Phase 1 Bioavailability Study of Apixaban Solution Formulation Relative to Apixaban Tablets in Healthy Subjects: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 1 Bioavailability Study of Apixaban Solution Formulation Relative to Apixaban Tablets in Healthy Subjects (NCT02034565), a randomized phase 1 study. The primary outcome is Adjusted Geometric Mean of the Maximum Observed Plasma Concentration (Cmax) of Apixaban.

2. Clinical Question

This is a pharmacokinetic bioavailability question, rather than a question about whether either formulation improves a clinical health outcome. Cmax, the maximum observed plasma concentration, provides a measure of the peak concentration recorded after dosing. Comparing it across formulations addresses whether the solution and tablet yield similar peak concentrations under the study conditions. The registry record also lists serial blood sampling through 72 hours after each dose, but it does not report the full sampling or analysis protocol beyond the stated time points and endpoint description.

The record identifies healthy subjects as the study population and does not describe a patient population. The result therefore pertains to the reported pharmacokinetic comparison in this study population and should not be read as a comparison of clinical effectiveness or long-term outcomes.

3. Trial Design

The registry record describes a Phase 1 randomized, unmasked crossover study of apixaban solution relative to apixaban tablets in healthy subjects. Enrollment was 48, and the study status is completed. The listed start was 2010-02 and primary completion was 2010-03. Each formulation was administered as a single oral dose of 10 mg: the tablet arm is described as 2 x 5 mg tablets, and the solution arm as 25 mL x 0.4 mg/mL.

A crossover design means that participants receive more than one intervention in a planned sequence, so comparisons can be made within participants. In general, this can reduce the influence of stable differences between people. Randomization can help assign intervention order, while an unmasked design means treatment assignment is not concealed from those involved in the study in the way it would be in a masked trial. The registry record does not report the treatment sequences, washout interval, or other details needed to describe how crossover periods were implemented.

The primary outcome is the adjusted geometric mean of apixaban Cmax, measured in ng/mL. The posted endpoint population is all treated participants with available pharmacokinetic data. The reported arm counts are 14 for the tablet and 13 for the solution; the record does not explain why these counts differ from total enrollment or from one another. The registry record lists two secondary outcomes concerning serious adverse events, treatment-related adverse events, deaths or discontinuation due to adverse events, and marked laboratory abnormalities. It does not report a full statistical analysis plan, sample-size justification, interim-analysis plan, or detailed accounting of participants through each crossover period.

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: 48 participants were enrolled; 14 were randomized and treated. Reasons for non-randomization include 23 no longer met study criteria, 4 withdrew consent, 6 due to study being full, and 1 completed an alternate treatment. 13 participants completed the study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All treated participants with available pharmacokinetic (pk) data

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: All randomized participants

6. Primary Endpoint

The registry lists the primary outcome as Adjusted Geometric Mean of the Maximum Observed Plasma Concentration (Cmax) of Apixaban, measured over Pre-dose and 0.25, 0.50, 1, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 60, 72 hours post-dose per intervention.

The primary endpoint is the adjusted geometric mean of maximum observed plasma concentration, or Cmax, for apixaban. It is measured in ng/mL. Blood samples were collected at the listed pre-dose and post-dose times, with sampling described as continuing up to 72 hours after each dose. Cmax is the highest observed concentration among the sampled measurements for a participant and intervention. It is a pharmacokinetic measure of peak exposure, not a direct measure of symptoms, disease outcomes, or clinical benefit.

Geometric means are commonly used for positive measurements that are analyzed on a logarithmic scale, particularly when values are skewed. In general, the geometric mean represents a central value on a multiplicative scale, whereas an arithmetic mean represents a central value on an additive scale. A ratio of geometric means is therefore a natural way to compare peak concentrations between formulations. Ratios below or above one indicate the direction of the reported comparison according to its numerator and denominator; the registry record gives the ratio but does not state the ordering in words. Its listed analysis groups are tablet followed by solution.

The record reports adjusted geometric means and a 90% confidence interval for each arm, along with a ratio of adjusted geometric means. It does not explain the adjustment variables or the statistical model used. The endpoint is useful for comparing formulation-related pharmacokinetic exposure, but its interpretation is specific to the sampling schedule, study population, and single-dose conditions described in the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a continuous pharmacokinetic measurement: maximum observed plasma concentration. The record expresses it in ng/mL and reports adjusted geometric means. In general, a geometric mean is calculated by working on a logarithmic scale and then returning to the original scale. This approach is often suited to positive measurements whose distribution is asymmetric. It also makes ratios of group summaries more interpretable as multiplicative comparisons.

What does the ratio describe?

The posted contrast is a ratio of adjusted geometric means, reported as 0.977. In general, a ratio compares one quantity with another on a relative scale. A value of one indicates equal quantities; values on either side indicate different relative levels, with direction determined by which group is in the numerator. The record lists the tablet and solution groups for the analysis, but does not state the ratio's numerator and denominator in words. The reported estimate should therefore be read together with the analysis group ordering rather than detached from it.

The ratio is labeled adjusted. Adjustment means that the comparison comes from a statistical analysis that accounts for one or more terms or features of the study, rather than only comparing unadjusted summaries. The registry record does not identify the adjustment terms or model. It is therefore not possible to determine from the posted results whether the analysis accounts for period, sequence, or other crossover features, or to recreate the adjusted result from the arm-level geometric means.

How should the confidence interval be read?

The reported 90% confidence interval for the ratio extends from 0.756 to 1.261. In general, a confidence interval gives a range of estimates compatible with the observed data and the assumptions of the specified analysis. Greater width indicates less precision. The interval is not a description of the range of individual participants' Cmax values, and it does not mean that every value within the interval is equally plausible. The record does not provide a p-value for the ratio.

The interval includes one, the reference value for equality on a ratio scale. This indicates that the posted interval includes both equality and values on either side of equality. It does not by itself prove equivalence or establish that the formulations are interchangeable. Formal equivalence assessment generally requires a prespecified margin and an analysis designed around that margin. Such a margin and an equivalence-testing plan are not reported in the registry record.

Why does the crossover design matter?

In general, crossover studies compare interventions within the same participants, which can control for stable participant characteristics in the comparison. They also require attention to the treatment sequence, period, and possible carryover from an earlier intervention. Randomization can help balance assigned sequences. The registry record identifies randomization and a crossover model, but does not report the sequence structure, washout interval, or analysis details needed to assess these features. The posted adjusted ratio is consequently the available inferential comparison, but its underlying model cannot be fully evaluated from the registry record.

What can arm counts tell us?

The endpoint entries list 14 participants for the tablet and 13 for the solution. The primary endpoint population is described as all treated participants with available pharmacokinetic data. These posted counts are not the same as the total enrollment of 48, and the record does not explain the difference. In a crossover study, group counts may not convey how many people contributed paired measurements or how incomplete periods were handled. The record does not report those details, so the counts should be read as the endpoint counts attached to the posted arm estimates, not as a complete participant-flow account.

Why can variability matter?

Pharmacokinetic measurements can vary across participants and sampling occasions. General statistical reasoning distinguishes the estimated central tendency from uncertainty in that estimate. The geometric means describe central values on the multiplicative scale, while confidence intervals communicate precision around the reported summaries or contrast. Over-dispersion, in general, occurs when observed variability exceeds what a chosen model assumes; if unaccounted for, it can make uncertainty estimates too narrow. The registry record does not provide dispersion estimates or enough model information to assess this issue for the reported analysis.

The record does not report the statistical analysis plan, model specification, handling of missing pharmacokinetic measurements, or a sample-size justification. No conclusion about prespecified hypotheses, power, interim analyses, or data exclusions can be drawn from the posted information. The numerical estimates should be interpreted as the results of the reported analysis, with these methodological details remaining unavailable.

10. Analyses Reported by the Sponsor

The registry record reports the sponsor's comparison as a ratio of adjusted geometric means of 0.977, with a 90% confidence interval from 0.756 to 1.261. It does not report a p-value for this analysis. Because the comparison is adjusted and the adjustment method is not described, the ratio cannot be reconstructed from the arm-specific geometric means alone. The arm estimates are 294.0 ng/mL for the tablet and 287.2 ng/mL for the solution, but the record does not give sufficient detail to treat a direct calculation from those summaries as the same analysis.

The registry record does not present a separate recalculated ratio for this endpoint. A recalculation based only on posted summary statistics, if one were available, would be an unadjusted analysis and would not replace the sponsor's adjusted analysis. The record does not flag a discrepancy between a sponsor analysis and a recalculation. The sponsor-reported estimate and interval therefore remain the inferential results to interpret, while the model details and adjustment terms remain unavailable in the registry record.

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary Cmax endpoint, two secondary outcomes concerning adverse events and laboratory abnormalities, five outcome measures, and three analyses. It does not report a multiplicity plan describing how inference across outcomes or analyses was controlled. When several endpoints or comparisons are examined, general statistical practice recognizes that the chance of at least one apparently unusual result can increase unless the analysis plan addresses multiplicity. Without a reported plan, it is not possible to determine whether the posted confidence interval was intended as part of a broader confirmatory family of tests or how secondary analyses should be interpreted.

The primary endpoint population is described as all treated participants with available pharmacokinetic data. The posted arm counts are 14 for the tablet and 13 for the solution, while total enrollment was 48. The registry record does not explain why the endpoint counts are smaller than enrollment, identify missing observations, or describe how missing data were handled. It also does not report how many participants contributed paired measurements across both periods. These omissions limit assessment of whether the analyzed participants differed from those enrolled or whether incomplete pharmacokinetic data could affect the comparison.

The record does not report a statistical analysis plan, sample-size justification, interim analyses, or a detailed account of analysis populations. The randomized crossover design is stated, but sequence assignment and analysis of period or carryover effects are not described. No assumptions about those matters should be inferred. The listed secondary outcomes include serious adverse events, treatment-related adverse events, deaths or discontinuation due to adverse events, and marked laboratory abnormalities; the record does not present enough detail in the listed information to assess multiplicity across those outcomes.

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 5% reporting threshold.

Most frequent non-serious adverse event terms

The posted safety counts show zero participants with serious adverse events in each arm: the tablet group had 0 of 14 at risk, and the solution group had 0 of 13 at risk. These are participant counts, not a guarantee that no other safety events occurred. The record also lists 4 participants with other adverse events in the tablet group and 2 in the solution group. The listed secondary outcome refers to serious adverse events, treatment-related adverse events, deaths or discontinuation of study drug due to adverse events, but the posted counts do not provide event descriptions or a detailed breakdown of those categories.

Deaths are not reported in the registry record. The record lists no top serious-event terms, but this does not supply detail about non-serious events or laboratory abnormalities. The study involved single-dose administration in healthy subjects, and the posted safety counts should be read in that context. With the endpoint counts and event descriptions available, the registry record does not support detailed comparisons of event types, timing, severity, or relationship to treatment.

Safety counts are descriptive. In general, small numbers of participants and events can leave considerable uncertainty about uncommon outcomes. The posted counts alone do not establish that one formulation is safer than the other, nor do they determine the likelihood of an event for individuals outside the study.

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

The result is a comparison of peak apixaban concentrations after single-dose solution and tablet administration in healthy subjects. The posted adjusted geometric mean ratio is 0.977, with a 90% confidence interval from 0.756 to 1.261. The interval includes the equality value of one and spans a range of relative values on both sides. Its width indicates that the estimate is not highly precise. The registry record does not report a p-value or an equivalence margin.

That result does not, by itself, establish equivalence. Equivalence is a specific statistical claim that usually depends on prespecified boundaries defining an acceptably small difference and an analysis that evaluates those boundaries. The registry record does not report such boundaries or an equivalence-testing plan. Nor does an interval that includes one prove that the formulations have exactly equal peak concentrations.

The endpoint is Cmax, a pharmacokinetic measure, not a clinical outcome. The findings do not establish effects on health outcomes, symptoms, adverse events beyond the posted counts, or longer-term use. The study concerns single doses in healthy subjects; the registry record does not report results in a patient population or under repeated dosing. The endpoint also reflects the sampled measurements and does not describe every aspect of drug exposure.

The posted arm estimates and the adjusted ratio are subject to important reporting limits. The record does not describe the adjustment model, crossover sequences, missing-data handling, or the reason the endpoint counts are 14 and 13 despite enrollment of 48. These gaps prevent a full independent assessment of the analysis and its precision. The result should therefore be read as the registry's reported adjusted pharmacokinetic comparison, with uncertainty and limits in generalizability, rather than as a broad claim about clinical outcomes or treatment choice.

14. Why This Trial Matters Statistically

This trial illustrates how a formulation comparison can be framed as a pharmacokinetic question rather than a clinical-outcome question. The primary endpoint, Cmax, measures peak observed concentration, and the reported ratio of adjusted geometric means expresses the comparison on a relative scale. This is a useful statistical structure for positive measurements where multiplicative differences may be more interpretable than absolute differences.

The study's crossover model is also statistically important. In general, within-participant comparisons can control for stable differences between people, but crossover analyses need to account for treatment order and period. The registry record identifies randomization and crossover design without giving the sequence, washout, or model details. This makes the design easy to identify but the implementation and analysis difficult to evaluate fully.

The confidence interval helps distinguish an estimate from its precision. The ratio of 0.977 is accompanied by a 90% interval from 0.756 to 1.261. Its span makes clear that the point estimate should not be read in isolation. At the same time, the absence of a reported equivalence margin means the interval cannot be used to declare equivalence from the registry record alone.

The difference between enrollment and endpoint counts is another important interpretive issue. Enrollment was 48, whereas the arm estimates list 14 and 13 participants. Without a participant-flow account and missing-data explanation, readers cannot determine why the endpoint counts are smaller or how incomplete data were handled. This is a reminder that endpoint definitions, analysis populations, and participant accounting are part of interpreting a statistical estimate—not administrative details separate from it.

Finally, the safety counts are descriptive and limited. The absence of reported serious adverse events in the posted arm counts does not establish the absence of risk, particularly when the study population and exposure were narrowly defined. The record is most informative when read as a single-dose pharmacokinetic comparison, with the analysis and reporting limitations kept in view.

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 registry record does not describe the statistical model used to estimate adjusted geometric means or the adjusted ratio. It does not identify adjustment terms, explain the ratio's numerator and denominator in words, or report a p-value. Consequently, the posted adjusted contrast cannot be reconstructed from the arm summaries, and the assumptions behind its confidence interval cannot be fully assessed.

Although the study is described as randomized and crossover, treatment sequences, washout interval, period effects, and carryover assessment are not reported in the registry record. These details matter when evaluating whether the analysis appropriately reflects the crossover structure. The record also does not say how many participants contributed paired measurements or how incomplete periods were handled.

The endpoint population is all treated participants with available pharmacokinetic data, while the posted endpoint counts are 14 and 13 and enrollment is 48. Reasons for this difference, missing-data handling, exclusions, and participant flow are not reported in the registry record. The record does not provide dispersion estimates beyond the confidence intervals, nor does it provide enough information to assess model fit or the impact of unusual observations.

The registry record does not report a sample-size justification, statistical analysis plan, interim analyses, multiplicity strategy, or prespecified equivalence margin. It also does not report a detailed breakdown of adverse events, deaths, or marked laboratory abnormalities in the listed information. These omissions limit assessment of both the inferential framework and the safety findings.

Finally, the study concerns single-dose administration in healthy subjects and measures Cmax. The registry record does not provide results for other populations, repeated dosing, or clinical outcomes. Generalization beyond the study conditions is therefore limited by the population, intervention conditions, endpoint, and reporting detail available.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase 1 Bioavailability Study of Apixaban Solution Formulation Relative to Apixaban Tablets in Healthy Subjects — NCT02034565.
• Registry record last updated 2016-08-22; status last verified 2016-07.
• Results first posted 2016-08-22.
• 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

NCT02034565 is a completed Phase 1 randomized, unmasked crossover study of apixaban solution relative to apixaban tablets in healthy subjects. Enrollment was 48. The interventions were single oral doses of 10 mg: 2 x 5 mg tablets or 25 mL x 0.4 mg/mL solution.

The primary endpoint was adjusted geometric mean maximum observed plasma concentration, measured in ng/mL, with a 90% confidence interval. The posted arm estimates were 294.0 for the tablet and 287.2 for the solution. The reported ratio of adjusted geometric means was 0.977, with a 90% confidence interval from 0.756 to 1.261. The endpoint population was treated participants with available pharmacokinetic data; the posted counts were 14 and 13.

The registry record lists secondary safety outcomes, but deaths and detailed event terms are not reported in the registry record. The adjustment model, crossover implementation details, missing-data handling, sample-size justification, and multiplicity plan are also not reported in the registry record. The findings are a reported single-dose pharmacokinetic comparison in healthy subjects, not a clinical-outcome comparison.