Study to Assess the Bioavailability of Ticagrelor OD Tablet vs. IR Tablet: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Assess the Bioavailability of Ticagrelor OD Tablet vs. IR Tablet (NCT02400333), a randomized phase 1 study. The primary outcome is Maximum Observed Plasma Concentration (Cmax) of Ticagrelor and Its Active Metabolite AR-C124910XX..

2. Clinical Question

3. Trial Design

This was a Phase 1, randomized, open-label, four-period, four-treatment crossover study conducted at a single centre. Each participant was assigned to a sequence of four treatments across four periods. The registry lists four sequence patterns: A-D-B-C, B-A-C-D, C-B-D-A, and D-C-A-B. The record does not specify how many participants were assigned to each sequence or provide a mapping from the letter labels to the named formulations.

The four treatments were three administration conditions for a single 90 mg dose of ticagrelor orodispersible tablets and one single 90 mg dose of ticagrelor immediate-release tablets with water. The orodispersible tablet was administered with 200 ml of water, without water, or suspended in water and administered through a nasogastric tube. The immediate-release tablet was administered with 200mL of water. Because the same study enrolled participants into a crossover design, treatment comparisons could be made within participants in principle; the numerical estimates and the precise statistical model used for those comparisons are not reported in the registry record.

The planned endpoint measurements included plasma concentrations of ticagrelor and AR-C124910XX. Blood sampling was scheduled before dosing and at post-dose times through 48 hours during each treatment period. The primary outcome description specifies 14 samples per treatment period, including the pre-dose sample. The registry reports enrollment of 100 and status as completed. It lists the study start as 2015-06 and primary completion as 2015-07.

The record does not describe the interval between treatment periods, any washout rationale, randomization generation or concealment procedures, or rules for sequence allocation. Those details are not reported in the registry record. The trial is described as single-dose and open-label; it was not a blinded comparison of clinical outcomes.

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: Participants were randomized in 4 sequence Williams design for 4 periods and 4 treatments:Ticagrelor orodispersible (OD) tablets with water (Treatment A);Ticagrelor OD tablets without water (Treatment B);Ticagrelor OD tablets suspended in water through nasogastric tube (Treatment C);Ticagrelor immediate-release (IR) tablets with water(Treatment D).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Pharmacokinetic (PK) analysis set consisted of all participants in the safety analysis set for whom at least one of the primary PK parameters, for a given analyte, can be calculated for at least two treatment periods and who had no major protocol deviations.

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 Maximum Observed Plasma Concentration (Cmax) of Ticagrelor and Its Active Metabolite AR-C124910XX., measured over 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours in each treatment period..

The primary endpoint was maximum observed plasma concentration, Cmax, of ticagrelor and its active metabolite AR-C124910XX. Cmax is the highest measured concentration in the sampling series for an analyte after dosing. It describes the observed peak exposure, rather than the total amount of drug exposure over time. The registry specifies geometric means and geometric coefficients of variation for this endpoint.

In general, pharmacokinetic studies use Cmax to characterize peak concentration after a dose and to compare exposure profiles across formulations or administration conditions. For an orodispersible formulation, the scientific question is whether the observed concentration profile differs when the tablet is administered under the specified conditions, including with water, without water, or through a nasogastric tube. Measurement of the active metabolite adds information about its concentration profile alongside that of the parent drug. These are pharmacokinetic questions, not direct measures of clinical benefit.

Blood sampling was scheduled at pre-dose (0 hours) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours in each treatment period. The endpoint therefore depends on the observed values at those sampling times; it is not a continuously observed peak. The registry's definition of the pharmacokinetic analysis set also matters, since it requires calculable primary parameters in at least two treatment periods for a given analyte and excludes participants with major protocol deviations.

The numerical geometric means, variability estimates, and treatment comparisons for Cmax are not reported in the registry record. Without those estimates, the magnitude and precision of any contrast cannot be evaluated.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The methods description separates what is specified in the registry from general statistical principles. The record identifies a randomized crossover design, concentration-based endpoints, and a pharmacokinetic analysis set. It does not report the full analysis model, its assumptions, or numerical primary outcome estimates. General explanations below should not be read as a claim that a particular model or procedure was used.

What does a crossover design contribute?

In general, a crossover study assigns participants to receive multiple treatments in different periods. A within-participant comparison can reduce the influence of stable characteristics that differ across people, because each participant can contribute measurements under more than one treatment. The registry describes four treatment periods and four treatment-sequence patterns. It does not state the number assigned to each sequence, the washout interval, or how sequence and period effects were handled in the analysis.

Crossover comparisons also require attention to the possibility that exposure from an earlier period could affect a later period. In general, washout planning and assessment of period and sequence effects can be relevant to that concern. The washout details and the statistical procedures used to address carryover are not reported in the registry record. It is therefore not possible to determine from the record whether or how these considerations entered the analysis.

Why use geometric summaries for concentrations?

The primary endpoint specifies geometric means and geometric coefficients of variation. In general, concentration measurements are positive and may be skewed, so geometric summaries can describe a multiplicative pattern of variation more naturally than arithmetic summaries. A geometric mean is based on averaging on a logarithmic scale and then expressing the result on the original scale. The geometric coefficient of variation describes relative dispersion rather than variation in the original measurement units. These are general definitions; the registry does not provide the calculated summaries or the transformation and model details used to obtain them.

In many pharmacokinetic comparisons, treatment estimates are analyzed on a logarithmic scale and then expressed as ratios on the original scale. Such a ratio would describe relative exposure between treatments. The registry record does not report treatment ratios, confidence intervals, or a specified equivalence margin. It would therefore be inappropriate to infer an equivalence conclusion from the endpoint name or from the fact that the study compared formulations.

What does Cmax capture?

Cmax is the highest observed concentration among the scheduled samples for an analyte. It represents peak concentration within the measured profile, rather than the complete concentration-time exposure. The scheduled sampling was at pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours after dosing in each treatment period. In general, a maximum derived from discrete sampling can depend on when samples are collected: an actual peak between scheduled collections may not be directly observed. The registry defines the endpoint as maximum observed concentration and does not report any interpolation approach.

The primary endpoint includes both ticagrelor and AR-C124910XX. This means there are two analytes of interest, each with its own concentration measurements. The registry does not report the analyte-specific estimates or specify how it treated the relationship between the parent compound and metabolite in a joint analysis.

Why can over-dispersion matter?

In general, over-dispersion means that observed variability is larger than a statistical model expects. It can make standard errors too small if the model assumes less variability than the data contain, leading to intervals that are too narrow or tests that are too optimistic. This concept may be relevant to many kinds of clinical data, but the registry does not describe an over-dispersion assessment or report a model for the primary concentration outcome that would permit such an assessment.

For this trial, the primary endpoint is continuous pharmacokinetic data summarized geometrically, so the record's key missing elements are the estimated concentrations or contrasts and their uncertainty. No confidence intervals or p-values for the primary comparison are reported in the registry record. A confidence interval, in general, describes the range of values compatible with an estimate under a specified procedure and its assumptions; it can show precision in a way that a point estimate alone cannot. No interval can be interpreted for the primary endpoint without the posted estimate and interval.

What can be inferred from the reported analysis population?

The pharmacokinetic analysis set consists of participants in the safety analysis set for whom at least one primary pharmacokinetic parameter, for a given analyte, can be calculated for at least two treatment periods and who had no major protocol deviations. This definition makes clear that inclusion in the pharmacokinetic analysis depends on usable measurements across periods and protocol adherence. It does not state the number of participants who met the definition, the handling of individual missing samples, or the exact criteria for a major deviation. Those details and the analysis population counts are not reported in the registry record.

The safety counts are presented by treatment group, but the record does not explain the statistical treatment of repeated exposure or give comparative estimates for adverse events. General statistical practice would distinguish descriptive event counts from model-based comparisons, especially when participants can receive multiple treatments. No inferential safety procedure is reported.

What do planning calculations mean?

The registry's sample-size assumptions describe a planning illustration based on an observed effect, not the design justification for this trial. The stated assumptions include a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect defined as a stated fraction of the observed effect. The registry notes that time-to-event illustrations report total events, while other illustrations report participants per arm. No calculated illustration values or protocol sample-size justification are reported in the registry record. Such planning quantities are not observed power and should not be interpreted as evidence about the strength of the trial's actual results.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 13 outcome measures and 18 analyses, covering the primary concentration endpoint, additional pharmacokinetic measures, adverse events, and changes in vital signs. The primary endpoint itself concerns Cmax for two analytes. Examining several outcomes or contrasts can raise a multiplicity question: in general, the chance of at least one apparently unusual result may increase as the number of tests increases. How this issue was addressed, whether any outcomes were considered confirmatory, and whether any adjustment was planned are not reported in the registry record.

The primary outcome description identifies the pharmacokinetic analysis set. Participants had to belong to the safety analysis set, have at least one primary pharmacokinetic parameter calculable for a given analyte in at least two treatment periods, and have no major protocol deviations. This gives an eligibility definition for that analysis, but the number included and the number excluded are not reported in the registry record. The record does not describe how missing concentration samples, incomplete treatment periods, or other missing outcome measurements were handled.

In general, missing-data methods depend on why data are missing and on the analysis objective. A complete-case analysis, imputation, or a model that uses available repeated measurements makes different assumptions. The registry does not identify which method, if any, was used for missing observations. It also does not report sensitivity analyses or the detailed definition of major protocol deviations.

The record names both a safety analysis set and a pharmacokinetic analysis set, but it does not report the full population counts or a complete analysis plan. The handling of multiplicity, missing data, protocol deviations, and population membership should therefore be treated as not reported in the registry record rather than inferred from the crossover design or from the listed outcomes.

11. 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 serious adverse event figures are reported separately for Treatment A, Treatment B, Treatment C, and Treatment D. The registry lists 0 affected for serious adverse events in each group. The corresponding at-risk counts are 31, 32, 34, and 33, respectively. These are the posted treatment-group counts; the registry excerpt does not give event terms because no serious-event terms are listed.

The registry also lists other adverse event affected counts of 3 for Treatment A, 5 for Treatment B, 3 for Treatment C, and 2 for Treatment D. These figures should be read as descriptive counts in the registry's categories. The record does not specify in the available information whether an affected count represents unique participants or event episodes, and it does not provide a comparative statistical analysis of these counts.

Since this was a crossover study, the treatment-group at-risk figures should not automatically be read as four independent groups of different people. Participants received treatments in periods, and the record does not explain the derivation of the treatment-level denominators. Death counts are not reported in the registry record. The posted counts describe what was entered for safety outcomes; they do not by themselves establish a comparative safety effect.

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

The study asks a focused pharmacokinetic question: how the observed concentrations of ticagrelor and its active metabolite compare when the orodispersible tablet is administered under three conditions, relative to an immediate-release tablet administered with water. The randomized crossover design is suited to comparisons across treatment periods within participants, in general, and the planned sampling times characterize concentration profiles through 48 hours.

What the registry record does not establish is the result of those comparisons. It does not report the primary Cmax estimates, their variability, treatment contrasts, confidence intervals, or p-values. It therefore does not show how large any difference was, whether an estimate was precise, or whether a comparison met a prespecified criterion. The stated study objective and the formulation names are not a substitute for numerical outcome results.

The record does report serious adverse event affected counts of 0 across all four treatment groups and other adverse event affected counts of 3, 5, 3, and 2, respectively. These are descriptive safety summaries, with at-risk counts of 31, 32, 34, and 33. The available information does not include a statistical comparison or enough detail about the denominator convention to support a broader comparative interpretation. Death counts are not reported in the registry record.

More generally, pharmacokinetic measures such as Cmax describe drug exposure and are not themselves measures of clinical outcomes. Even a well-estimated concentration difference would need interpretation in the context of an appropriate clinical or regulatory question; that context and any decision criterion are not reported in the registry record. No statement about treatment benefit or lack of benefit follows from the endpoint definition alone.

The defensible conclusion is limited to the design, scheduled measurements, analysis-set definition, and safety counts that are documented. Comparative bioavailability findings and their precision are not reported in the registry record.

13. Why This Trial Matters Statistically

This trial is statistically informative as an example of a pharmacokinetic crossover question with multiple administration conditions. Rather than compare only two separate groups, the design assigns participants to sequences of treatments across periods. In general, measurements from the same participant can help distinguish treatment-related variation from stable between-person differences. The usefulness of that feature depends on complete period data and appropriate handling of period, sequence, and potential carryover effects.

The endpoint also illustrates the distinction between a peak concentration and broader exposure. Cmax captures the maximum observed concentration, while the registry separately lists secondary outcomes including time to maximum concentration, half-life, and ratios involving the metabolite and parent drug. These measures represent different aspects of the concentration profile; one endpoint cannot stand in for all the others. The primary sampling schedule was defined in detail, but the numerical results are not reported in the registry record.

The study also shows why outcome reporting and analysis-plan transparency matter. The registry lists 13 outcome measures and 18 analyses, yet does not report the primary numerical comparisons, confidence intervals, p-values, or multiplicity strategy. Without those, a reader cannot assess the size and precision of the principal contrast, or determine how multiple outcomes were interpreted. The record's definition of a pharmacokinetic analysis set is useful, but the number analyzed and the handling of missing samples are not reported.

Finally, the safety figures require design-aware reading. The posted counts are organized by treatment, but this is a multi-period crossover and the record does not fully explain the denominator convention or provide inferential comparisons. Descriptive values should not be treated as independent-arm evidence without those details. The statistical value of this trial's question is clear; the registry entry, as available, does not supply enough outcome reporting to quantify its answer.

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.

A central limitation for interpretation is that the numerical results for the primary endpoint are not reported in the registry record. Without the geometric means, variability estimates, treatment contrasts, and uncertainty intervals, readers cannot evaluate the magnitude or precision of differences in Cmax. The record also does not report the secondary pharmacokinetic results, including time to maximum concentration, half-life, or the listed metabolite-to-parent ratios.

The description does not provide a detailed statistical analysis plan. The model for the crossover comparisons, treatment of period and sequence, any assessment of carryover, and any multiplicity procedure are not reported in the registry record. The sample-size assumptions describe a planning illustration rather than the trial's own design justification; the protocol sample-size rationale is not reported in the registry record.

The pharmacokinetic analysis set is defined, but the number of participants included in that set, the reasons for exclusion, and the handling of incomplete concentration profiles are not reported. The registry does not describe missing-data methods, sensitivity analyses, or the specific criteria for major protocol deviations. These omissions limit assessment of how the analyzed data may differ from the enrolled population.

Safety reporting is also limited in the available record. Serious adverse event affected counts are zero for each treatment group, and other adverse event affected counts are listed, but death counts are not reported. The record does not clarify the denominator convention for the treatment-level risk counts or give inferential comparisons. As a single-centre, single-dose study in healthy subjects, the design addresses a defined pharmacokinetic setting; the record does not provide information to extend conclusions beyond that setting. These limitations concern what can be assessed from the registry entry, not necessarily what may have been included in other study documents.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study to Assess the Bioavailability of Ticagrelor OD Tablet vs. IR Tablet — NCT02400333.
• Registry record last updated 2016-09-29; status last verified 2016-08.
• Results first posted 2016-08-03.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

The registry identifies NCT02400333 as a completed Phase 1, randomized, open-label, four-period, four-treatment crossover study at a single centre, sponsored by AstraZeneca. Enrollment was 100. The study compared three administration conditions for a single 90 mg ticagrelor orodispersible tablet dose with a single 90 mg immediate-release dose administered with water, in healthy subjects.

The primary outcome was maximum observed plasma concentration of ticagrelor and AR-C124910XX, measured from scheduled samples spanning pre-dose to 48 hours in each treatment period. The pharmacokinetic analysis set required usable primary parameter data in at least two periods for the analyte and no major protocol deviations. Serious adverse event affected counts were 0 in each treatment group; other adverse event affected counts were 3, 5, 3, and 2. Primary pharmacokinetic estimates and detailed statistical analysis methods are not reported in the registry record.