14 participants at risk for F06. It also reports zero deaths in each formulation group. These are the serious-event counts recorded for the groups; they do not establish that serious events are impossible or that the formulations have identical safety profiles.

The record lists other adverse events in 4 participants for F1 and 3 for F06. These are descriptive counts, not a statistical comparison. No serious adverse event terms are listed. The registry does not report event-level descriptions, timing, recurrence, severity grading beyond the serious-event classification, attribution, or a method for comparing safety between formulations.

Because the study used a crossover design, participants could receive both formulations. The group counts should therefore not be interpreted as observations from independent parallel groups. The registry does not explain how repeated exposure or within-participant event occurrence was handled analytically. The counts can describe what was recorded, but they do not quantify comparative risk or support a conclusion about broader safety.

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

The study addresses a focused pharmacokinetic question: how entrectinib capsule formulations F1 and F06 compare under fed conditions in healthy participants. It uses a randomized crossover design and specifies AUC0-inf for entrectinib and its M5 metabolite as the primary outcome. This describes the intended comparison, not its outcome.

The registry record does not report the primary endpoint estimates, a treatment contrast, confidence intervals, or p-values. As a result, the direction and size of any observed difference and its statistical precision are not available. It is not possible to state from this record whether the formulations produced similar or different exposure, or whether any observed difference would meet a defined criterion.

The record also does not report equivalence margins or another prespecified decision framework for interpreting relative bioavailability. In general, equivalence is not established merely by failing to detect a difference. A defensible equivalence interpretation requires an appropriate estimate and uncertainty assessment against prespecified limits. Those details are not reported in the registry record.

The completed status, enrollment, and outcome definition do not resolve these limitations. Nor do the adverse-event counts answer the pharmacokinetic question. They provide limited descriptive safety information for the reported groups, without a comparative statistical analysis or enough event detail to characterize patterns.

The findings should therefore be understood narrowly: the registry describes a Phase 1 study comparing two formulations in healthy participants, with exposure and adverse events among its planned areas of evaluation. It does not provide the numerical results needed to judge relative exposure or its precision. It also cannot establish how these findings would apply outside the studied population or conditions. No treatment recommendation or conclusion about clinical effectiveness follows from the registry information.

13. Why This Trial Matters Statistically

This trial is statistically informative as an example of a design tailored to compare drug exposure rather than clinical efficacy. A crossover study can make efficient use of within-participant comparisons when the endpoint is measurable in each period and the design assumptions are reasonable. Randomizing the order of F1 and F06 helps separate treatment from sequence assignment. These design features explain why a crossover is used in some formulation comparisons, but they do not guarantee an unbiased or precise result.

The endpoint also illustrates the distinction between a measure and an estimate. AUC0-inf is defined as an exposure measure, and geometric summaries are specified, but the registry does not report the numerical estimates or uncertainty needed to interpret the comparison. Statistical reporting is essential: design descriptions alone cannot show the size of an effect or how precisely it was measured.

The study also highlights the value of reporting analysis populations and missing-data handling. A pharmacokinetic population definition is present, but the record does not explain whether all participants had evaluable paired observations or how incomplete data were treated. In a crossover, those details matter because the intended within-participant comparison depends on data across treatment periods.

Finally, the safety counts illustrate why descriptive event totals should not be mistaken for comparative evidence. The registry reports serious adverse event counts and other adverse-event counts, but does not report event details or an inferential safety analysis. Readers need both the design context and the limits of the reported results to avoid over-interpreting small descriptive summaries.

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 main limitation for interpreting this specific study is that the registry record does not report numerical AUC0-inf results for entrectinib or M5. It also does not report a relative treatment estimate, confidence interval, or p-value. Without those quantities, the magnitude and precision of the primary comparison cannot be assessed.

The primary outcome description refers to values based on all 14 participants receiving F1 in the crossover pattern, while the registry separately defines a pharmacokinetic population by dose receipt and evaluable postdose sampling. The record does not explain the relationship between these statements, whether all participants contributed to each analyte and treatment period, or whether paired data were complete.

The arm descriptions are incomplete in the registry text. The study is described as randomized, open-label, and crossover, and the available descriptions specify the treatment sequence, meal condition, single-dose administration, and minimum 14-day washout. However, the registry does not report the full dosing details, exact sampling schedule, or analysis of possible period, sequence, and carryover effects.

The statistical analysis plan, handling of missing observations, multiplicity approach, and criteria for interpreting relative bioavailability are not reported. Although the endpoint summaries are identified as geometric means and geometric coefficients of variation, the inferential method and uncertainty estimates are absent.

Safety interpretation is also limited. Serious events and deaths are recorded as zero in both groups, but event-level details and comparative analyses are not reported. The study population is healthy participants, and the record does not establish how any findings would generalize to other populations or conditions. These limitations concern the information available in the registry record and do not establish that unreported analyses were not performed elsewhere.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study to Investigate the Relative Bioavailability of Entrectinib Capsule Formulations F1 and F06 Under Fed Conditions in Healthy Participants — NCT03796260.
• Registry record last updated 2020-02-26; status last verified 2020-02.
• Results first posted 2020-02-26.
• 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

NCT03796260 is a completed Phase 1 randomized, open-label, two-treatment, two-period, two-way crossover study of entrectinib capsule formulations F1 and F06 under fed conditions in healthy participants. The registry lists enrollment of 14, a start date of 2019-01-09, and a primary completion date of 2019-02-04.

The primary endpoint is AUC0-inf for entrectinib and M5, summarized using geometric means and geometric coefficients of variation. The pharmacokinetic population is defined by receipt of at least 1 dose and at least 1 evaluable postdose PK sample. The registry reports no numerical primary comparison or inferential analysis. Serious adverse events and deaths are recorded as zero in each formulation group; other adverse events are recorded in 4 participants for F1 and 3 for F06. Statistical interpretation is limited by the absence of endpoint estimates, uncertainty measures, and detailed analysis methods.